UNITED STATES

 SECURITIES AND EXCHANGE COMMISSION

 Washington, DC 20549

 FORM 10-K

 ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

 For the fiscal year ended December 31, 2023

 TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES
 EXCHANGE ACT OF 1934

 For the transition period from ___________ to ___________

 Commission file number 000-19125

 Ionis Pharmaceuticals, Inc.

 (Exact name of Registrant as specified in its charter)

 Delaware

 33-0336973

 (State or other jurisdiction of incorporation or organization)

 (IRS Employer Identification No.)

 2855 Gazelle Court, Carlsbad, CA

 92010

 (Address of Principal Executive Offices)

 (Zip Code)

 760 - 931-9200

 (Registrant's telephone number, including area code)

 Securities registered pursuant to Section 12(b) of the Act:

 Title of each class

 Trading symbol

 Name of each exchange on which registered

 Common Stock, $.001 Par Value

 "IONS "

 The Nasdaq Stock Market LLC

 Securities registered pursuant to Section 12(g) of the Act: None

 Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes No

 Indicate by check if the Registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes No

 Indicate by check mark whether the Registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934
 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes No

 Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of
 Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes No

 Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an
 emerging growth company. See the definitions of "large accelerated filer," "accelerated filer," "smaller reporting company," and "emerging growth company" in Rule 12b-2 of the Exchange Act.

 Large Accelerated Filer

 Accelerated Filer

 Non-accelerated Filer

 Smaller Reporting Company

 Emerging Growth Company

 If an emerging growth company, indicate by check mark if the registrant has
 elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.

 Indicate by check mark whether the registrant has filed a report on and attestation to its management assessment of the effectiveness of its internal
 controls over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report

 If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the
 filing reflect the correction of an error to previously issued financial statements.

 Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by
 any of the registrant's executive officers during the relevant recovery period pursuant to §240.10D-1(b).

 Indicate by check mark whether the Registrant is a shell company (as defined in
 Rule 12b-2 of the Act). Yes No

 The approximate aggregate market value of the voting common stock held by non-affiliates of the Registrant, based upon the last sale price of the common
 stock reported on The Nasdaq Global Select Market was $ 4,243,321,410 as of June 30, 2023.*

 The number of shares of voting common stock outstanding as of February 15, 2024 was 145,751,797.

 DOCUMENTS INCORPORATED BY REFERENCE

 Portions of the Registrant's definitive Proxy Statement to be filed on or about April 25, 2024 with the Securities and Exchange Commission in connection with
 the Registrant's annual meeting of stockholders to be held on June 6, 2024 are incorporated by reference into Part III of this Report.

 *

 Excludes 39,747,443 shares of common stock held by directors and officers and by stockholders whose beneficial ownership is known by the Registrant to exceed 10 percent
 of the common stock outstanding at June 30, 2023. Exclusion of shares held by any person should not be construed to indicate that such
 person possesses the power, direct or indirect, to direct or cause the direction of the management or policies of the Registrant, or that such person is controlled by or under common control with the Registrant.

 FORWARD-LOOKING STATEMENTS

 This report on Form 10-K and the information incorporated herein by reference includes forward-looking statements
 regarding our business and the therapeutic and commercial potential of our commercial medicines, additional medicines in development and technologies. Any statement describing our goals, expectations, financial or other projections, intentions or
 beliefs, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties and particularly those inherent in the process of discovering, developing and commercializing
 medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause
 our results to differ materially from those expressed or implied by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in this report on Form 10-K, including
 those identified in Item 1A entitled "Risk Factors". Although our forward-looking statements reflect the good faith judgment of our management, these statements are based only on facts and factors currently known by us. Except as required by law, we
 undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements.

 In this report, unless the context requires otherwise, "Ionis," "Company," "we," "our," and "us" refers to Ionis Pharmaceuticals, Inc. and
 its subsidiaries.

 Summary of Risk Factors

 There are a number of risks related to our business and our securities. Below is a summary of material factors that make an investment in
 our securities speculative or risky. Importantly, this summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, as well as other risks that we face, can be found in this report
 on Form 10-K in Item 1A entitled "Risk Factors":

 Our ability to generate substantial revenue from the sale of our medicines;

 The availability of adequate coverage and payment rates for our medicines;

 Our and our partners' ability to compete effectively;

 Our ability to successfully manufacture our medicines;

 Our ability to successfully develop and obtain marketing approvals for our medicines;

 Our ability to secure and maintain effective corporate partnerships;

 Our ability to sustain cash flows and achieve consistent profitability;

 Our ability to protect our intellectual property;

 Our ability to maintain the effectiveness of our personnel; and

 The impacts of pandemics, climate change, wars and other global events.

 TRADEMARKS

 "Ionis," the Ionis logo, and other trademarks or service marks of Ionis Pharmaceuticals, Inc. appearing in this report are the property of
 Ionis Pharmaceuticals, Inc. "Akcea," the Akcea logo, and other trademarks or service marks of Akcea Therapeutics, Inc. appearing in this report are the property of Akcea Therapeutics, Inc., Ionis' wholly owned subsidiary. This report contains
 additional trade names, trademarks and service marks of others, which are the property of their respective owners. Solely for convenience, trademarks and trade names referred to in this report may appear without the or TM symbols.

 CORPORATE INFORMATION

 We incorporated in California in 1989 and in January 1991 we changed our state of incorporation to Delaware. In December 2015, we changed
 our name to Ionis Pharmaceuticals, Inc. from Isis Pharmaceuticals, Inc. Our principal offices are in Carlsbad, California.

 We make available, free of charge, on our website, www.ionispharma.com, our reports on Forms 10-K, 10-Q, 8-K and amendments thereto, as soon as reasonably practicable after we file such materials with, or furnish such materials to, the Securities and Exchange Commission,
 or SEC. Periodically, we provide updates about the company in the Newsroom section of the Investors & Media page of our website. Any information that we include on or link to our website is not a part of this report or any registration statement
 that incorporates this report by reference. The SEC maintains an internet site, www.sec.gov, that contains reports, proxy and information
 statements, and other information that we file electronically with the SEC.

 FORM 10-K

 For the Fiscal Year Ended December 31, 2023

 Page

 Item 1.

 Business

 Item 1A.

 Risk Factors

 Item 1B.

 Unresolved Staff Comments

 Item 1C.

 Cybersecurity

 Item 2.

 Properties

 Item 3.

 Legal Proceedings

 Item 4.

 Mine Safety Disclosures

 Item 5.

 Market for Registrant's Common Equity, Related Stockholder
 Matters and Issuer Purchases of Equity Securities

 Item 6.

 Reserved

 Item 7.

 Management's Discussion and Analysis of Financial Condition and
 Results of Operations

 Item 7A.

 Quantitative and Qualitative Disclosures About Market Risk

 Item 8.

 Financial Statements and Supplementary Data

 Item 9.

 Changes in and Disagreements With Accountants on Accounting and
 Financial Disclosure

 Item 9A.

 Controls and Procedures

 Item 9B.

 Other Information

 Item 9C.

 Disclosure Regarding Foreign Jurisdictions that Prevent
 Inspections

 Item 10.

 Directors, Executive Officers and Corporate Governance

 Item 11.

 Executive Compensation

 Item 12.

 Security Ownership of Certain Beneficial Owners and Management
 and Related Stockholder Matters

 Item 13.

 Certain Relationships and Related Transactions, and Director
 Independence

 Item 14.

 Principal Accountant Fees and Services

 Item 15.

 Exhibits, Financial Statement Schedules

 Signatures

 Item 1. Business

 Overview

 For three decades as a pioneer in RNA-targeted medicines, we have focused on bringing better futures to people with serious diseases.
 Today, we continue to drive innovation in RNA therapies. A deep understanding of disease biology and an industry-leading drug discovery technology propels our work, coupled with a passion and urgency to deliver better futures for patients.

 We currently have five marketed medicines to treat serious diseases: SPINRAZA (nusinersen), QALSODY (tofersen), WAINUA (eplontersen),
 TEGSEDI (inotersen) and WAYLIVRA (volanesorsen). We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and other areas of high patient need. We currently have nine medicines in Phase 3 development and multiple additional
 medicines in early and mid-stage development.

 Over the past year, we made important progress executing on
 our vision to bring next-level value to patients and all stakeholders. We achieved this progress by focusing on a clear vision to prioritize and expand the Ionis wholly owned pipeline, deliver Ionis medicines directly to patients and enhance our
 technology leadership, all underscored by continued financial strength and responsibility. The United States, or U.S., Food and Drug Administration, or FDA, approved two Ionis-discovered medicines, QALSODY and WAINUA. We delivered positive Phase 3
 data readouts for WAINUA, olezarsen and donidalorsen. Our Phase 3 pipeline expanded with study starts for bepirovirsen, IONIS-FB-L Rx and zilganersen and we
 reported five additional positive data readouts from our mid- and late-stage pipeline. Our recent achievements position us to continue to deliver a steady cadence of potentially transformational medicines to patients in need in the near and mid-term.
 We also advanced our go-to-market plans for our near-term commercial opportunities, WAINUA, olezarsen and donidalorsen. And we expanded and diversified our technology when we advanced our first cardiac myocyte targeting medicine and medicines using
 our mesyl phosphoramidate, or MsPA, backbone into preclinical development.

 We accomplished all of this while earning revenues of $788 million for 2023 and ending the year with a cash and short-term investment balance of $2.3 billion. Our multiple sources of revenue and capital structure enable us to continue investing in
 our commercial readiness efforts for multiple late-stage programs, our innovative pipeline and our technology. By continuing to focus on these priorities, we believe we are well positioned to drive future growth and to bring next-level value to
 patients and shareholders.

 Marketed Medicines

 SPINRAZA is the global market leader for the treatment of patients with spinal muscular atrophy, or SMA, a progressive, debilitating and
 often fatal genetic disease. Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide. From inception through December 31, 2023,
 we have earned more than $2.1 billion in revenues from our SPINRAZA collaboration, including more than $1.6 billion in royalties on sales of SPINRAZA.

 QALSODY is an antisense medicine that received accelerated approval in April 2023 from the FDA for the treatment of adult patients with
 superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS, a rare, neurodegenerative disorder that causes progressive loss of motor neurons leading to death. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. The
 European Medicines Agency, or EMA, is currently reviewing QALSODY for approval in the European Union, or EU.

 WAINUA is a once monthly, self-administered subcutaneous LIgand-Conjugated Antisense, or LICA, medicine that received FDA approval in
 December 2023 for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis, or ATTRv-PN, a debilitating, progressive, and fatal disease. WAINUA is the only approved medicine for the treatment of ATTRv-PN that can
 be self-administered via an auto-injector. We and AstraZeneca are commercializing WAINUA in the U.S. with the launch having commenced in January 2024. We and AstraZeneca are seeking regulatory approval for WAINUA in Europe and other parts of the
 world. AstraZeneca has exclusive rights to commercialize WAINUA outside of the U.S.

 TEGSEDI is a once weekly, self-administered subcutaneous medicine approved in the U.S., Europe, Canada and Brazil for the treatment of
 patients with ATTRv-PN. We sell TEGSEDI in the U.S. and Canada (collectively, North America) and Europe through our distribution agreement with Swedish Orphan Biovitrum AB, or Sobi. In October 2023, our agreement for TEGSEDI in North America was
 terminated. As a result, Sobi is transitioning responsibilities to us. In February 2024, we began the process to withdraw the TEGSEDI New Drug Application, or NDA. In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing
 TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us.

 WAYLIVRA is a once weekly, self-administered, subcutaneous medicine approved in Europe and Brazil as an adjunct to diet in adult
 patients with genetically confirmed familial chylomicronemia syndrome, or FCS, and at high risk for pancreatitis. We sell WAYLIVRA in Europe through our distribution agreement with Sobi. In Latin America, PTC is commercializing WAYLIVRA in Brazil for
 two indications, FCS and familial partial lipodystrophy, or FPL, and is pursuing access in additional Latin American countries through its exclusive license agreement with us.

 Medicines in Registration and Phase 3 Studies

 We currently have nine medicines in registration or Phase 3 studies for eleven indications, which are:

 WAINUA (eplontersen) is our medicine to treat patients with transthyretin amyloidosis, or ATTR, that is approved in the U.S. for the
 treatment of adults with ATTRv-PN, under regulatory review in other countries for ATTRv-PN and in development for ATTR cardiomyopathy, or ATTR-CM. In September 2023, The Journal of the American Medical Association, or JAMA, published positive results from the Phase 3 NEURO-TTRansform
 study in patients with ATTRv-PN showing WAINUA halted disease progression and continuously improved quality of life at 35-, 66- and 85-week analyses. In July 2023, we completed enrollment of the Phase 3 CARDIO-TTRansform study of WAINUA in patients
 with ATTR-CM with data planned for as early as 2025. In February 2024, the FDA granted Fast Track designation to WAINUA for the treatment of patients with ATTR-CM. Additionally, in January 2022 and October 2023, the FDA and EMA, respectively, granted
 orphan drug designation to WAINUA for the treatment of ATTR.

 Olezarsen is our medicine in development for FCS, an ultra-rare indication and severe hypertriglyceridemia, or SHTG, a much broader
 indication. In September 2023, we reported positive results from the Phase 3 Balance study in patients with FCS showing statistically significant triglyceride lowering and a substantial reduction in acute pancreatitis events in addition to a favorable
 safety and tolerability profile. Based on our positive Phase 3 results in FCS patients we are preparing regulatory submissions to the FDA and EMA. In January 2023, the
 FDA granted fast track designation to olezarsen for the treatment of patients with FCS. Additionally, we are currently conducting a broad Phase 3 development program for
 olezarsen for the treatment of SHTG including three Phase 3 studies supporting development (CORE, CORE2 and ESSENCE). In February 2024, the FDA granted Breakthrough Therapy designation and orphan drug designation to olezarsen for the treatment of
 FCS. Additionally, in January 2023, the FDA granted olezarsen Fast Track designation for the treatment of patients with FCS.

 Donidalorsen is our medicine in development for hereditary angioedema, or HAE. In January 2024, we reported positive data from the Phase 3 OASIS-HAE study in patients treated every four weeks or patients treated every eight weeks. We are currently conducting OASIS-Plus, our open-label study in patients who were either previously treated with other prophylactic therapies or who have completed OASIS-HAE. Throughout 2022 and 2023, we reported positive data from the Phase 2 study and Phase 2 open-label extension, or OLE, study,
 including two-year OLE data. In December 2023, we licensed European commercialization rights of donidalorsen to Otsuka Pharmaceutical Co., Ltd., or Otsuka. We are preparing to submit an NDA to the FDA. Otsuka is preparing to submit a Marketing
 Authorization Application, or MAA, to the EMA. In September 2023 and February 2024, the FDA and EMA, respectively, granted orphan drug designation to donidalorsen.

 Zilganersen is our medicine in development for Alexander disease, or AxD. In September 2023, we advanced zilganersen into the Phase 3 portion of its ongoing study for patients with AxD. In September 2020 and October 2019, the FDA and EMA, respectively, granted orphan drug designation to
 zilganersen. Additionally in August 2020, the FDA granted rare pediatric designation to zilganersen.

 Ulefnersen is our medicine in development for amyotrophic lateral sclerosis, or ALS, with mutations in the fused in sarcoma gene, or FUS. We are currently conducting a Phase 3 study of ulefnersen in juvenile
 and adult patients with FUS-ALS. In August 2023 and September 2023, the FDA and EMA, respectively, granted orphan drug designation to ulefnersen.

 QALSODY (tofersen) is our medicine to treat patients with SOD1-ALS. In April 2023, the FDA granted Biogen accelerated approval of QALSODY for patients with SOD1-ALS. QALSODY is currently under regulatory review in the EU. Additionally, Biogen is developing QALSODY to treat presymptomatic SOD1-ALS
 patients in the ongoing ATLAS study. In September 2016 and August 2016, the FDA and EMA, respectively, granted orphan drug designation to QALSODY.

 Pelacarsen is our medicine in development to treat patients with elevated lipoprotein(a), or Lp(a)-driven cardiovascular disease, or CVD.
 Novartis is developing pelacarsen, including conducting the ongoing Lp(a) HORIZON Phase 3 cardiovascular outcome study in patients with elevated Lp(a)-driven CVD, which
 achieved full enrollment in July 2022 with more than 8,000 patients. In April 2020, the FDA granted Fast Track designation to pelacarsen.

 Bepirovirsen is our medicine in development for chronic hepatitis B virus, or HBV. GSK is developing bepirovirsen, including conducting the ongoing B-Well Phase 3 program in patients with HBV. GSK reported positive results from Phase 2 studies in 2023, including durable response data from the Phase 2 B-Sure
 long-term follow-up study of bepirovirsen in complete responder patients from the Phase 2b B-Clear study of patients with HBV. In February 2024, the FDA granted Fast Track designation to bepirovirsen.

 IONIS-FB-L Rx is our medicine in development for immunoglobulin A, or IgA, nephropathy, or IgAN, and geographic atrophy, or GA.
 In the second quarter of 2023, Roche advanced IONIS-FB-L Rx into Phase 3
 development in patients with IgAN. In October 2023, we reported positive interim data from the ongoing Phase 2 study of IONIS-FB-L Rx in patients with IgAN.
 Additionally, IONIS-FB-L Rx is in an ongoing Phase 2 study in patients with GA, refer to the IONIS-FB-L Rx description below for further details.

 Our Marketed Medicines –Bringing Value to Patients Today

 SPINRAZA – SPINRAZA (nusinersen)
 injection for intrathecal use is a survival motor neuron-2, or SMN2, directed antisense medicine indicated for the treatment of SMA in pediatric and adult patients.

 SPINRAZA is the global market leader for the treatment of
 patients with SMA, a progressive, debilitating and often fatal genetic disease. Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide.

 SMA is characterized by loss of motor neu rons in the spinal
 cord and lower brain stem. People with SMA have a deletion or defect in their SMN1 gene and rely on their SMN2 gene to
 produce functional SMN protein, which motor neurons need to maintain motor function and muscle strength. However, in untreated people the SMN2 gene can only produce approximately 10% of the SMN protein critical for motor neurons, resulting in severe and progressive loss of motor function and strength.

 The rate and severity of degeneration varies depending on the amount of functional SMN protein a patient can produce. Type 1, or
 infantile-onset, SMA is the most severe form of the disease. Type 1 SMA patients produce very little SMN protein and often progress to death or permanent ventilation by the age of 2. Patients with Type 2 or Type 3, or later-onset, SMA produce more SMN
 protein, but also suffer from a progressive loss of muscle strength and function and a reduced life expectancy.

 Biogen continues to expand the body of evidence supporting SPINRAZA's durable efficacy and well-established safety profile to address
 the remaining needs of SMA patients of all ages. This includes the following ongoing studies:

 •

 DEVOTE: In the Phase 2/3 DEVOTE study, Biogen is evaluating the safety and potential to achieve increased efficacy with a higher dose of SPINRAZA
 compared to the currently approved dose. In 2022, Biogen reported final data from Part A of the ongoing, three-part DEVOTE study. Results from Part A, an open-label safety evaluation period in children and teens with later-onset SMA, suggest
 that the higher dosing regimen of SPINRAZA leads to higher levels of the drug in the cerebrospinal fluid, or CSF, supporting further development of a higher dose of SPINRAZA. Additionally, the results indicated that SPINRAZA was generally
 well-tolerated.

 •

 RESPOND: In the Phase 4 RESPOND study, Biogen is evaluating the benefit of SPINRAZA in infants and children with a suboptimal clinical response to
 the gene therapy, onasemnogene abeparvovec. In 2023, Biogen presented interim results from the RESPOND study that showed improved motor function in most participants treated with SPINRAZA following treatment with onasemnogene abeparvovec.

 •

 ASCEND: In the Phase 3b ASCEND study, Biogen is evaluating the clinical outcomes and assessing the safety of a higher dose of SPINRAZA in children,
 teens and adults with later-onset SMA following treatment with risdiplam.

 Additionally, Biogen continues to conduct the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when
 administered before symptom onset in patients genetically diagnosed with SMA, and likely to develop Type 1 or Type 2 SMA. NURTURE was the first study to investigate the potential to slow or stop SMA disease progression in presymptomatic SMA patients.
 In 2022, Biogen reported new NURTURE study data, showing that early and sustained treatment with SPINRAZA helped participants to maintain and/or make progressive gains in motor function. These data showed that after 11 months of additional follow-up
 since the 2020 interim analysis, all children who were able to walk alone maintained this ability and one child gained the ability to walk alone, increasing the total percentage of study participants able to walk from 92% to 96%. Further, most children
 achieved motor milestones within age-appropriate timelines and no major motor milestones were lost. The safety of SPINRAZA over this extended follow-up period was consistent with previously reported findings.

 The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized,
 placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an OLE study for patients with SMA who participated in prior SPINRAZA studies.

 QALSODY – QALSODY (tofersen) is
 an antisense medicine used to treat ALS in adults who have a mutation in the superoxide dismutase 1, or SOD1, gene, or SOD1-ALS. The FDA granted QALSODY accelerated approval based on reduction in plasma neurofilament light chain, or NfL, observed in
 patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

 SOD1- ALS is a rare, fatal, neurodegenerative disorder
 caused by a mutation in the SOD1 gene leading to a
 progressive loss of motor neurons. As a result, people with SOD1-ALS experience increasing muscle weakness, loss of movement, difficulty breathing and swallowing and eventually succumb to the disease. Current treatment options for people with
 SOD1-ALS are extremely limited. It is estimated that there are approximately 1,400 patients with SOD1-ALS in the G7 countries (comprised of Canada, France, Germany, Italy, Japan, the United Kingdom and the U.S.).

 Biogen is also evaluating QALSODY for treatment of presymptomatic

 individuals who have a SOD1 genetic mutation. See the "Tofersen" description under "Our Phase 3 Pipeline" section below for further information on the development program for presymptomatic individuals. Tofersen is one of three medicines we have in development to treat ALS.

 QALSODY received accelerated approval from the U.S. FDA in April 2023 and is currently under regulatory review in the EU. The QALSODY NDA and MAA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 3 VALOR study, and the Phase 3
 OLE study, as well as 12-month integrated results from the Phase 3 VALOR study and the Phase 3 OLE study. The 12-month integrated data show that earlier initiation of QALSODY, compared to delayed initiation, slowed declines in clinical function,
 respiratory function, muscle strength and quality of life and build on the results previously observed in the initial readout. The 12-month data compare patients with early initiation of QALSODY (at the start of VALOR) to those who had a delayed
 initiation of QALSODY (six months later, in the OLE).

 At the time of the 12-month analysis, because the majority of participants survived without permanent ventilation, the median time to
 death or permanent ventilation, could not be estimated. However, early survival data suggest a lower risk of death or permanent ventilation with earlier initiation of QALSODY. Additionally, the latest 12-month results showed that reductions in total
 SOD1 protein (a marker of target engagement) and neurofilament (a marker of axonal injury and neurodegeneration) were sustained over time. QALSODY reduced total CSF SOD1 protein and plasma neurofilament levels in both early- and delayed-start groups as
 follows:

 •

 33% and 21% reduction in SOD1 protein, the intended target for QALSODY, respectively

 •

 51% and 41% reduction in plasma neurofilament, a marker of neuron injury, respectively

 QALSODY had a favorable safety and tolerability profile.

 The FDA and EMA granted QALSODY orphan drug designation for the treatment of ALS in September 2016 and August 2016, respectively.

 In December 2018, Biogen exercised its option to license QALSODY. As a result, Biogen is responsible for global development, regulatory
 and commercialization activities, and costs for QALSODY.

 WAINUA – WAINUA (eplontersen) injection is a LICA medicine indicated for the treatment of adults with ATTRv-PN. WAINUA prevents the production of TTR protein, reducing the amount of amyloid buildup that
 damages organs and tissues. WAINUA was approved by the FDA in December 2023.

 ATTR amyloidosis is a systemic, progressive and fatal disease in which patients experience multiple overlapping clinical manifestations
 caused by the inappropriate formation and aggregation of TTR amyloid deposits in various tissues and organs, including peripheral nerves, heart, intestinal tract, eyes, kidneys, central nervous system, thyroid and bone marrow. The progressive
 accumulation of TTR amyloid deposits in these tissues and organs leads to organ failure and eventually death.

 ATTRv-PN is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with ATTRv-PN experience
 ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromises their function and eventually
 leads to death within five to fifteen years of disease onset. There are an estimated 40,000 addressable patients, which includes those with ATTRv-PN and those with ATTRv- mixed phenotype worldwide.

 Often, patients with ATTRv-PN will have TTR build up in the heart and experience cardiomyopathy symptoms. Similarly, patients with
 ATTR-CM may often have TTR build up in their peripheral nerves and experience nerve damage and a variety of symptoms, including progressive difficulty with motor functions. As a result, we are developing WAINUA to treat all types of ATTR. See the
 "WAINUA" description under "Our Phase 3 Pipeline" section below for further information on our development program for ATTR-CM.

 FDA approval was based on the interim analysis of the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN. NEURO-TTRansform was a global, multi-center, randomized, open-label study designed to evaluate the efficacy, safety and tolerability of WAINUA. The study compared WAINUA to the historical placebo
 arm from the TEGSEDI (inotersen) NEURO-TTR Phase 3 study. In the interim analysis, WAINUA demonstrated a statistically significant and clinically meaningful change from baseline for the co-primary and secondary endpoints at 35 weeks
 compared to the external placebo group. In the study, WAINUA achieved an 81% (p<0.0001) least squares, or LS, mean reduction in the co-primary endpoint of serum TTR concentration compared to baseline, demonstrating reduced TTR protein production.
 WAINUA also demonstrated a significant treatment effect on the co-primary endpoint of modified Neuropathy Impairment Score +7, or mNIS+7, a measure of neuropathic disease progression, with a statistically significant difference in mean change from
 baseline versus the external placebo group (p<0.0001). The study also met its key secondary endpoint of change from baseline in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy, or Norfolk QoL-DN, showing that treatment with WAINUA
 significantly improved patient-reported quality of life compared to the external placebo group (p<0.0001). In September 2023, The Journal of American
 Medical Association, or JAMA, published the Phase 3 NEURO-TTRansform study results.

 Additionally, in April 2023, we presented positive data that WAINUA met all co-primary and secondary endpoints in the NEURO-TTRansform
 study at the final analysis at week 66. At week 66:

 •

 WAINUA achieved a LS mean reduction of 82% in serum TTR concentration from baseline, compared to an 11% reduction from baseline in the external
 placebo group (p<0.0001).

 •

 WAINUA stopped disease progression as measured by mNIS+7 resulting in a 0.28 point LS mean increase compared to a 25.06 point increase for the
 external placebo group from baseline (24.8 point LS mean improvement; p<0.0001).

 •

 WAINUA improved quality of life demonstrating a 5.5 point LS mean decrease (improvement) on the Norfolk QoL-DN, compared to a 14.2 point increase
 (worsening) in the external placebo group (19.7 point LS mean improvement; p<0.0001).

 And in July 2023, we reported that WAINUA continued to halt neuropathy disease progression and improve quality of life in patients with
 ATTRv-PN through the end of treatment analysis at week 85.

 WAINUA is currently under regulatory review in the EU and other countries for the treatment of patients with ATTRv-PN.

 In January 2022 and October 2023, the FDA and EMA, respectively, granted orphan drug designation to WAINUA for the treatment of ATTR.

 In December 2021, we entered into an agreement with AstraZeneca to jointly develop and commercialize WAINUA in the U.S. We initially
 granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S., except for certain Latin American countries. In July 2023, we expanded those rights to include Latin America.

 TEGSEDI – TEGSEDI (inotersen)
 injection is an antisense medicine indicated for the treatment of ATTRv-PN in adults. TEGSEDI prevents the production of TTR protein, reducing the amount of amyloid buildup
 that damages organs and tissues.

 TEGSEDI is commercially available in numerous countries, including the U.S., many European countries, Canada, and Latin America. We
 launched TEGSEDI in the U.S. and EU in late 2018. In 2021, we began selling TEGSEDI in the U.S., Canada and Europe through our distribution agreement with Sobi. Refer to the
 section titled, Overview, for further details on our
 distribution agreement with Sobi. In Latin America, PTC is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us.

 The approvals of TEGSEDI were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with ATTRv-PN.

 WAYLIVRA – WAYLIVRA (volanesorsen)
 is an antisense medicine indicated as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for acute, potentially fatal pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate. WAYLIVRA reduces triglyceride levels by inhibiting the production of apolipoprotein C-III, or apoC-III, a protein that is a key regulator of triglyceride levels.

 FCS is a rare, genetic disease estimated to affect one to two individuals per million and characterized by extremely elevated
 triglyceride levels, typically greater than 1,000 mg/dl. FCS can lead to many chronic health issues including severe, recurrent abdominal pain, fatigue, high risk of life-threatening pancreatitis and abnormal enlargement of the liver or spleen. In
 addition, people with FCS are often unable to work, adding to their disease burden. In severe cases, patients can have bleeding into the pancreas, serious tissue damage, infection, and cyst formation, as well as damage to other vital organs such as the
 heart, lungs, and kidneys.

 WAYLIVRA received conditional marketing authorization in May 2019 from the European Commission, or EC. WAYLIVRA is commercially available
 in multiple European countries and in Latin America. We launched WAYLIVRA in the EU in the third quarter of 2019. In 2021, we began selling WAYLIVRA in Europe through our
 distribution agreement with Sobi. In Latin America, WAYLIVRA is approved for two indications, FCS and FPL. PTC is commercializing WAYLIVRA in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement
 with us. In the fourth quarter of 2022, WAYLIVRA was approved in Brazil for a second indication, FPL.

 WAYLIVRA's conditional marketing authorization in the EU for FCS and approval in Brazil for FCS we re based on efficacy and safety data from the Phase 3 APPROACH study and
 supported by results from the Phase 3 COMPASS study. WAYLIVRA's approval in Brazil for FPL was based on efficacy and safety data
 from the Phase 3 BROADEN study in patients with FPL.

 Our Innovative Pipeline of Investigational Medicines

 As a pioneer in RNA-targeted therapeutics, we continue to drive innovation with a leading pipeline in neurology, cardiology and other
 areas of high patient need.

 The table below lists the medicines in our clinical pipeline and includes the disease indication, the partner (if the medicine is
 partnered), and the development status of each medicine. We categorize first-in-patient studies to establish a medicine's safety profile as Phase 1/2 and in the table below these are listed in the Phase 2 column. Studies in patients that are designed
 to establish an investigational medicine's proof of concept and additional safety profile are also listed in Phase 2. Pivotal studies designed to enable registrational filing for marketing authorization are listed in Phase 3. We have included
 descriptions for each of our medicines in Phase 2 and Phase 3 development below.

 1 Granted Otsuka exclusive rights to commercialize donidalorsen in Europe.

 Our Phase 3 Pipeline

 We currently have nine medicines in our Phase 3 pipeline:

 1 Granted Otsuka exclusive rights to commercialize donidalorsen in Europe.

 Eplontersen (TTR) – Eplontersen (TTR) – Eplontersen

 (formerly IONIS-TTR-L Rx) is an investigational LICA medicine we designed to inhibit the production of TTR protein. As discussed above under "WAINUA" in our "Marketed Medicines" section, we are developing eplontersen as
 a monthly self-administered subcutaneous injection to treat all types of ATTR, including ATTR-CM.

 ATTR-CM is caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing
 debilitating heart damage resulting in progressive heart failure, which results in death within three to five years from disease onset. ATTR-CM includes both the genetic and wild-type form of the disease. There are an estimated 300,000 to 500,000
 patients with ATTR-CM worldwide.

 Often, patients with ATTRv-PN will have TTR build up in the heart and experience cardiomyopathy symptoms.
 Similarly, patients with ATTR-CM may often have TTR build up in their peripheral nerves and experience nerve damage and a variety of symptoms, including progressive difficulty with motor functions.

 In January 2020, we initiated the CARDIO-TTRansform Phase 3 cardiovascular outcome study of eplontersen in patients with ATTR-CM.
 CARDIO-TTRansform i s a global, multi-center, randomized, double-blind, placebo-controlled study in approximately 1,400 patients with ATTR-CM. We designed the study to
 evaluate the efficacy, safety and tolerability of eplontersen in patients with ATTR-CM. The primary endpoint in the CARDIO-TTRansform study is a composite outcome of cardiovascular mortality and recurrent cardiovascular clinical events up to Week 140. In July 2023, we announced that the CARDIO-TTRansform study had completed enrollment.

 In January 2022 and October 2023, the FDA and EMA, respectively, granted orphan drug designation to WAINUA for the treatment of ATTR.

 Olezarsen (ApoC-III) – Olezarsen (formerly IONIS-APOCIII-L Rx) is an investigational LICA medicine we designed to inhibit
 the production of apoC-III for patients who are at risk of disease due to elevated triglyceride levels. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood. People with severely elevated triglycerides, such
 as people with FCS, are at high risk for acute pancreatitis and an increased risk of cardiovascular disease, or CVD. It is estimated that FCS affects one to two individuals per million worldwide and more than three million patients have SHTG in the
 U.S.

 We are currently conducting a broad development program for olezarsen that includes the Phase 3 Balance study in patients with FCS and
 three Phase 3 studies supporting development for the treatment of SHTG: CORE, CORE2 and ESSENCE.

 In September 2023, we reported positive topline data from
 the Phase 3 Balance study in patients with FCS. The study met its primary efficacy endpoint with a statistically significant reduction in triglyceride (TG) levels with the olezarsen 80 mg monthly dose at six months compared to placebo (p=0.0009);
 triglyceride lowering continued to improve at 12 months. In addition, olezarsen 80 mg showed a substantial reduction in acute pancreatitis events compared to placebo, a key secondary endpoint. Treatment with olezarsen 80 mg resulted in a >75%
 reduction in apoC-III, a protein produced in the liver that regulates TG metabolism in the blood. In addition to the 80 mg monthly dose, the study also evaluated a 50 mg monthly dose. Olezarsen demonstrated a dose-dependent effect, with both study
 doses showing a substantial reduction in acute pancreatitis compared to placebo. The 50 mg dose did not reach statistical significance at six months on the primary endpoint of triglyceride lowering (p=0.0775). Olezarsen demonstrated a favorable
 safety and tolerability profile in the study. Based on
 the positive results, we plan to file a New Drug Application, or NDA, in 2024 with the U.S. FDA in addition to EU regulatory filings for patients with FCS.

 We are also conducting ongoing Phase 3 studies for the expanded SHTG patient population. CORE and CORE2 are global, multi-center,
 randomized, double-blind, placebo-controlled studies enrolling approximately 540 and 390 patients, respectively, designed to assess the efficacy, safety and tolerability of olezarsen in patients with SHTG. The CORE and CORE2 studies compare olezarsen
 to placebo in patients with triglyceride levels equal to or greater than 500 mg/dL who are on currently available therapies for elevated triglycerides. The primary endpoint of the studies is the percent change in fasting triglycerides from baseline at
 month six. Additionally, in November 2022, we initiated ESSENCE, a global, multi-center, randomized, double-blind, placebo-controlled study enrolling approximately 1,300 patients to provide a robust safety database. The primary endpoint of the study is
 the percent change in fasting triglycerides from baseline at month six.

 In January 2020, we reported positive results from a Phase
 2 clinical study in patients with hypertriglyceridemia and at high risk of or with established CVD. Olezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels.
 Olezarsen also achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III. Olezarsen had a favorable safety and tolerability profile supportive of continued development.

 In February 2024, the FDA granted Breakthrough Therapy
 designation and orphan drug designation to olezarsen for the treatment of FCS. Additionally, in January 2023, the FDA granted olezarsen Fast Track designation for the treatment of patients with FCS.

 Donidalorsen (PKK) – Donidalorsen (formerly IONIS-PKK-L Rx) is an investigational LICA medicine we designed to inhibit the production of prekallikrein, or PKK.
 HAE is a rare genetic disease that is characterized by severe and potentially fatal swelling of the arms, legs, face and throat. PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE. By inhibiting
 the production of PKK, donidalorsen could be an effective prophylactic approach to preventing HAE attacks. It is estimated that there are more than 20,000 patients with HAE in the U.S. and Europe.

 In January 2024, we reported positive topline data from the Phase 3 OASIS-HAE study in patients with HAE. The study met its primary
 efficacy endpoint with a statistically significant reduction in the rate of HAE attacks in patients treated with 80 mg of donidalorsen via subcutaneous injection dosed every four weeks, or Q4W, (p<0.001) or every eight weeks, or Q8W, (p=0.004)
 compared to placebo. In addition, the trial showed donidalorsen achieved statistical significance on all secondary endpoints in the Q4W group and key secondary endpoints in the Q8W group. Donidalorsen demonstrated a favorable safety and tolerability
 profile in the study. Based on the positive results, we plan to file a NDA in 2024 with the U.S. FDA. Otsuka, which has exclusive rights to commercialize donidalorsen in Europe, is preparing to submit a Marketing Authorization Application to the
 European Medicines Agency, or EMA.

 In May 2022, we initiated OASIS-Plus, a multi-center, open-label, global study in approximately 110 patients who were either previously
 treated with other prophylactic therapies or who have completed OASIS-HAE.

 In 2021 and 2022 we reported positive results from the Phase 2 clinical study of donidalorsen in patients with HAE. And in 2022 and
 2023, we presented positive results from the Phase 2 OLE study of donidalorsen in patients with HAE. Following the 13-week blinded, placebo-controlled Phase 2 study with a fixed 13-week dosing period where they received donidalorsen 80 mg every four
 weeks, patients were eligible for enrollment in the OLE study. Of the 20 Phase 2 study participants, 17 entered the OLE study and were on a fixed 13-week dosing period where they received 80 mg every four weeks. From week 17 through two years, patients
 entered a flexible dosing period where they either received donidalorsen 80 mg every four weeks, 80 mg every eight weeks, or 100 mg every four weeks. Over

 the two years, patients treated with donidalorsen via subcutaneous injection showed an overall sustained mean reduction in HAE attack rates of 96% from baseline, from 2.70 to 0.06 attacks per month, across all dosing groups. Furthermore, all patients
 treated with donidalorsen reported a clinically meaningful improvement in quality of life as measured by the Angioedema Quality of Life Questionnaire (AE-QoL) over two years. Donidalorsen had a favorable safety and tolerability profile in the study.

 In September 2023 and February 2024, the FDA and EMA granted orphan drug designation to donidalorsen.

 In December 2023, we granted Otsuka exclusive rights to commercialize donidalorsen in Europe.

 Pelacarsen (Apo(a)) (TQJ230) – Pelacarsen (formerly IONIS-APO(a)-L Rx) is an investigational LICA antisense medicine we designed to inhibit the
 production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD. Lp(a) levels are determined at birth and lifestyle modification, including
 diet and exercise, do not impact Lp(a) levels. Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, potentially slowing down or reversing CVD in people with hyperlipoproteinemia(a), a condition in which individuals
 have levels of Lp(a) greater than 50 mg/dL, the recognized threshold for risk of CVD. We believe antisense technology is well suited to address hyperlipoproteinemia(a) because it specifically targets the RNA that codes for all forms of the Apo(a)
 molecule. It is estimated that there are more than eight million people living with CVD and elevated levels of Lp(a).

 In December 2019, Novartis initiated the Phase 3 study
 of pelacarsen, Lp(a) HORIZON, in patients with elevated Lp(a) levels and a prior cardiovascular event. Lp(a) HORIZON is a global, multi-center, randomized, double-blind, placebo-controlled cardiovascular outcomes study in more than 8,000 patients designed to assess the efficacy, safety and tolerability of pelacarsen. Patients are treated with 80 mg of pelacarsen administered monthly by subcutaneous injection. The

 primary endpoint in Lp(a) HORIZON is the time to occurrence of first major adverse cardiovascular event, or MACE. In July 2022, we announced that the Lp(a) HORIZON study had completed enrollment.

 In November 2018, at the American Heart Association, or AHA, annual meeting, we reported results of the Phase 2 study of pelacarsen in
 patients with hyperlipoproteinemia(a). In the Phase 2 study, we observed statistically significant and dose dependent reductions from baseline in Lp(a) levels. Approximately 98% of patients who received the highest dose in the study demonstrated a
 reduction in Lp(a) levels to below the recommended threshold for CVD events (<50 mg/dL). Pelacarsen had a favorable safety and tolerability profile supportive of continued development.

 In February 2019, Novartis exercised its option to license pelacarsen. As a result, Novartis is responsible for global development,
 regulatory and commercialization activities, and costs for pelacarsen.

 In April 2020, the FDA granted pelacarsen Fast Track designation for the treatment of patients with elevated Lp(a) and CVD. In December
 2020, the Center for Drug Evaluation, or CDE, of China National Medical Products Administration granted breakthrough therapy designation to pelacarsen.

 Zilganersen – Zilganersen
 (formerly ION373) is an investigational antisense medicine we designed to inhibit the production of glial fibrillary acidic protein, or GFAP. We are developing zilganersen as a potential therapy for AxD, a rare, progressive and fatal neurological
 disease that affects the myelin sheath which protects nerve fibers. AxD is caused by a gain-of-function mutation in the GFAP gene and is
 characterized by progressive deterioration, including loss of skills and independence, generally leading to death in childhood or early adulthood.

 Two major types of AxD have been defined. Type I onset typically occurs before four years of age and patients can experience head
 enlargement, seizures, limb stiffness, delayed or declining cognition, and lack of growth. Type II onset typically occurs after the age of four and symptoms can include difficulty speaking, swallowing, and making coordinated movements. AxD is most
 often fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.

 In April 2021, we initiated a pivotal study of zilganersen in patients with AxD and in September 2023, we advanced zilganersen into the
 Phase 3 portion of the pivotal study. The pivotal study of zilganersen is a multi-center, double-blind, placebo-controlled, multiple-ascending dose study in approximately 55 patients with AxD designed to assess the efficacy, safety and tolerability of
 zilganersen. Patients will receive zilganersen or placebo for a 60-week period, after which all patients in the study will receive zilganersen for a 60-week open-label treatment period. The primary endpoint is the change from baseline in the 10-Meter
 Walk Test, or 10MWT.

 In September 2020 and October 2019, the FDA and
 EMA, respectively, granted orphan drug designation to zilganersen. Additionally in August 2020, the FDA granted rare pediatric designation to zilganersen.

 Ulefnersen (FUS) – Ulefnersen
 (formerly ION363) is an investigational antisense medicine we designed to reduce the production of the FUS protein to treat people with ALS caused by mutations in the FUS gene. Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent
 disease progression in FUS-ALS patients. It is estimated that there are approximately 350 patients with FUS-ALS in G7 countries.

 In April 2021, we initiated a Phase 3 study of ulefnersen in patients with FUS-ALS. The Phase 3 trial of ulefnersen is a global,
 multi-center, randomized, double-blind, placebo-controlled study in approximately 75 patients designed to assess the efficacy, safety and tolerability of ulefnersen. Part 1 of the trial consists of patients randomized to receive a loading regimen of
 ulefnersen or placebo for days one, 28 and 85 after which patients are dosed quarterly for a total of 61 weeks, followed by a 12 week follow up for participants entering Part 2 or 40 week follow up for participants not entering Part 2. Part 2 is an
 open-label period in which all patients in the trial will receive ulefnersen or placebo loading regimen at week four followed by one dose every 12 weeks for 85 weeks. The primary endpoint is the change from baseline as measured by joint rank analysis
 of the combined assessment of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, or ALSFRS-R, Total Score, time of rescue or discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and Ventilation
 Assistance-free survival, or VAFS.

 In August 2023 and September 2023, the FDA and EMA, respectively, granted orphan drug designation to ulefnersen.

 Tofersen (SOD1) (BIIB067) – Tofersen (formerly IONIS-SOD1 Rx) is an investigational antisense medicine we designed to inhibit the production of SOD1 protein, which
 is a well understood genetic cause of ALS. As discussed above under the "QALSODY" section in our "Marketed Medicines" section, Biogen is also evaluating tofersen for treatment of presymptomatic individuals who have a SOD1 genetic mutation.

 In April 2021, Biogen initiated a Phase 3 study of tofersen, called ATLAS, in presymptomatic individuals with a SOD1 genetic mutation.
 ATLAS is a multi-center, randomized, double-blind, placebo-controlled study enrolling approximately 150 subjects designed to assess the efficacy, safety and tolerability of tofersen. Patients are only given tofersen if they meet a defined biomarker
 threshold or progress to develop clinically manifest SOD1-ALS.

 In September 2016 and August 2016, the FDA and EMA, respectively, granted orphan drug designation to tofersen.

 In December 2018, Biogen exercised its option to license tofersen. As a result, Biogen is responsible for global development, regulatory
 and commercialization activities, and costs for tofersen.

 Bepirovirsen (HBV) (GSK3228836) – Bepirovirsen (formerly IONIS-HBV Rx) is an investigational antisense medicine we designed to inhibit the production of viral proteins
 associated with HBV. These include proteins associated with infection and replication, including the hepatitis B surface antigen, or HBsAg, which is present in both acute and chronic infections and is associated with a poor prognosis in people with
 chronic HBV infection.

 HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions, including cirrhosis,
 liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world, affecting nearly 300 million people and resulting in approximately 900,000 deaths annually. Currently available therapies,
 although effective in reducing circulating HBV in the blood, do not effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.

 In January 2023, GSK initiated the Phase 3 program of bepirovirsen, B-Well, in patients with chronic HBV. B-Well 1 and B-Well 2 are global, multi-center, randomized, double-blind, placebo-controlled studies enrolling more
 than 500 patients each. GSK designed these studies to assess the efficacy, safety and tolerability of bepirovirsen. The arms will be stratified based on HBsAg levels at screening. The primary endpoint is the number of patients achieving functional cure with baseline HBsAg 1,000 IU/mL. Functional cure is defined as a sustained suppression (24 weeks or longer) of HBV DNA (< Lower Limit of
 Quantification, or LLOQ) while off all HBV treatments with HBsAg loss (<0.05 IU/mL) with or without HBsAg after a finite duration of therapy.

 In June 2022, GSK presented positive results from the Phase 2b B-CLEAR study of bepirovirsen in patients with chronic HBV infection. The end of study results showed that treatment with bepirovirsen in some patients resulted in sustained clearance of HBsAg and HBV DNA for 24 weeks
 after end of bepirovirsen treatment in people with chronic HBV infection. Treatment with bepirovirsen that was administered weekly at a dose of 300 mg per week for 24 weeks, with loading doses administered on day four and 11 (treatment arm 1), resulted
 in 9% of patients on NA treatment and 10% of patients not on NA treatment both achieving the primary outcome of HBsAg levels and HBV DNA levels below the LLOQ. This is defined as a sustained response and was observed for 24 weeks post last dose.
 Patients with low baseline HBsAg levels responded best to treatment with bepirovirsen with 16% and 25% of patients achieving the primary outcome in treatment arm one of the on NA and not on NA cohorts, respectively. Additionally in June 2023, GSK
 presented durable response data from the Phase 2 B-Sure long-term follow-up study of bepirovirsen in complete responder patients from the Phase 2b B-Clear study of patients with HBV. Bepirovirsen had a favorable safety and tolerability profile supportive of continued development.

 In October 2023, GSK reported data from the B-Together Phase 2b study of bepirovirsen in patients with chronic HBV infection at the
 AASLD Liver Meeting. The data showed that between 9-15% of patients attained the primary outcome of HBsAg and HBV DNA below the LLOQ for 24 weeks after planned end of sequential treatment with pegylated interferon, in the absence of newly initiated
 antiviral therapy. Additionally, all patients who achieved the primary endpoint had a baseline HBsAg 3000 IU/mL. Bepirovirsen had a favorable safety and tolerability profile
 supportive of continued development.

 In August 2019, GSK exercised its option to license our HBV program following the positive results of the Phase 2a study of bepirovirsen
 in patients with chronic HBV infection. As a result, GSK is responsible for global development, regulatory and commercialization activities, and costs for the HBV program.

 In February 2024, the FDA granted bepirovirsen Fast Track designation for the treatment of patients with chronic HBV infection.

 IONIS-FB-L Rx (IgAN) (RG6299) – IONIS-FB-L Rx is an investigational LICA medicine we designed to inhibit the
 production of complement factor B, or FB, and the alternative complement pathway. Genetic association studies have shown that overaction of the alternative complement pathway has been associated with the development of several complement-mediated
 diseases, including IgAN. As discussed below under the "IONIS-FB-L Rx " section in our "Other Medicines in Development" section, we are also developing IONIS-FB-L Rx for GA, secondary to age-related macular degeneration, or AMD.

 IgAN is one of the most common causes of inflammation that impairs the filtering ability of kidneys and is an important cause of chronic
 kidney disease and kidney failure. Also known as Berger's disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage.

 In April 2023, Roche initiated a Phase 3 study of
 IONIS-FB-L Rx, called IMAGINATION, in patients with IgAN. IMAGINATION is a multi-center, randomized, double-blind, placebo-controlled study enrolling
 approximately 430 patients designed to assess the efficacy, safety and tolerability of IONIS-FB-L Rx. The primary endpoint is the change from
 baseline in the urine protein-to-creatinine ratio, or UPCR, at week 37.

 In November 2022, we presented positive results from the Phase 2 open-label study of IONIS-FB-L Rx in patients with IgAN at
 the American Society of Nephrology's, or ASN, Kidney Week. In the Phase 2 study, which included results from the first 10 patients treated with IONIS-FB-L Rx, IONIS-FB-L Rx met its primary endpoint of change in 24-hour urinary
 protein, demonstrating a 44% mean reduction in proteinuria from baseline to week 29. Kidney function, as measured by estimated glomerular filtration rate, or eGFR, was maintained in all patients in the study. The results from the Phase 2 study provided
 proof-of-concept for the potential of IONIS-FB-L Rx to treat patients with IgAN by inhibiting complement FB and the alternative complement pathway. Additionally, in November 2023 at ASN Kidney Week, we presented new positive interim results
 from the ongoing Phase 2 study, which included results from 13 patients. The results showed that IONIS-FB-L Rx effectively and selectively reduced circulating FB, Alternate Pathway Activity, or AH50 and urinary complement Ba. Additionally,
 IONIS-FB-L Rx reduced established proteinuria in patients with IgAN after six-months of treatment. The Phase 2 open-label study remains ongoing and will evaluate IONIS-FB-L Rx in approximately 25 patients with IgAN. IONIS-FB-L Rx
 had a favorable safety and tolerability profile supportive of continued development.

 In July 2022, Roche exercised its option to license IONIS-FB-L Rx following the positive Phase 2 results described above. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L Rx, except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding.

 Our Neurological Medicines in Development

 We have a leading neurology franchise that includes three approved medicines for serious neurological diseases and a pipeline of
 investigational potential disease-modifying treatments for a broad range of neurological diseases. As we look to expand our wholly owned pipeline, we are focused on four pillars within our neurology franchise. We are first focusing on two areas: rare
 pediatric neurology and dementia, with plans to move into neuromuscular and peripheral neuropathies and motor diseases and then common neurological diseases in the future. We recently added ION717 for prion disease to our pipeline with plans to add
 three additional medicines by the end of 2024.

 Zilganersen – See the medicine

 Ulefnersen – See the medicine

 Tofersen – See the medicine

 ION717 (PRNP) – ION717 is an investigational antisense medicine we designed to
 inhibit the production of prion protein, or PrP, for the potential treatment of prion disease. Prion disease is a rare, fatal neurodegenerative disease caused by misfolding of PrP which accumulates in the brain. People with prion disease often
 experience progressive memory impairment, personality changes, difficulties with movement and loss of independence. There are currently no effective disease-modifying treatments for prion disease. In most cases, a person succumbs to prion disease
 within a year following symptom onset.

 In December 2023, we initiated the Phase 1/2, PrProfile, study of ION717 in patients with prion disease. The current study is a
 randomized, multi-center, double-blind, placebo-controlled study in approximately 55 patients designed to assess the safety, tolerability and pharmacokinetics of multiple dose levels of ION717 administered intrathecally.

 IONIS-MAPT Rx (TAU) (BIIB080) – IONIS-MAPT Rx is an investigational antisense medicine we designed to selectively
 inhibit production of the microtubule-associated protein tau (MAPT), or tau protein in the brain. We are developing IONIS-MAPT Rx to treat people with Alzheimer's disease, or AD.

 AD is characterized predominantly by memory impairment and behavioral changes, resulting in a person's inability to independently perform
 daily activities. AD generally occurs late in life and may progress to death in five to 20 years after the onset of the disease.

 In December 2022, Biogen initiated a Phase 2 clinical study of IONIS-MAPT Rx in patients with mild cognitive impairment or
 mild dementia due to AD. The study is a randomized, double-blinded, placebo-controlled, dose-escalation study in approximately 735 patients designed to assess the efficacy, safety and tolerability of IONIS-MAPT Rx administered intrathecally.

 The primary endpoint is the change from baseline to week 76 on the Clinical Dementia Rating scale Sum of Boxes, or CDR-SB.

 In March 2023, Biogen presented ne w data from the
 Phase 1/2 study at the International Conference on Alzheimer's and Parkinson's Diseases. The data showed that IONIS-MAPT Rx reduced soluble tau protein in CSF in a dose-dependent and sustained manner in patients with early-stage AD. IONIS-MAPT Rx also reduced aggregated tau pathology, as measured by positron emission tomography, or PET, in all brain composites assessed. In October 2023, these data were published in JAMA. Additionally in October 2023, Biogen presented new data from the Phase 1/2 study at The Clinical Trials on Alzheimer's Disease, or CTAD, conference. The data showed a numerical difference
 favoring IONIS-MAPT Rx on multiple cognitive and functional scales for the patients receiving higher doses of IONIS-MAPT Rx throughout the multiple ascending dose and long-term extension compared to matched external control patients receiving placebo. The assessments included: Clinical Dementia Rating
 Sum of Boxes, or CDR-SB, Mini-Mental State Examination, or MMSE and, Functional Activities Questionnaire, or FAQ.

 In July 2021, we and Biogen reported positive topline data from our Phase 1/2 study of IONIS-MAPT Rx in patients with mild AD
 at the Alzheimer's Association International Conference, or AAIC. The Phase 1/2 study was a blinded, randomized, placebo-controlled, dose-escalation study of IONIS-MAPT Rx to evaluate the safety and activity of once-monthly intrathecal
 injections of IONIS-MAPT Rx in patients with mild AD. The study showed that IONIS-MAPT Rx met its primary objective of safety and tolerability in patients with mild AD. The study demonstrated robust time and dose dependent lowering
 of tau protein in CSF over the three-month treatment period and sustained reductions during the six-month post-treatment period. IONIS-MAPT Rx had a favorable safety and tolerability profile supportive of continued development.

 In December 2019, Biogen exercised its option to license IONIS-MAPT Rx. Biogen has responsibility for global development,
 regulatory and commercialization activities, and costs for IONIS-MAPT Rx.

 ION859 (LRRK2) (BIIB094) –
 ION859 is an investigational antisense medicine we designed to inhibit the production of the Leucine Rich Repeat Kinase 2, or LRRK2, protein as a potential therapy for Parkinson's disease, or PD. The most common genetic mutations in PD are found in the
 LRRK2 protein. It is believed that increased LRRK2 protein activity could be one of the key drivers for developing PD. PD is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. Patients with PD can experience
 tremors, loss of balance and coordination, stiffness, slowing of movement, changes in speech and in some cases cognitive decline. PD is ultimately fatal. There are treatments that can relieve symptoms, but there are no approved disease modifying
 therapies.

 In August 2019, Biogen initiated a Phase 1/2 study evaluating ION859 in patients with PD. The Phase 1/2 study is a global, multi-center,
 randomized, double-blinded, placebo-controlled study in approximately 80 patients designed to assess the safety, tolerability and activity of multiple ascending doses of ION859 administered intrathecally.

 ION859 is being developed under our 2013 Strategic Neurology collaboration with Biogen.

 ION464 (SNCA) (BIIB101) – ION464
 is an investigational antisense medicine we designed to inhibit the production of the alpha-synuclein protein as a potential therapy for PD, Multiple System Atrophy, or MSA, and related synucleinopathies. Alpha-synuclein protein abnormally accumulates
 in the brains of PD and MSA patients and is thought to be one of the key drivers of these diseases. It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations.

 In July 2020, we initiated a Phase 1/2 study evaluating ION464 in patients with MSA. The current study is a multi-center, randomized,
 double-blinded, placebo-controlled study in approximately 40 patients designed to assess the safety and tolerability of multiple ascending doses of ION464 administered intrathecally.

 ION464 is being developed under our 2013 Strategic Neurology collaboration with Biogen.

 ION541 (ATXN2) (BIIB105) – ION541
 is an investigational antisense medicine we designed to reduce the production of the ataxin-2, or ATXN2, protein for the potential treatment of ALS. The reduction of ATXN2 has been shown to decrease toxic aggregation of TDP-43, an RNA binding protein
 found in most patients with ALS, including the approximately 90% of the ALS population with no known family history of ALS.

 In October 2020, Biogen initiated a Phase 1/2 clinical study evaluating ION541 in patients with ALS. The current study is a randomized,
 blinded, placebo-controlled study in approximately 110 patients designed to assess the safety, tolerability, and pharmacokinetics of multiple ascending doses of ION541 administered intrathecally.

 ION541 is being developed under our 2013 Strategic Neurology collaboration with Biogen.

 ION582 (UBE3A) (BIIB121) – ION582
 is an investigational antisense medicine we designed to inhibit the expression of the UBE3A antisense transcript, or UBE3A-ATS for the potential treatment of Angelman Syndrome, or AS. AS is a rare, genetic neurological disease caused by the loss of
 function of the maternally inherited UBE3A gene. AS typically presents in infancy and is characterized by intellectual disability, balance issues,
 motor impairment, and debilitating seizures. Some patients are unable to walk or speak. Some symptoms can be managed with existing drugs; however, there are no approved disease modifying therapies.

 In December 2021, we initiated the Phase 1/2 study, HALOS, of ION582 in patients with AS. The study is an open label dose-escalation
 study enrolling approximately 50 patients designed to assess the safety, tolerability and activity of multiple ascending doses of ION582 administered intrathecally. In November 2023, we announced that the HALOS study had completed enrollment.

 In November 2023, we presented initial observations from the ongoing Phase 1/2 study at the Foundation for Angelman Syndrome, or FAST,
 summit. The data demonstrated that approximately 70% of patients showed a reduction in slow-wave electroencephalogram, or EEG, delta activity and over 80% showed an increase in faster frequency rhythms. Additionally, a majority of patients showed
 improvement in overall functioning on the SAS-CGI-C scale. A majority of patients also showed improvement on the total Bayley score, which is a direct assessment of clinical functioning.

 In May 2022 and June 2022, the FDA and EMA, respectively, granted orphan drug designation to ION582. Additionally in July 2022 and May
 2022, the FDA granted Fast Track designation and rare pediatric designation to ION582, respectively.

 ION582 is being developed under our 2012 Neurology collaboration with Biogen.

 Tominersen (HTT) ( RG6042) – Tominersen (formerly IONIS-HTT Rx) is an
 investigational antisense medicine we designed to target the underlying cause of Huntington's disease, or HD, by reducing the production of all forms of the huntingtin protein, or HTT, including its mutated variant, or mHTT. HD is an inherited genetic
 brain disorder that results in the progressive loss of both mental faculties and physical control. It is caused by the expansion of the cytosine-adenine-guanine, or CAG, trinucleotide sequence in the HTT gene. The resulting mutant HTT protein is toxic and gradually destroys neurons. Symptoms usually appear between the ages of 30 and 50 and worsen over a 10 to 25-year period. Ultimately, the
 weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there is no effective treatment or cure for the disease, and currently available medicines only mask the patient's symptoms but do not slow down the underlying
 loss of neurons.

 In January 2023, Roche initiated the Phase 2, GENERATION HD2, study of tominersen in patients aged 25 to 50 years old with prodromal and
 early manifest HD. The Phase 2 study of tominersen is a multi-center, double-blind, placebo-controlled study in approximately 360 patients designed to assess the efficacy, safety and tolerability of tominersen. Patients will receive tominersen or
 placebo every 16 weeks for 16 months, after which patients may receive tominersen in an open-label study. The primary endpoint is the change from baseline in the composite Unified Huntington's Disease Ratings Scale, or cUHDRS, (non-U.S.) and overall
 functional capacity, or TFC, (U.S.) at 16 months.

 Roche conducted the Phase 3 study, GENERATION HD1, of tominersen in patients with HD. The Phase 3 study was a randomized, multicenter,
 double-blind, placebo-controlled study that recruited 791 participants. In March 2021, Roche announced that dosing would be stopped in the study following a recommendation from the independent data monitoring committee, or iDMC, based on an overall
 benefit/risk assessment. In January 2022, Roche announced findings from a post-hoc analysis of the GENERATION HD1 study that suggested tominersen may benefit younger adult patients with lower disease burden.

 In December 2015 and March 2015, the FDA and EMA, respectively, granted orphan drug designation to tominersen. Additionally in August
 2018, the EMA granted PRIME designation to tominersen.

 In December 2017, Roche exercised its option to license tominersen. As a result, Roche is responsible for global development, regulatory
 and commercialization activities, and costs for tominersen.

 Our Cardiovascular Medicines in Development

 Our cardiovascular franchise includes investigational medicines that target the major risk factors of CVD.

 Eplontersen – See the medicine

 Olezarsen – See the medicine

 Pelacarsen – See the medicine

 Fesomersen (FXI) – Fesomersen
 (formerly IONIS-FXI-L Rx) is an investigational LICA medicine we designed to inhibit the production of Factor XI. Factor XI is a clotting factor produced in the liver that is important in the growth of blood clots. Thrombosis, characterized
 by the formation of a blood clot inside blood vessels, can cause heart attacks and strokes. People who are deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk. Although currently available
 anticoagulants reduce the risk of thrombosis, physicians associate these anticoagulants with increased bleeding, which can be fatal. By inhibiting Factor XI production, we believe that fesomersen can be used for the treatment of a number of non-acute
 forms of thrombosis where additional safe and well tolerated anti-thrombotic medicines are needed.

 In November 2022, Bayer presented positive results from the RE-THINc Phase 2b study of fesomersen in patients with end-stage renal
 disease, or ESRD, on hemodialysis at the ASN Kidney Week. In the study, fesomersen achieved its primary endpoint, demonstrating no increase in the incidence of the composite of major bleeding and clinically relevant non-major bleeding with 24 weeks of
 treatment. Fesomersen also achieved dose-dependent and sustained median reductions in steady-state FXI levels of 53.1%, 72.2% and 86.6% in the 40 mg, 80 mg, and 120 mg doses of fesomersen, respectively, administered once every four weeks. Incidences of
 dialysis circuit clotting and arteriovenous access, or AV-access, thrombosis diminished significantly with decreasing FXI levels, both of which were exploratory efficacy endpoints. Fesomersen had a favorable safety and tolerability profile supportive
 of continued development.

 In November 2022, we regained all rights to fesomersen, which we had previously licensed to Bayer in February 2017.

 ION904 (AGT) – ION904 is an investigational next-generation LICA medicine designed to inhibit the production of angiotensinogen to decrease blood pressure in people
 with uncontrolled hypertension. ION904 is a follow-on medicine targeting AGT, designed to enable less frequent dosing compared to IONIS-AGT-L Rx.

 In November 2023 at the AHA annual meeting we presented
 positive results from the Phase 2 clinical study of ION904 in patients with mild to moderate uncontrolled hypertension on one or more anti-hypertensive medications for at least one month. ION904 significantly reduced AGT levels compared to placebo.
 ION904 had a favorable safety and tolerability profile supportive of continued development.

 Other Medicines for High Patient Need in Development

 We also have other medicines for high patient need in development that are outside of our cardiovascular and neurological franchises
 that we believe could represent compelling opportunities for us, including our Specialty Rare medicines, donidalorsen and sapablursen.

 1 Granted Otsuka exclusive rights to commercialize donidalorsen in Europe.

 Donidalorsen – See the medicine

 Sapablursen (TMPRSS6) –
 Sapablursen (formerly IONIS-TMPRSS6-L Rx) is an investigational LICA medicine we designed to target the TMPRSS6 gene to modulate the
 production of hepcidin, which is the key regulator of iron homeostasis. By modulating hepcidin expression, sapablursen has the potential to positively impact diseases characterized by iron deficiency, such as polycythemia vera, or PV.

 PV is a rare disease driven by a mutation in the JAK2 gene that is potentially fatal and characterized by overproduction of red blood cells. This overproduction leads to a thickening of the blood, which increases patients' risk of life-threatening blood clots, including
 in the lungs, heart and brain. Patients with PV also experience severe iron deficiency and symptoms such as fatigue and impaired cognitive function. There are no approved disease-modifying treatments for PV.

 In January 2022, we initiated a Phase 2 study evaluating sapablursen in patients with phlebotomy dependent PV, or PD-PV. The Phase 2
 study is a multi-center, randomized, open-label study in approximately 40 patients designed to assess the efficacy, safety and tolerability of sapablursen. The primary endpoint is the change in the frequency of phlebotomy comparing baseline with the
 last 20 weeks of the 37-week treatment period.

 In December 2018, we presented positive data from our Phase 1 study of sapablursen in healthy volunteers at the American Society of
 Hematology Annual Meeting. The Phase 1 study demonstrated dose-dependent reductions of serum iron and serum transferrin saturation with sapablursen. Additionally, we observed an increase in serum hepcidin and predicted changes in hemoglobin.
 Sapablursen had a favorable safety and tolerability profile supportive of continued development.

 In September 2020, the FDA granted Fast Track designation to sapablursen for polycythemia vera.

 Bepirovirsen – See the medicine description under "Our Phase 3 Pipeline " section above.

 IONIS-FB-L Rx (IgAN) – See the medicine
 description under "Our Phase 3 Pipeline " section above.

 ION224 (DGAT2) –
 ION224 is an investigational LICA medicine we designed to reduce the production of diacylglycerol acyltransferase 2, or DGAT2, to treat patients with nonalcoholic steatohepatitis, or NASH. NASH is a common liver disease characterized by liver
 steatosis, inflammation and scarring and can lead to increased risk of CVD, liver cancer, need for liver transplantation and early death. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production
 of DGAT2 should therefore decrease triglyceride synthesis in the liver. In animal studies, antisense inhibition of DGAT2 significantly improved liver steatosis, lowered blood lipid levels and reversed diet-induced insulin resistance.

 Nonalcoholic fatty liver disease, or NAFLD, describes the full spectrum of liver disease progression from fatty liver to NASH to
 cirrhosis to hepatocellular carcinoma. NASH epidemiology studies have estimated 13% to 32% of the global population has NAFLD, 1.5% to 6.5% have NASH, and up to 10% of NASH patients progress to advanced liver disease. There are currently no
 commercially available medications to treat NASH.

 NASH is sometimes considered a "silent" liver disease because people with early-stage NASH feel well, even though they are starting to
 accumulate fat in their livers and may not be aware that they have the disease. However, NASH can develop into more severe diseases such as liver cirrhosis and liver failure. Currently, liver transplant is the only therapeutic option for patients with
 liver cirrhosis. In addition, NASH has been shown to be a major risk factor for the development of liver cancer.

 In June 2021, we initiated a Phase 2 study of ION224 in patients with confirmed non-alcoholic steatohepatitis. The Phase 2 study is a multi-center, randomized, double-blind, placebo-controlled clinical study in approximately 160 patients designed to assess the efficacy, safety and tolerability of multiple subcutaneous doses of ION224 on NASH histologic improvement.

 IONIS-FB-L Rx – IONIS-FB-L Rx (RG6299) is an
 investigational LICA medicine we designed to inhibit the production of FB, and the alternative complement pathway. Genetic association studies have shown that overaction of the alternative complement pathway has been associated with the development
 of several complement-mediated diseases, including IgAN (see section above "Our Phase 3 Pipeline " for discussion of IgAN) and GA secondary to AMD.

 AMD is the leading cause of central vision loss in developed countries. GA is an advanced form of AMD.

 In June 2019, we initiated a Phase 2 GOLDEN study
 evaluating IONIS-FB-L Rx in patients with GA secondary to AMD. The study is a randomized, masked, placebo-controlled study in approximately 330 patients
 designed to assess the efficacy, safety and tolerability of multiple ascending doses of IONIS-FB-L Rx administered subcutaneously in adults with GA.
 The primary endpoint is the absolute change from baseline in GA area at week 49. In August 2023, we announced that the GOLDEN study had completed enrollment.

 In July 2022, Roche exercised its option to license IONIS-FB-L Rx following the positive Phase 2 results for IgAN. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L Rx, except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding.

 ION839 (PNPLA3) – ION839 (AZD2693) is an investigational LICA medicine we designed to inhibit the production of patatin-like phospholipase domain-containing 3, or PNPLA3, protein. PNPLA3 is a
 protein that is found on the surface of intracellular lipid droplets. Studies have shown that a common genetic mutation of PNPLA3 is strongly associated with an increased risk for NASH. The mutant PNPLA3 protein is resistant to degradation, causing
 it to accumulate on the surface of lipid droplets, which disrupts the normal process for degrading lipid droplets, leading to increased liver fat accumulation, the underlying pathology of NASH.

 In March 2023, AstraZeneca initiated a Phase 2b study of ION839 in patients with confirmed NASH with fibrosis and who are carriers of the PNPLA3 mutation. The Phase 2b study is a multi-center, randomized, double-blind, placebo-controlled clinical study in approximately 180 patients designed to assess the efficacy, safety and tolerability of multiple subcutaneous doses of
 ION839. The primary endpoint is the proportion of patients achieving NASH resolution without worsening of fibrosis based on histology after 52 weeks of treatment.

 In April 2018, AstraZeneca exercised its option to license ION839. As a result, AstraZeneca is responsible for global development, regulatory and commercialization activities, and costs for ION839.

 Our Technology

 For three decades through our innovations in science and technology, we have enhanced the profiles of RNA-targeted medicines and pursued
 new opportunities in emerging areas of genetic medicine. Our recent technology advancements have enabled us to advance programs with the potential
 for extended dosing and delivery to new tissues, such as muscle. We have also added capabilities to utilize RNA interference, or RNAi, and potentially gene editing in addition to our novel antisense technology, which gives us the potential to deliver
 medicines to a greater number of people living with serious diseases.

 Overview of Ionis' Technology

 All of the medicines currently in our clinical pipeline use our antisense technology — an innovative platform for discovering
 first-in-class and/or best-in-class medicines. Antisense medicines target RNA, the intermediary that conveys genetic information from a gene to the protein synthesis machinery in the cell. By targeting RNA instead of proteins, we can use antisense
 technology to increase, decrease or alter the production of specific proteins. Most of our antisense medicines are designed to bind to mRNAs and inhibit the production of disease-causing proteins. Examples of these include WAINUA, olezarsen and
 donidalorsen. SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein, which is critical to the health and survival of nerve cells in the spinal cord that are responsible for
 neuro-muscular function. The SMN protein is deficient in people with SMA. Our antisense technology is also broadly applicable to many additional antisense mechanisms including decreasing toxic RNAs.

 We also now use small interfering RNA (siRNA) technology, in addition to antisense technology, in the development of new medicines. Like
 antisense, siRNA medicines target RNA, and can decrease the production of specific proteins involved in disease. For each program we work on, we choose the approach which demonstrates the best potential product profile for the indication we are
 pursuing.

 Our advanced LICA technology is a chemical technology we developed that involves attaching a molecule called a ligand that binds with
 receptors on the surface of cells in a highly specific manner. Because these receptors are often found only on certain cell types, LICA allows us to increase effective delivery of our antisense medicines with higher specificity to certain cell types
 that express these receptors relative to non-conjugated antisense medicines. We currently have an integrated assessment of data from multiple LICA medicines and clinical programs which demonstrates that our LICA technology for liver targets can
 increase potency by 20-30-fold over our non-LICA antisense medicines. Our LICA medicines have also demonstrated consistently favorable safety and tolerability in clinical trials, including in our Phase 3 studies of WAINUA (for ATTRv-PN), olezarsen (for
 FCS patients) and donidalorsen (for HAE).

 Emerging Technology Advancements

 Our recent technology advancements have enabled us to

 create even more potent medicines amenable to more potential targets and tissue types. We have also diversified the approaches we can use in designing our medicines in order
 to reach more patients with severe diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including our Bicycle LICA technology, siRNA technology and MsPA backbone chemistry. And through our Metagenomi collaboration, we added the potential to use gene editing, which modifies DNA.

 Mesyl phosphoramidate Backbone Chemistry

 We designed our MsPA backbone chemistry to improve both therapeutic index and durability. It does this by increasing metabolic stability
 relative to the other backbone chemistries we utilize. We have also shown it can improve potency in certain circumstances and reduce non-specific interactions with proteins that can cause undesirable effects, such as proinflammatory effects. We
 currently have multiple new programs using our MsPA backbone, designed to improve both efficacy and durability, in preclinical development.

 Bicycle Collaboration

 In 2021, we entered into a collaboration with Bicycle Therapeutics that we expect can expand our LICA platform to target both skeletal
 and cardiac muscle, and potentially deliver medicines across the blood brain barrier. Bicycles are small, bicyclic peptides that have high affinity and selectivity for protein targets. Our collaboration with Bicycle allows us to utilize Bicycles that
 bind transferrin receptor 1 to facilitate the tissue specific delivery of oligonucleotide drugs (both antisense and siRNAs). We advanced our first Bicycle LICA program into preclinical development in 2023.

 Gene Editing and Metagenomi Collaboration

 In 2022, we entered into a collaboration with Metagenomi that leverages our extensive expertise in RNA-targeted therapeutics and
 Metagenomi's versatile next-generation gene editing systems to pursue a mix of validated and novel genetic targets with the goal of discovering and developing new drugs. These targets have the potential to expand therapeutic options for patients.

 Gene editing utilizes specific RNA-guided nucleases known as Cas enzymes to precisely and permanently modify a DNA sequence. Because of
 this, gene editing holds the promise of treatments that could provide long-term, potentially permanent, therapeutic benefits.

 Gene editing is highly complementary and synergistic with RNA-targeted therapeutics. Both platforms rely on the same nucleic acid
 hybridization principals to precisely target nucleases to either RNA, in the case of RNase H and siRNA drugs, or to DNA in the case of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems. This enables us to leverage our
 expertise in nucleic acids and modified nucleic acid chemistry with the goal to enhance gene editing's ability to treat diseases for which there are limited treatment options.

 Collaborative Arrangements

 We have established alliances with a cadre of leading global pharmaceutical companies. Our partners include the following companies,
 among others: AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone
 payments. In addition, we are eligible to receive royalties under our partnerships. Below, we include the significant terms of our collaboration agreements. For additional details, including other financial information, refer to Part IV, Item 15,
 Note 4, Collaborative Arrangements and Licensing Agreements, in the Notes to the Consolidated Financial Statements.

 Strategic Partnership

 Biogen

 We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological
 disorders. These collaborations combine our expertise in creating antisense medicines with Biogen's expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with
 SMA. In April 2023, the FDA granted accelerated approval for QALSODY (tofersen) in the U.S. to treat patients with SOD1-ALS. Biogen developed QALSODY under our 2013 strategic neurology collaboration. In addition, we and Biogen are currently developing
 numerous other investigational medicines to treat neurodegenerative diseases, including medicines in development to treat people with ALS, SMA, AS, AD, and PD. From inception through December 31, 2023, we have generated more than $3.8 billion in payments from our Biogen collaborations.

 Spinal Muscular Atrophy Collaborations

 In 2012, we entered into a collaboration agreement with
 Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. We are receiving tiered royalties ranging from 11 percent to 15
 percent on sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single
 digit royalty on net sales of SPINRAZA. Under our agreement, Biogen is responsible for global development, regulatory and commercialization activities and costs for SPINRAZA. From inception through December 31, 2023, we recognized more than $2.0 billion in total revenue under our SPINRAZA
 collaboration, including more than $1.6 billion in revenue from SPINRAZA royalties and more than $425 million in R&D revenue.

 New antisense medicines for the treatment of SMA

 In 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of SMA. Biogen has
 the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization activities and costs for such
 therapies.

 In 2021, Biogen exercised its option to license ION306. Biogen

 is solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We will receive development and regulatory milestone payments from
 Biogen if new medicines, including ION306, advance towards marketing approval.

 Over the term of this collaboration, we are eligible to receive development, regulatory and sales milestone payments. In addition, we are
 eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2023, we have generated $85 million in payments under this collaboration.

 Neurology Collaborations

 2018 Strategic Neurology

 In 2018, we and Biogen entered into a strategic collaboration to develop novel antisense medicines for a broad range of neurological
 diseases. We also entered into a Stock Purchase Agreement, or SPA. As a result, we received a payment related to the SPA in addition to an upfront payment at the commencement of this collaboration. As part of the collaboration, Biogen gained exclusive
 rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible for the identification of antisense drug candidates based on selected targets. In most cases, Biogen will be responsible for
 conducting IND-enabling toxicology studies for the selected medicine. Biogen has the option to license the selected medicine after it completes the IND-enabling toxicology study. If Biogen exercises its option to license a medicine, it will assume
 global development, regulatory and commercialization responsibilities and costs for that medicine.

 For each medicine under this collaboration, we are eligible to receive a license fee, development milestone payments and regulatory
 milestone payments. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. We are currently advancing multiple programs under
 this collaboration. From inception through December 31, 2023, we have generated nearly $1.1 billion in payments under this collaboration.

 2013 Strategic Neurology

 In 2013, we and Biogen entered into a strategic relationship focused on applying antisense technology to advance the treatment of
 neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. In
 most cases, we are responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In 2016, we expanded our collaboration to include additional
 research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

 We are currently advancing four investigational medicines in development under this collaboration, including a medicine for Parkinson's
 disease (ION859), two medicines for ALS (QALSODY and ION541) and a medicine for multiple system atrophy (ION464). In 2018, Biogen exercised its option to license QALSODY, our medicine that received accelerated approval in April 2023 from the FDA for
 the treatment of adult patients with SOD1-ALS. As a result, Biogen is responsible for global development, regulatory and commercialization activities and costs for QALSODY.

 Under the terms of the agreement, we are eligible to receive milestone payments, license fees and royalty payments for all medicines
 developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen.

 Over the term of the collaboration for QALSODY, we are eligible to receive a license fee, development milestone payments and regulatory
 milestone payments. In addition, we are eligible to receive tiered royalties ranging from 11 percent to 15 percent on net sales of QALSODY.

 For each of the other antisense molecules that are chosen for drug discovery and development under this collaboration, we are eligible to
 receive a license fee, development milestone payments and regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that Biogen successfully commercializes under this
 collaboration. From inception through December 31, 2023, we have generated more than $325 million in payments under our 2013 strategic
 neurology collaboration.

 2012 Neurology

 In 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to treat
 neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through
 the completion of the first Phase 2 study for each program. Under this collaboration, Biogen is conducting the IONIS-MAPT Rx study for AD and we are currently advancing ION582 for AS. If Biogen exercises its option to license a medicine, it
 will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In 2019, Biogen exercised its option to license IONIS-MAPT Rx and as a result Biogen is responsible for global development,
 regulatory and commercialization activities and costs for IONIS-MAPT Rx.

 For each program under this collaboration, we are eligible to receive a license fee, development milestone payments and regulatory
 milestone payments, plus a mark-up on the costs of the Phase 1 and 2 studies. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that Biogen successfully commercializes under this collaboration.
 From inception through December 31, 2023, we have generated more than $230 million in payments under this collaboration.

 Joint Development and Commercialization Arrangement

 WAINUA (Eplontersen) Collaboration

 In 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for
 the treatment of ATTR. In December 2023, the FDA approved eplontersen with the brand name, WAINUA, in the U.S. for ATTRv-PN. We are jointly developing and commercializing WAINUA with AstraZeneca in the U.S. We initially granted AstraZeneca exclusive
 rights to commercialize WAINUA outside the U.S., except for certain Latin American countries. In July 2023, we expanded those rights to include Latin America.

 The collaboration includes territory-specific development, commercial and medical affairs cost-sharing provisions. AstraZeneca is
 currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing
 WAINUA to market outside the U.S.

 Over the term of the collaboration, we are eligible to receive an upfront payment, license fee, development and approval milestone
 payments and sales milestone payments. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties ranging from mid to high teens for sales outside the U.S. From inception through December 31, 2023, we have generated more than $425 million in payments under this collaboration, including a milestone payment for the approval of WAINUA
 in the U.S. and revenue we earned from cost sharing provisions.

 Research and Development Partners

 In addition to our collaboration for WAINUA, we have a collaboration with AstraZeneca focused on discovering and developing treatments for
 cardiovascular, renal and metabolic diseases, which we formed in 2015. Under our collaboration, AstraZeneca has licensed multiple medicines from us. AstraZeneca is responsible for global development, regulatory and commercialization activities and
 costs for each of the medicines it has licensed from us.

 Over the term of the collaboration, we are eligible to receive an upfront payment, license fees, development milestone payments and
 regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 31, 2023, we have generated more than $340 million in payments under this collaboration.

 GSK

 In 2010, we entered into a collaboration with GSK using our antisense drug discovery platform to discover and develop new medicines
 against targets for serious and rare diseases, including infectious diseases. Under our collaboration, GSK is developing bepirovirsen for the treatment of chronic HBV infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program.
 GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.

 Over the term of the collaboration, we are eligible to receive an upfront payment, a license fee, development milestone payments,
 regulatory milestone payments and sales milestone payments if GSK successfully develops and commercializes bepirovirsen. In addition, we are eligible to receive tiered royalties up to the low-teens on net sales of bepirovirsen. From inception through December 31, 2023, we have generated more than $105 million in payments under the HBV program collaboration.

 Pelacarsen Collaboration

 In 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen. Novartis is responsible for conducting and
 funding development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study that Novartis initiated in 2019.

 Over the term of the collaboration, we are eligible to
 receive an upfront payment, a license fee, a development milestone payment, regulatory milestone payments and sales milestone payments. We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of
 pelacarsen. From inception through December 31, 2023, w e
 have generated more than $275 million in payments under this collaboration.

 New Medicine for the Treatment of Lp(a)-Driven Cardiovascular Disease

 In August 2023, we entered into a collaboration and license agreement with Novartis for the discovery, development and commercialization
 of a novel medicine for patients with Lp(a)-driven cardiovascular disease, or CVD. Novartis is solely responsible for the development, manufacturing and potential commercialization of the next generation Lp(a) therapy.

 Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments, regulatory milestone
 payments and sales milestone payments. In addition, we are eligible to receive tiered royalties ranging from 10 percent to 20 percent on net sales. From inception through December 31, 2023, we have generated $60 million in payments under this collaboration.

 Roche

 Huntington's Disease

 In 2013, we entered into an agreement with Hoffmann-La Roche Inc and F. Hoffmann-La Roche Ltd, collectively Roche, to develop treatments
 for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in people with
 early-stage HD. In 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. As a result, Roche is responsible for all global development, regulatory and commercialization activities and costs for tominersen.

 Over the term of the collaboration, we are eligible to receive a license fee, development milestone payments, regulatory milestone
 payments and sales milestone payments as tominersen advances. In addition, we are eligible to receive milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on net
 sales of any product resulting from this collaboration. From inception through December 31, 2023, we have generated more than $150 million
 in payments under this collaboration.

 IONIS-FB-L Rx for Complement-Mediated Diseases

 In 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-L Rx for the treatment of complement-mediated
 diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-L Rx, one for the treatment of patients with IgAN and one for the treatment of patients with GA, the advanced stage of dry AMD. In April 2023, Roche
 initiated a Phase 3 study of IONIS-FB-L Rx in patients with IgAN.

 After positive data from a Phase 2 clinical study in patients with IgAN, Roche licensed IONIS-FB-L Rx in 2022. As a result,
 Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L Rx, except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we
 are conducting and funding.

 Over the term of the collaboration, we are eligible to receive an upfront payment, a license fee, development milestone payments,
 regulatory milestone payments and sales milestone payments. In addition, we are also eligible to receive tiered royalties from the high teens to 20 percent on net sales. From inception through December 31, 2023, we have generated more than $135 million in payments under this collaboration.

 RNA-Targeting Medicines for Alzheimer's Disease and Huntington's Disease

 In September 2023, we entered into an agreement with Roche to develop two undisclosed early-stage programs for RNA-targeting
 investigational medicines for the treatment of AD and HD. Under the agreement, we are responsible for advancing the two programs through preclinical studies and Roche is responsible for clinical development, manufacturing and commercialization of the
 medicines if they receive regulatory approval.

 Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments and sales milestone
 payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through December 31, 2023,
 we have generated $60 million in payments under this collaboration.

 Commercialization Partnerships

 Otsuka

 In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize donidalorsen in Europe.
 We are responsible for the ongoing development of donidalorsen. We retained the rights to commercialize donidalorsen in the U.S. and in the rest of the world assuming regulatory approval.

 Over the term of the collaboration, we are eligible to receive an upfront payment, regulatory milestone payments and sales milestone
 payments. In addition, we are eligible to receive tiered royalties ranging from 20 percent to 30 percent on net sales of donidalorsen in Europe. From inception through December 31, 2023, we have generated $65 million in payments under this collaboration.

 PTC Therapeutics

 In August 2018, we entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin
 America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-20 percent range on net sales for each medicine. In December 2021 and September 2023, we started receiving royalties from PTC
 for TEGSEDI and WAYLIVRA sales, respectively.

 Swedish Orphan Biovitrum AB (Sobi)

 We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through distribution
 agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from Sobi for each
 medicine. Refer to the section titled, Overview, for further details on our distribution agreement with Sobi.

 Technology Enhancement Collaborations

 Bicycle Therapeutics

 In 2020, we entered into a collaboration agreement with Bicycle Therapeutics, or Bicycle, and obtained an option to license its peptide
 technology to potentially increase the delivery capabilities of our LICA medicines. In 2021, we exercised our option to license Bicycle's technology. Our payment to Bicycle for licensing its technology included an equity investment in Bicycle.

 Metagenomi

 In 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize investigational
 medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four additional genetic targets using gene editing technologies. As a result, we paid Metagenomi to license its technologies and will pay
 Metagenomi certain fees for the selection of genetic targets. In addition, we will pay Metagenomi milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events. We will also reimburse
 Metagenomi for certain of its costs in conducting its research and drug discovery activities under the collaboration.

 Vect-Horus

 In December 2023, we entered into a license agreement with Vect-Horus to provide us with worldwide, exclusive license for a specified
 number of targets using Vect-Horus' platform technology "VECTrans" for systemic delivery of RNA-targeted therapeutics that can cross the blood-brain barrier and address targets in the central nervous system. As a result, we paid Vect-Horus to license
 its technologies. In addition, we will pay Vect-Horus milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events.

 Other Agreements

 Alnylam Pharmaceuticals, Inc.

 Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate relating to
 antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alnylam gave us a
 technology access fee, participation in fees from Alnylam's partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited
 number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide
 chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi therapeutics
 targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained exclusive
 license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including FXI and
 Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam also
 granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new platform
 technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.

 Manufacturing

 We manufacture most of the active pharmaceutical ingredient, or API, we use for our research and development, or R&D, activities
 ourselves. We have also manufactured API and commercial supply for our approved medicines. We have dedicated significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use variants of the same nucleotide
 building blocks and the same type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our other
 medicines. By developing several proprietary chemical processes to scale up our manufacturing capabilities, we have greatly reduced the cost of producing oligonucleotide medicines. For example, we have significantly reduced the cost of raw materials
 through improved yield efficiency, while at the same time increasing our capacity to make our medicines. Through both our internal research and development programs and collaborations with outside vendors, we may achieve even greater efficiency and
 further cost reductions.

 Our manufacturing facility is located in a 26,800 square foot building in Carlsbad, California. We purchased this building in 2017. In
 addition, we have a 25,800 square foot building that houses support functions for our manufacturing activities. We lease this facility under a lease that has a term ending in August 2026 with an option to extend the lease for an additional five-year
 period. Our manufacturing facility is subject to periodic inspections by the FDA and foreign equivalents to ensure that it is operating in compliance with current Good Manufacturing Practices, or cGMP, requirements.

 As part of our collaborations, we may agree to manufacture clinical trial material and/or commercial drug supply for our partners. For
 example, in the past we have manufactured clinical trial material for AstraZeneca, Biogen, GSK and Novartis and commercial drug supply for Biogen.

 We believe we have sufficient manufacturing capacity at our own facility or at contract manufacturing organizations, or CMOs, to meet our
 current internal research, development and potential commercial needs, as well as our obligations under existing agreements with our partners for research, development and commercial material. We and/or our CMOs manufacture process performance
 qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory submissions and, pending regulatory approval, commercial sale. We believe our current network of CMOs are capable of providing sufficient
 quantities to meet anticipated commercial demands. Additionally, we continue to evaluate relationships with additional suppliers to increase overall capacity and diversify our supply chain. While we believe that there are alternate sources of supply
 that can satisfy our commercial requirements, it is possible that identifying and establishing relationships with such sources, if necessary, could result in significant delay or material additional costs. We also could experience a disruption in
 supply from our current CMOs.

 CMOs are subject to the FDA's cGMP requirements and other rules and regulations prescribed by foreign regulatory authorities. We depend on
 our CMOs for continued compliance with cGMP requirements and applicable foreign standards.

 Specifically, we have the following in place for our commercial medicines and our medicines in Phase 3 development.

 Biogen is responsible for SPINRAZA drug supply.

 QALSODY

 Biogen is responsible for QALSODY drug supply.

 WAINUA

 AstraZeneca is responsible for WAINUA's commercial drug supply. Our CMOs supplied the API and the finished drug product for WAINUA's Phase
 3 program. Pursuant to our collaboration with AstraZeneca, we will manufacture and supply WAINUA using CMOs for the ongoing clinical trials, process performance qualification batches and pre-approval inspection batches.

 TEGSEDI and WAYLIVRA

 For TEGSEDI's commercial drug supply, we are using CMOs to produce API and finished goods. For WAYLIVRA's commercial drug supply, we are
 using API that we have manufactured and CMOs to produce the finished goods.

 Olezarsen, Donidalorsen, Zilganersen, Ulefnersen

 We and/or our CMOs have supplied the API and the finished
 drug product for olezarsen, donidalorsen, zilganersen and ulefnersen that we believe will be sufficient through the completion of the Phase 3 programs for each
 medicine, including process performance qualification batches and pre-approval inspection batches. We plan to leverage our relationships with CMOs to maintain long-term supply at competitive prices in the future.

 Pelacarsen

 We supplied API and finished drug product for pelacarsen's Phase 3 program. Pursuant to our collaboration with Novartis, Novartis is
 responsible for any further pelacarsen drug supply.

 Bepirovirsen

 We supplied API for bepirovirsen's Phase 1 and Phase 2 programs. Pursuant to our collaboration with GSK, GSK is responsible for any
 further bepirovirsen drug supply.

 IONIS-FB-L Rx

 We supplied API for the IONIS-FB-L Rx Phase 1 and Phase 2 IgAN programs. Pursuant to our collaboration with Roche, Roche is
 responsible for any further drug supply for the IONIS-FB-L Rx program.

 Commercial Operations

 We have established sales and marketing capabilities to support our commercial launch of WAINUA in the U.S. and anticipated near-term
 commercial launches of olezarsen and donidalorsen. We began with our co-commercialization partnership with AstraZeneca for WAINUA in which we combine our experience in RNA-targeted therapeutics and deep knowledge of the TTR amyloidosis market with
 AstraZeneca's global scale in drug development and commercialization to enable market penetration for the benefit of patients.

 As we approach our first potential independent commercial launches of olezarsen and donidalorsen in the U.S., we have been refining our
 portfolio strategy and recruiting experienced professionals with relevant backgrounds in sales, marketing, patient education, market access, portfolio planning and market insight, new product commercial strategy and commercial operations in the
 pharmaceutical industry. We are focused on developing a unique and innovative approach to bring our medicines to patients living with serious diseases. We have built core capabilities and a commercial platform with the ability to scale as needed to
 meet our current and future commercialization needs. We plan to build our field sales teams as we approach each of our launches.

 In addition, we recently entered into a European licensing agreement with Otsuka for donidalorsen in HAE in which we will leverage
 Otsuka's strong commercial infrastructure and rare disease experience to reach European HAE patients.

 Medical Affairs

 We have built medical affairs capabilities to disseminate information about our medicines and increase disease awareness through various
 channels of communication with key stakeholders. Our medical affairs function is responsible for funding and coordinating investigator-sponsored trials, communicating scientific and clinical information to healthcare providers, medical professionals
 and patients, and managing publications.

 Intellectual Proprietary Rights

 We rely on patents, trademarks, trade secrets, and proprietary know-how to develop and maintain a competitive position in RNA-targeted
 therapeutics generally and to protect our investment in specific products. To this end, we focus our resources on intellectual property, or IP, that drives value for our company.

 Product-Specific IP

 Each of our medicines is protected worldwide by product-specific patents claiming oligonucleotides having the nucleobase sequences and
 chemical modifications of our medicines; and methods of achieving cellular or clinical endpoints using such oligonucleotides. We pursue such patents in significant markets and/or countries for each medicine in development. We also seek to maximize
 patent term. In some cases, the patent term can be extended to recapture a portion of the term lost during regulatory review. Expiration dates listed below do not reflect any such extensions.

 Commercial products are also protected by trademarks filed throughout the world.

 Marketed Products

 SPINRAZA and Survival Motor Neuron 2

 We believe SPINRAZA (nusinersen) is protected from generic competition in the U.S. until at least 2035 and in Europe until at least 2030
 by a suite of patents. These issued patents include: (i) patents licensed from the University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification, and uses of such compounds for treating
 SMA, (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2'-MOE compounds targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions; and (iii) dosing and therapeutic methods
 of using such compounds and compositions. With Biogen's license of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe:

 Title

 10,266,822

 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES

 2025

 Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA

 8,110,560

 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES

 2025

 Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA

 1910395

 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING

 2026

 Sequence and chemistry (full 2'-MOE) of SPINRAZA

 3308788

 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING

 2026

 Pharmaceutical compositions that include SPINRAZA

 7,838,657

 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES

 2027

 Oligonucleotides having sequence of SPINRAZA

 8,361,977

 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING

 2030

 Sequence and chemistry (full 2'-MOE) of SPINRAZA

 8,980,853

 2030

 Methods of administering SPINRAZA

 9,717,750

 2030

 Methods of administering SPINRAZA to a patient

 3449926

 2030

 Pharmaceutical compositions that include SPINRAZA for treating SMA

 3305302

 2030

 Antisense compounds including SPINRAZA for treating SMA

 9,926,559

 2034

 SPINRAZA doses for treating SMA

 10,436,802

 METHODS FOR TREATING SPINAL MUSCULAR ATROPHY

 2035

 SPINRAZA dosing regimen for treating SMA

 Trademarks

 The name "SPINRAZA" is protected throughout the world by trademarks owned by our commercial partner Biogen. Particulars for the United
 States and European marks are listed below:

 Registration No.

 Mark

 5156572

 _

 013388145

 014812291 and 015309941

 (design mark)

 QALSODY and SOD-1

 We believe QALSODY is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent applications
 designed to protect QALSODY in other foreign jurisdictions are being pursued. With Biogen's license of QALSODY, we assigned our interest in these patents to Biogen. The table
 below lists some key issued patents protecting QALSODY in the U.S. and Europe:

 Title

 10,385,341

 COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION

 2035

 Composition of QALSODY

 10,669,546

 COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION

 2035

 Methods of treating a SOD-1 associated neurodegenerative disorder by administering QALSODY

 10,968,453

 COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION

 2035

 Methods of treating a SOD-1 associated neurodegenerative disorder by administering a pharmaceutical composition of QALSODY

 3126499

 COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION

 2035

 Composition of QALSODY

 Trademarks

 The name "QALSODY" is protected throughout the world by trademarks owned by our commercial partner Biogen. Particulars for the United
 States and European marks are listed below:

 Registration No.

 Mark

 7164425

 QALSODY

 _

 7116182

 (design mark)

 1542485

 QALSODY

 018517819

 (design mark)

 WAINUA and
 Transthyretin

 We believe WAINUA (eplontersen) is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent
 applications to protect WAINUA in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting WAINUA in the U.S. and Europe:

 Title

 10,683,499

 COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION

 2034

 Composition of eplontersen

 3524680

 COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION

 2034

 Composition of eplontersen

 Trademarks

 The name "WAINUA" is protected by trademarks owned by our commercial partner Astra Zeneca. Particulars for the United States marks are
 listed below:

 Application No.

 Mark

 98054331

 WAINUA

 _

 98228658

 (design mark)

 TEGSEDI and Transthyretin

 We believe TEGSEDI (inotersen) is protected from generic competition in the U.S. and Europe until at least 2031. The table below lists
 some key issued patents protecting TEGSEDI in the U.S. and Europe:

 Title

 8,101,743

 MODULATION OF TRANSTHYRETIN EXPRESSION

 2025

 Antisense sequence and chemistry of TEGSEDI

 8,697,860

 DIAGNOSIS AND TREATMENT OF DISEASE

 2031

 Composition of TEGSEDI

 9,061,044

 MODULATION OF TRANSTHYRETIN EXPRESSION

 2031

 Sodium salt composition of TEGSEDI

 9,399,774

 MODULATION OF TRANSTHYRETIN EXPRESSION

 2031

 Methods of treating transthyretin amyloidosis by administering TEGSEDI

 2563920

 MODULATION OF TRANSTHYRETIN EXPRESSION

 2031

 Composition of TEGSEDI

 Trademarks

 The name "TEGSEDI" is protected by trademark throughout the world. Particulars for the United States and European marks are listed below:

 Registration No.

 Mark

 5740635

 TEGSEDI

 _

 017224742

 TEGSEDI

 WAYLIVRA and Apolipoprotein C-III

 We believe WAYLIVRA (volanesorsen) is protected from generic competition in Europe until at least 2034. We have obtained patent claims in
 the U.S. and Europe drawn to the use of antisense compounds complementary to a broad active region of human apoC-III, including the site targeted by WAYLIVRA. We have also obtained issued patents claiming the specific sequence and chemical composition
 of WAYLIVRA in the U.S. and Europe. The table below lists some key issued patents protecting WAYLIVRA in the U.S. and Europe:

 Title

 1622597

 MODULATION OF APOLIPOPROTEIN C-III EXPRESSION

 2024

 Antisense sequence and chemistry of WAYLIVRA

 2441449

 MODULATION OF APOLIPOPROTEIN C-III EXPRESSION

 2024

 Antisense compounds that hybridize within the nucleotide region of apo-CIII targeted by WAYLIVRA

 3002007

 MODULATION OF APOLIPOPROTEIN C-III EXPRESSION

 2024

 Antisense compounds complementary to an apo-CIII nucleic acid for use in therapy

 9,157,082

 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION

 2032

 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL

 9,593,333

 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS

 2034

 Methods of treating lipoprotein lipase deficiency with an apo-CIII specific inhibitor wherein triglyceride levels are reduced

 2956176

 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS

 2034

 Apo-CIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or FCS

 Trademark

 The name "WAYLIVRA" is protected by trademark in Europe. Particulars for the European mark are listed below:

 Registration No.

 Mark

 016409609

 WAYLIVRA

 Phase 3 Programs

 Olezarsen and ApoC-III

 We believe olezarsen is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent applications to
 protect olezarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting olezarsen in the U.S. and Europe.

 Title

 9,163,239

 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION

 2034

 Composition of olezarsen

 2991656

 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION

 2034

 Composition of olezarsen

 Donidalorsen and PKK

 We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent applications
 to protect donidalorsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting donidalorsen in the U.S. and Europe.

 Title

 9,315,811

 METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION

 2032

 Methods of treating HAE

 2717923

 METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION

 2032

 Compounds for use in treating an inflammatory condition, including HAE

 10,294,477

 COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION

 2035

 Composition of donidalorsen

 3137091

 COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION

 2035

 Composition of donidalorsen

 Zilganersen and GFAP

 We believe zilganersen is protected from generic competition
 in the U.S. until at least 2041. A patent application designed to protect zilganersen from generic competition is being pursued in Europe; a patent issuing
 from that application would have term until at least 2041. The table below lists a key issued patent protecting zilganersen in the U.S. and a pending application in Europe:

 (Patent Application No.)

 Title

 11,786,546

 COMPOUNDS AND METHODS FOR MODULATING GFAP

 2041

 Composition of zilganersen

 (20846055.0)

 COMPOUNDS AND METHODS FOR MODULATING GFAP

 2041

 Composition of zilganersen

 Ulefnersen and FUS

 Patent applications designed to protect ulefnersen from generic competition are being pursued in the U.S. and Europe. Patents issued from
 these applications would have terms until at least 2040. The table below lists some key pending patent applications designed to protect ulefnersen in the U.S. and
 Europe:

 Patent Application No.

 Title

 17/613,183

 COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION

 2040

 Composition of ulefnersen

 20815459.1

 COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION

 2040

 Composition of ulefnersen

 Pelacarsen and Apo(a)

 We believe pelacarsen is protected from generic competition
 in the U.S. and Europe until at least 2034. Additional patent protection designed to protect pelacarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting pelacarsen in the U.S. and Europe:

 Title

 9,574,193

 METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION

 2033

 Methods of lowering Apo(a) and/or Lp(a) levels with an oligonucleotide
 complementary within the nucleotide region of Apo(a) targeted by p elacarsen

 10,478,448

 METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION

 2033

 Methods of treating hyperlipidemia with an oligonucleotide complementary
 within the nucleotide region of Apo(a) targeted by p elacarsen

 9,884,072

 METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION

 2033

 Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen

 2855500

 METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION

 2033

 Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen for decreasing Apo(a) expression

 9,181,550

 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION

 2034

 Composition of p elacarsen

 2992009

 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION

 2034

 Composition of pelacarsen

 Bepirovirsen and Hepatitis B Virus

 We believe bepirovirsen is protected from generic competition
 in the U.S. and Europe until at least 2032. Additional patent protection designed to protect bepirovirsen in other foreign jurisdictions are being pursued. With GSK's license of bepirovirsen, we assigned our interest in these patents to GSK. The
 table below lists some key issued patents protecting bepirovirsen in the U.S. and Europe:

 Title

 8,642,752

 MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION

 2032

 Composition of bepirovirsen

 3505528

 MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION

 2032

 Composition of bepirovirsen

 IONIS-FB-L Rx and Factor B

 We believe IONIS-FB-L Rx is protected from generic
 competition in the U.S. and Europe until at least 2035. Additional patent protection designed to protect IONIS-FB-L Rx in other foreign jurisdictions are
 being pursued. The table below lists some key issued patents protecting IONIS-FB-L Rx in the U.S. and Europe:

 Title

 3043827

 MODULATORS OF COMPLEMENT FACTOR B

 2034

 Compound comprising the antisense oligonucleotide portion of IONIS-FB-L Rx.

 10,280,423

 COMPOSITIONS AND METHODS FOR MODULATING COMPLEMENT FACTOR B EXPRESSION

 2035

 Composition of IONIS-FB-L Rx.

 3137596

 COMPOSITIONS AND METHODS FOR MODULATING COMPLEMENT FACTOR B EXPRESSION

 2035

 Composition of IONIS-FB-L Rx.

 Platform IP

 In addition to the IP that provides exclusivity for specific products, we also pursue IP that provides exclusivity for our core technology
 in the field of oligonucleotides and RNA-targeting therapeutics more generally. Our core technology patents include claims to chemically modified oligonucleotides as well as designs utilizing these chemical modifications. Because these core claims are
 independent of specific therapeutic target, nucleic acid sequence, or clinical indication, they may reach several products.

 Chemically Modified Nucleosides and Oligonucleotides

 The most broadly applicable of our patents are those that claim modified nucleosides and oligonucleotides comprising the modified
 nucleosides that we incorporate into our medicines to increase their therapeutic efficacy. The following are some of our patents in this category in the U.S. and Europe:

 Title

 7,399,845

 2027

 cEt nucleosides and oligonucleotides containing these nucleoside analogs

 7,741,457

 2027

 cEt nucleosides and oligonucleotides containing these nucleoside analogs

 8,022,193

 2027

 Oligonucleotides containing cEt nucleoside analogs

 1984381

 2027

 cEt nucleosides and oligonucleotides containing these nucleoside analogs

 2314594

 2027

 Oligonucleotides containing cEt nucleoside analogs and methods of use

 7,569,686

 COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS

 2027

 Methods of synthesizing cEt nucleosides

 2092065

 2027

 Gapmer oligonucleotides having 2'-modifed and LNA nucleosides

 2410053

 2027

 Gapmer oligonucleotides having wings comprised of 2'-MOE and bicyclic nucleosides

 2410054

 2027

 Gapmer oligonucleotides having a 2'-modifed nucleoside in the 5'-wing and a bicyclic nucleoside in the 3'-wing

 9,550,988

 2028

 Gapmer oligonucleotides having BNA nucleosides and 2'-MOE nucleosides

 10,493,092

 2028

 Gapmer oligonucleotides having BNA nucleosides and 2'-MOE nucleosides and/or 2'-OMe nucleosides

 3067421

 OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF

 2032

 Gapmer oligonucleotides having at least one bicyclic, one 2'-modified nucleoside and one 2'-deoxynucleoside

 11,629,348

 LINKAGE MODIFIED OLIGONUCLEOTIDES AND USES THEREOF

 2040

 Gapmer oligonucleotides having 2-4 mesyl phosphoramidate internucleoside linkages at specified positions in the gap

 LIgand-Conjugated Antisense (LICA) Technology

 We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve
 a drug's properties. We designed our GalNAc LICA medicines to provide an increase in potency for targets in the liver. We have successfully obtained issued patent claims covering our LICA technology conjugated to any modified oligonucleotide, including
 gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides. The following patents are some examples of our issued patents in this category:

 Title

 9,127,276

 CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE

 2034

 Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides

 9,181,549

 CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE

 2034

 Preferred THA conjugate having our preferred linker and cleavable moiety conjugated to any oligomeric compound or any nucleoside having a 2'-MOE
 modification or a cEt modification

 2991661

 CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE

 2034

 Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides

 Manufacturing

 We also own patents claiming methods of manufacturing and purifying oligonucleotides and related compounds. These patents claim methods
 for improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide synthesis and purification.

 Government Regulation

 Regulation by government authorities in the U.S. and other countries is a significant component in the development, manufacture and
 commercialization of pharmaceutical products and services. In addition to regulations enforced by the FDA and relevant foreign regulatory authorities, we are also subject to regulation under the Occupational Safety and Health Act, the Environmental
 Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential future federal, state and local regulations.

 Extensive regulation by the U.S. and foreign governmental authorities governs the development, manufacture and sale of our medicines. In
 particular, our medicines are subject to a number of approval requirements by the FDA in the U.S. under the Federal Food, Drug and Cosmetic Act, or FDCA, and other laws and by comparable agencies in those foreign countries in which we conduct business.
 The FDCA and other various federal, state and foreign statutes govern or influence the research, testing, manufacture, safety, labeling, storage, recordkeeping, approval, promotion, marketing, distribution, post-approval monitoring and reporting,
 sampling, quality, and import and export of our medicines. State, local, and other authorities also regulate pharmaceutical manufacturing facilities and procedures.

 Our manufacturing facility and our CMOs are subject to periodic inspection by the FDA and other foreign equivalents to ensure that they
 are operating in compliance with cGMP requirements. In addition, marketing authorization for each new medicine may require a rigorous manufacturing pre-approval inspection by regulatory authorities. Post approval, there are strict regulations regarding
 changes to the manufacturing process, and, depending on the significance of the change, changes may require prior FDA approval. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation
 requirements upon us and any third-party manufacturers that we may decide to use.

 The FDA must approve any new medicine before a manufacturer can market it in the U.S. In order to obtain approval, we and our partners
 must complete clinical studies and prepare and submit an NDA to the FDA. If the FDA approves a medicine, it will issue an approval letter authorizing commercial marketing of the medicine and may require a risk evaluation and mitigation strategy, or
 REMS, to help ensure the benefits of the medicine outweigh the potential risks. The requirements for REMS can materially affect the potential market and profitability of our medicines. In foreign jurisdictions, the drug approval process is similarly
 demanding.

 Pricing and Reimbursement

 For any approved medicine, domestic and foreign sales of the medicine depend, in part, on the availability and amount of coverage and
 adequate reimbursement by third-party payers, including governments and private health plans. The process for determining whether a payer will provide coverage for a product may be separate from the process for setting the reimbursement rate that the
 payer will pay for the product, or procedures that utilize such product. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations. For example, third-party payers may limit coverage to
 specific products on an approved list, or formulary, which might not include all U.S. FDA-approved products for a particular indication. Moreover, a payer's decision to provide coverage for a medicine does not imply that an adequate reimbursement rate
 will be approved. Additionally, coverage and reimbursement for drugs can differ significantly from payer to payer. One third-party payer's decision to cover a particular medicine does not ensure that other payers will also provide coverage for the
 medicine or will provide coverage at an adequate reimbursement rate.

 Third-party payers are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medicines and
 services, in addition to their safety and efficacy. To obtain coverage and reimbursement for any medicine that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies to demonstrate the medical necessity and
 cost-effectiveness of our medicine. These studies will be in addition to the studies required to obtain regulatory approvals. If third-party payers do not consider a medicine to be cost-effective compared to other available therapies, they may not
 cover the medicine after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to sell such medicine at a profit.

 In certain jurisdictions, governments may also regulate or influence coverage, reimbursement and/or pricing of our medicines to control
 cost or affect use. In the European community, governments influence the price of drugs through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those medicines to consumers. Some
 jurisdictions operate positive and negative list systems under which medicines may only be marketed once a reimbursement price has been agreed to by the government. To obtain reimbursement or pricing approval, some of these countries may require the
 completion of clinical studies that compare the cost effectiveness of a particular drug candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines but monitor and control company profits.

 The marketability of any medicine for which we receive regulatory approval for commercial sale may suffer if the
 government and third-party payers fail to provide adequate coverage and reimbursement. In addition, the focus on cost containment measures in the U.S. and other countries has increased and we expect will continue to increase the pressure on
 pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if we attain favorable coverage and reimbursement status for one or more medicines for which we receive regulatory approval, less favorable
 coverage policies and reimbursement rates may be implemented in the future.

 Healthcare Reform

 Both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and regulations
 designed to contain or reduce the cost of healthcare. For example, in July 2021, the Biden administration released an executive order, "Promoting Competition in the American Economy," with multiple provisions aimed at prescription drugs. In response to
 Biden's executive order, on September 9, 2021, the U.S. Department of Health and Human Services, or HHS, released a report that outlined principles for drug pricing reform and set out a variety of potential legislative policies that Congress could
 pursue as well as potential administrative actions HHS could take to advance these principles. Congress is also considering additional health reform measures that may result in decreased reimbursement, which may further exacerbate industry-wide
 pressure to reduce the prices charged for medical products.

 There has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which
 has resulted in efforts to bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for medicines. For example, in August 2022,
 President Biden signed the Inflation Reduction Act of 2022, or the IRA, into law, which includes key actions aimed at reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare
 and establish a price cap on such drugs, known as the Maximum Fair Price. There are important exemptions to the Maximum Fair Price, including for medications that are orphan drug designated and approved for only one rare disease, and drugs with low
 Medicare spend as defined by the Centers for Medicare & Medicaid Services. Specifically, in an effort to curb Medicare patients' out-of-pocket costs for prescription drugs, the Part D redesign legislation under the IRA requires, among other
 things, (1) a cap on out-of-pocket drug spending under Part D, (2) drug manufacturers to pay a rebate to the federal government if prices for drugs covered under Part D and Part B increase faster than the rate of inflation, and (3) drug manufacturers
 to contribute to the catastrophic coverage phase for Part D drugs as discounts through a manufacturer discount program. The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. These
 provisions take effect progressively starting in fiscal year 2023. On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject
 to legal challenges. In response to the Biden administration's October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to
 lower the cost of drugs, promote accessibility, and improve quality of care. It is unclear whether the models will be utilized in any health reform measures in the future. Further, on December 7, 2023, the Biden administration announced an initiative
 to control the price of prescription drugs using march-in rights under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise
 of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if that will continue under
 the new framework.

 Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private
 payers. Our future product sales may be subject to additional discounts from list price in the form of rebates and discounts provided to 340B covered entities. Changes to the 340B program or to Medicare or Medicaid programs at the federal or state
 level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.

 In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Chain Security Act, or DSCA, which
 regulates the distribution and tracing of prescription drugs and prescription drug samples at the federal level and sets minimum standards for the regulation of drug distributors by the states. The DSCA imposes requirements to ensure accountability in
 distribution and to identify and remove counterfeit and other illegitimate products from the market.

 Other healthcare laws that may affect our ability to operate include, for example, the following:

 The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act,
 which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information;

 Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and the California
 Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and

 The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the HHS information related
 to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as physician assistants and nurse practitioners), and teaching
 hospitals, and ownership and investment interests held by physicians and their immediate family members.

 Sales and Marketing

 Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid Services, other
 divisions of the HHS, the U.S. Department of Justice, and similar foreign, state and local government authorities, regulate sales, promotion and other activities following drug approval. As described above, the FDA regulates all advertising and
 promotion activities for drugs under its jurisdiction both prior to and after approval. Only those claims relating to safety and efficacy that the FDA has approved may be used in labeling. Physicians may prescribe legally available drugs for uses that
 are not described in the drug's labeling and that differ from those tested and the FDA approved. The FDA does not regulate the behavior of physicians in their choice of treatments, but FDA regulations do impose stringent restrictions on manufacturers'
 communications regarding off-label uses. If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, corrective advertising, consent decrees and the full range of civil and criminal penalties
 available to the FDA. Promotion of off-label uses of drugs can also implicate the false claims laws described below.

 In the U.S., sales, marketing and scientific/educational programs must also comply with various federal and state laws pertaining to
 healthcare "fraud and abuse," including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal for a prescription drug manufacturer to solicit, offer, receive, or pay any remuneration in exchange for, or to induce, the referral of
 business, including the purchase or prescription of a particular drug. Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and very few court
 decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, healthcare reform legislation has strengthened these laws. For example, the Patient Protection and Affordable
 Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or Affordable Care Act, among other things, amends the intent requirement of the federal anti-kickback and criminal healthcare fraud statutes to clarify that a person or
 entity does not need to have actual knowledge of this statute or specific intent to violate it. In addition, the Affordable Care Act clarifies that the government may assert that a claim that includes items or services resulting from a violation of the
 federal anti-kickback statute constitutes a false or fraudulent claim for purposes of the false claims statutes. False claims laws prohibit anyone from knowingly and willingly presenting, or causing to be presented for payment, to third-party payers
 (including Medicare and Medicaid) claims for reimbursed drugs or services that are false or fraudulent, claims for items or services not provided as claimed, or claims for medically unnecessary items or services. Our activities relating to the sale and
 marketing of our drugs may be subject to scrutiny under these laws. Further, HIPAA also prohibits, among other things, executing or attempting to execute a scheme to defraud any healthcare benefit program or making false statements relating to
 healthcare matters. Violations of fraud and abuse laws may be punishable by criminal and civil sanctions, including fines and civil monetary penalties, the possibility of exclusion from federal healthcare programs (including Medicare and Medicaid) and
 corporate integrity agreements, which impose, among other things, rigorous operational and monitoring requirements on companies. Similar sanctions and penalties also can be imposed upon executive officers and employees, including criminal sanctions
 against executive officers under the so-called "responsible corporate officer" doctrine, even in situations where the executive officer did not intend to violate the law and was unaware of any wrongdoing.

 Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of such violations
 often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include significant civil sanctions, including fines and civil monetary penalties, corporate integrity agreements, and could
 include criminal penalties. If the government were to allege or convict us or our executive officers of violating these laws, our business could be harmed. In addition, private individuals can bring similar actions. Our activities could be subject to
 challenge for the reasons discussed above and due to the broad scope of these laws and the increasing attention being given to them by law enforcement authorities. As described above, other healthcare laws that may affect our ability to operate include
 HIPAA, analogous state laws governing the privacy and security of health information, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, and the Physician Payments
 Sunshine Act. Further, there are an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information. Many of these laws contain ambiguities as to what is required to comply with the laws. Given
 the lack of clarity in laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state authorities.

 Similar rigid restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries. Even in those countries
 where we may not be directly responsible for the promotion and marketing of our medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us.

 As discussed above, both the federal and state governments in the U.S. and foreign governments continue to propose and pass new
 legislation and regulations designed to contain or reduce the cost of healthcare, including new models aimed to lower of cost of drugs, promote accessibility, and improve quality of care and initiatives to control the price of prescription drugs using
 march-in rights under the Bayh-Dole Act.

 The Foreign Corrupt Practices Act

 The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including us, from promising, paying,
 offering to pay, or authorizing the payment of anything of value to any foreign government official, directly or indirectly, to obtain or retain business or an improper advantage. If we violate the FCPA, it could result in large civil and criminal
 penalties as well as an adverse effect on our reputation, operations, and financial condition. We could also face collateral consequences such as debarment and the loss of export privileges. In addition, in many other countries, the healthcare
 providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. There is
 no certainty that all employees and third-party business partners (including our contract research organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery
 laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions.

 Competition

 Our Business in General

 Some of our medicines may compete with existing therapies for market share and some of our medicines in development may compete for
 patients in clinical trials. In addition, there are a number of companies pursuing the development of genetic medicines and the development of pharmaceuticals utilizing these technologies. These companies include biopharmaceutical companies and large
 pharmaceutical companies acting either independently or together. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body, delivery technology, and formulations.

 Our commercial medicines and our medicines in development address numerous markets. The diseases our medicines target for which we have or
 may receive marketing authorization will determine our competition. For some of our medicines, an important factor may be the timing of market introduction of competitive products. Accordingly, the relative speed with which we can develop medicines,
 complete the clinical trials and marketing authorization processes and supply commercial quantities of the medicines to the market are important competitive factors. We expect to compete with products approved for sale based on a variety of factors,
 including, among other things, product efficacy, safety, mechanism of action, dosing administration, marketing and sales strategy and tactics, availability, price, and reimbursement.

 Below we have included what we believe to be medicines that compete or may compete directly with our marketed medicines and the medicines
 we currently have in Phase 3 trials. We included competitors, potential competitors that are past Phase 1 development or potential competitors that plan to start a pivotal study this year.

 We consider the following medicines as competitors to SPINRAZA for the indication of SMA:

 Zolgensma

 (Onasemnogene abeparvovec)

 Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene

 Approved for pediatric SMA patients less than 2 years of age

 Intravenous infusion

 Evrysdi

 (Risdiplam)

 Roche

 A small molecule medicine that modulates splicing of the SMN2 gene

 Approved for SMA in pediatric and adult patients

 Oral

 OAV101

 (Onasemnogene abeparvovec)

 Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene

 Phase 3

 Intrathecal injection

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 QALSODY

 We believe that the following medicine could compete with QALSODY in SOD1-ALS:

 NI-005 / AP-101

 Neurimmune (AL-S Pharma) / Lilly

 A human derived antibody targeting misfolded SOD1

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 WAINUA and TEGSEDI

 We consider the following medicines as competitors and potential future competitors to WAINUA and TEGSEDI for ATTRv-PN and/or ATTR-CM:

 Onpattro

 (Patisiran)

 Alnylam

 An RNAi medicine formulated with lipid nanoparticles to inhibit TTR mRNA

 Received CRL in the U.S. for ATTR-CM

 Approved in US, EU, Japan and select other markets for ATTRv-PN

 Intravenous infusion

 Vyndaqel/Vyndamax

 (Tafamidis and tafamidis meglumine)

 Pfizer

 A small molecule medicine to stabilize TTR protein

 Approved in EU, Japan and select other markets for ATTRv-PN, ATTR-CM; indications vary by region

 Oral

 Amvuttra

 (Vutrisiran)

 Alnylam

 An RNAi medicine conjugated with GalNAc to inhibit TTR mRNA

 Approved for ATTRv-PN in the U.S., EU and Japan, Phase 3 for ATTR-CM

 Acoramidis

 BridgeBio

 Small molecule that binds and stabilizes TTR in the blood

 Submitted in U.S., EU and Japan

 Oral

 NTLA-2001

 Intellia/ Regeneron

 CRISPR therapeutic candidate designed to reduce circulating TTR protein levels

 Phase 3 ATTR-CM

 ALXN2220

 A monoclonal IgG1 which acts by targeting and depleting TTR protein

 Phase 3 ATTR-CM

 NNC6019-0001

 Novo Nordisk

 A monoclonal antibody to deplete amyloid via antibody-mediated phagocytosis

 Phase 2 ATTR-CM

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 WAYLIVRA and Olezarsen

 We believe that the following medicines could compete with WAYLIVRA and olezarsen in FCS and SHTG:

 ARO-APOC3

 (Plozasiran)

 Arrowhead

 Targets APOCIII by utilizing Targeted RNAi Molecule Platform

 Phase 3 FCS,

 Phase 2 SHTG

 Pegozafermin

 89bio

 FGF21 analog

 Phase 3 SHTG

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 Donidalorsen

 We believe that the following medicines could compete with donidalorsen as a prophylactic treatment for patients with HAE:

 Takhzyro

 (lanadelumab-flyo)

 Takeda

 A monoclonal antibody that inhibits plasma kallikrein activity

 Approved for HAE patients two years and older

 Cinryze

 (C1 esterase inhibitor)

 Takeda

 A human plasma protein that mediates inflammation and coagulation

 Approved for HAE patients six years and older

 Orladeyo

 (berotralstat)

 BioCryst

 Oral plasma kallikrein inhibitor

 Approved for HAE patients 12 years and older

 Oral

 Haegarda

 (C1 esterase inhibitor)

 CSL Behring

 C1 esterase inhibitor

 Approved for HAE patients 6 years and older

 Garadacimab

 CSL Behring

 An anti-factor XIIa monoclonal antibody

 Under regulatory review in the U.S. and EU

 Deucrictibant

 Pharvaris

 An oral B2-receptor antagonist

 Oral

 STAR-0215

 Astria

 A monoclonal antibody inhibitor of plasma kallikrein

 NTLA-2002

 Intellia

 CRISPR therapeutic candidate designed to inactivate the kallikrein B1 gene

 Phase 1/2

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 Zilganersen

 We believe there are no medicines in clinical development for AxD.

 Ulefnersen

 We believe there are no medicines in clinical development for FUS-ALS.

 Pelacarsen

 We believe that the following medicines could compete with pelacarsen in CVD in patients with elevated LP(a):

 Olpasiran

 Amgen/ Arrowhead

 RNAi therapeutic designed to lower Lp(a)

 Phase 3

 Zerlasiran

 Silence

 RNAi therapeutic designed to lower Lp(a)

 Lepodisiran

 Lilly

 RNAi therapeutic designed to lower Lp(a)

 Muvalaplin

 Lilly

 Small molecule therapy to lower Lp(a)

 Oral

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 Bepirovirsen

 We believe that the following medicines could compete with bepirovirsen in HBV:

 Elebsiran

 (VIR-2218)

 Vir Biotech / Alnylam

 RNAi therapeutic to reduce HBV viral antigens

 Imdusiran

 (AB-729)

 Arbutus Biopharma

 RNAi therapeutic to reduce HBV viral antigens

 Xalnesiran

 Roche

 RNAi therapeutic to reduce HBV viral antigens

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 IONIS-FB-L Rx

 We believe that the following medicines could compete with I ONIS-FB-L Rx in IgAN:

 Tarpeyo (budesonide)

 Calliditas

 A corticosteroid indicated to reduce proteinuria in adults with primary IgAN

 Approved for IgAN

 Oral

 Filspari

 (Sparsentan)

 Travere

 An endothelin & angiotensin II receptor antagonist to reduce proteinuria in adults with primary IgAN

 Approved for IgAN

 Oral

 Atrasentan

 Novartis (Chinook)

 An endothelin A receptor antagonist

 Oral

 Iptacopan

 Novartis (Chinook)

 A factor B inhibitor of the alternative complement pathway

 Oral

 Zigakibart

 Novartis (Chinook)

 An anti-APRIL monoclonal antibody

 Sibeprenlimab

 Otsuka (Visterra)

 A humanized IgG2 monoclonal antibody that inhibits APRIL

 Atacicept

 Vera

 A recombinant fusion protein a dual inhibitor of BLyS and APRIL

 Ravulizumab

 Alexion (AstraZeneca)

 A humanized monoclonal antibody to complement factor 5

 Phase 2 (IgAN)

 Vemircopan

 Alexion (AstraZeneca)

 A complement factor D inhibitor

 Phase 2 (IgAN)

 Oral

 Felzartamab

 Hi-Bio

 A monoclonal antibody directed against CD38

 Phase 2 (IgAN)

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 We believe that the following medicines could compete with I ONIS-FB-L Rx in GA:

 Ivervay (avacincaptad pegol)

 Iveric Bio

 A complement C5 inhibitor approved for GA secondary to AMD

 Approved (GA)

 Intravitreal

 Syfovre (pegcetacoplan)

 Apellis

 A complement C5 inhibitor approved for GA secondary to AMD

 Approved (GA)

 Intravitreal

 Tinlarebant

 Belite Bio

 A small molecule RBP4 antagonist

 Phase 3 (GA)

 Oral

 Danicopan

 Alexion

 A factor D inhibitor

 Phase 2 (GA)

 Oral

 PPY988 (GT005)

 A gene therapy with encoding for human complement factor I

 Phase 2 (GA)

 Intraocular

 AVD-104

 Aviceda

 A glycomimetic nanoparticle

 Phase 2 (GA)

 Intravitreal

 ANX007

 Annexon Bio

 A fragment antigen-binding (fab) antibody

 Phase 2 (GA)

 Intravitreal

 (1)

 Taken from public documents including respective company press releases, company presentations, and scientific presentations.

 Corporate Responsibility and Environmental, Social and Governance Initiatives

 We believe operating responsibly and sustainably creates long-term value for our company and our stakeholders. We recognize the importance
 of Corporate Responsibility, or CR, and Environmental, Social and Governance, or ESG, initiatives as it relates to our business strategy and risk assessment. In 2023, we continued to evolve our CR program by building on our foundation and further
 defining our strategic direction. This includes completing our first CR materiality assessment, updating our CR framework to better focus on our ESG priorities and developing goals to drive and measure our performance.

 We began reporting on CR metrics in 2021 and have continued to expand disclosure since then. In 2023, we established three strategic CR
 pillars that we believe are most important to our business:

 Ionis Corporate Responsibility Strategic Pillars

 Innovate to improve the lives

 of people with serious diseases

 Empowering our

 employees and communities

 Operating

 responsibly and sustainably

 We innovate across the business and work tirelessly to discover, develop and deliver important new medicines for
 people with serious diseases.

 We are committed to fostering an inclusive culture that drives excellence, embraces diversity, and supports our
 communities.

 We operate with integrity to help create a better, more sustainable future for all through environmental
 stewardship and responsible business practices and stakeholder interactions.

 • Innovation and R&D

 • Access and Affordability

 • Patient Advocacy and Engagement

 • Workplace Culture, Talent Attraction and Development

 • Diversity, Equity and Inclusion

 • Social Impact and Community Engagement

 • Environmental Sustainability

 • Governance and Integrity

 • Data Privacy and Cybersecurity

 Our CR initiatives are driven by our Chief Executive Officer and executive-level CR Steering Committee, or CR Committee. The CR Committee
 consists of senior leaders in key functions across the company, including legal, finance, investor relations, human resources, research and development, manufacturing, commercial, compliance and corporate affairs. In 2023, we expanded our CR Committee
 to include a broader cross-section of senior leaders to ensure we continue to develop the right programs and policies.

 The CR Committee is part of our governance framework, which defines responsibilities and ensures we have the right systems and controls to
 oversee ethical and sustainable operations across our business. Our Board of Directors oversees our overall CR strategy and management of material ESG risks and opportunities and receives updates related to corporate governance and corporate
 responsibility from the CR Committee at least once annually. In 2023, the Nominating, Governance and Review Committee assumed responsibility for CR and ESG-related matters.

 We look to our stakeholders and third-party frameworks such as the Sustainability Accounting Standards Board Health Care – Biotechnology
 and Pharmaceuticals Standard and the Task Force on Climate-Related Financial Disclosures to inform our approach and our disclosures.

 We will share more details on our updated CR framework, goals and ESG initiatives in our 2023 CR Report, which will be published in April
 2024 and available on our website. Nothing in the report or on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K.

 Employees and Human Capital

 As of February 15, 2024, we
 employed 927 people, the vast majority of whom reside in the U.S. A significant number of our management and professional employees have had prior experience with pharmaceutical, biotechnology or medical product companies. Our average employee turnover
 rate in 2023 was 7 percent, while the turnover for life sciences and medical device companies over this period was 23 percent according to a survey published by Radford – an Aon Hewitt Company. Given the uniqueness and complexity of our technology, it
 is critical to retain the knowledge and experience of outstanding long service employees. The experience and seniority of our employees is as critical to our future success as it has been to the success we have enjoyed to date.

 Collective bargaining agreements do not cover any of our employees, and management considers relations with our employees to be good. We
 believe that the future will be defined by outstanding people and we are committed to recruiting, developing, motivating, and rewarding them.

 We encourage you to visit our website for more detailed information regarding our Human Capital programs and initiatives. Nothing on our
 website shall be deemed incorporated by reference into this Annual Report on Form 10-K.

 Benefits

 We reward our employees individually on the basis of their responsibilities and accomplishments. We offer competitive compensation and
 benefits to our employees. In addition to salary and bonus programs, we also offer:

 Comprehensive medical, dental and vision insurance;

 401(k) matching;

 Stock options, RSUs and an Employee Stock Purchase Plan, or ESPP;

 Vacation, holiday, sick time and paid time off for volunteering;

 Wellness programs;

 Flexible spending accounts for health and dependent day care needs;

 Family care benefits;

 Life, AD&D insurance and long-term disability insurance coverage options; and

 Employee Assistance Program, or EAP.

 We recognize achievements with salary increases, equity awards, promotions, and bonus opportunities.

 Pay Equity

 We are committed to paying our employees fairly, regardless of their gender, ethnicity, race, age or other personal characteristics. To
 ensure we are achieving our commitment, we benchmark and evaluate pay based on market data and consider factors such as an employee's role and experience, an employee's performance and internal equity. We also regularly review our compensation
 practices, in terms of our overall workforce and individual employees, to ensure our pay is fair and equitable.

 On an annual basis, we monitor our pay equity status and market competitiveness, and perform a pay equity analysis that reviews pay equity
 by gender, ethnicity, race and age. Our 2023 pay equity analysis confirmed we do not have a statistically significant difference in pay for the same or similar work, regardless of gender, ethnicity, race or age.

 Diversity, Equity and Inclusion

 At Ionis, we encourage diversity in our workforce. Prejudicial barriers to human potential and productivity are foreign to our values.
 We recognize that for the full potential of our workforce to be realized, we must cultivate an inclusive culture where all employees feel empowered to contribute fully in an environment that values different perspectives, leading to better
 ideas and increased innovation. We have several employee-led resource groups dedicated to different aspects of diversity and a diverse management team and board of directors.

 Training and Development

 We designed our training and development programs to help employees gain important Ionis knowledge and develop the skills to be successful
 at Ionis. All of our trainings from new hire through senior leader, are focused on the Ionis culture and core principles and learning what we mean when we say: "Working the Ionis Way."

 We empower our employees to build rewarding careers at Ionis, driven by a culture of having a bias to act that encourages personal and
 professional employee growth. Ionis offers robust training opportunities with course offerings and events available to every employee regardless of level or function. In addition, employees also have access to Ionis' learning and development library
 that houses important information on career growth and planning. By supporting our employees, we know that each professional development milestone enables our continued success.

 Information about our Executive Officers

 The following sets forth certain information regarding our executive officers as of February 15, 2024:

 Name

 Age

 Position

 Brett P. Monia, Ph. D.

 Chief Executive Officer

 Joseph T. Baroldi

 Executive Vice President, Chief Business Officer

 Brian Birchler

 Executive Vice President, Corporate and Development Operations

 C. Frank Bennett, Ph. D.

 Executive Vice President, Chief Scientific Officer

 Onaiza Cadoret-Manier

 Executive Vice President, Chief Global Product Strategy and Operations Officer

 Richard S. Geary, Ph. D.

 Executive Vice President, Chief Development Officer

 Elizabeth L. Hougen

 Executive Vice President, Finance and Chief Financial Officer

 Patrick R. O'Neil, Esq.

 Chief Legal Officer, General Counsel and Corporate Secretary

 Eugene Schneider, M.D.

 Executive Vice President, Chief Clinical Development and Operations Officer

 Eric E. Swayze, Ph. D.

 Executive Vice President, Research

 BRETT P. MONIA, Ph. D.

 Chief Executive Officer

 Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr. Monia served as Chief
 Operating Officer. From January 2012 to January 2018, Dr. Monia served as Senior Vice President. From February 2009 to January 2012, Dr. Monia served as our Vice President, Drug Discovery and Corporate Development and from October 2000 to February
 2009, he served as our Vice President, Preclinical Drug Discovery. From October 1989 to October 2000 he held various positions within our Molecular Pharmacology department.

 JOSEPH T. BAROLDI, M.A., M.B.A., M.S.

 Executive Vice President, Chief Business Officer

 Mr. Baroldi has served as Ionis' Executive Vice President, Chief Business Officer since January 2022. Prior to Ionis, Mr. Baroldi was the
 chief operating officer at Avidity Biosciences, a biotechnology company focused on oligonucleotide-based therapies. Prior to Avidity, Mr. Baroldi was Vice President, Business Development at Ionis, where he held several roles of increasing
 responsibility from 2009 to 2020. Mr. Baroldi has also held positions in strategic planning and scientific research for Gen-Probe Inc.

 BRIAN BIRCHLER

 Executive Vice President, Corporate and Development Operations

 Mr. Birchler has served as Ionis' Executive Vice President, Corporate and Development Operations since March 2022. From January 2008 to
 March 2022, Mr. Birchler served as our Senior Vice President, Drug Development Operations. From January 2005 to January 2008 he served as our Vice President, Drug Development Operations and from January 2003 to January 2005, as our Vice President,
 Development Chemistry and Operations. Mr. Birchler joined Ionis in 1995 as Senior Scientist/Senior Research Associate. Prior to joining Ionis, Mr. Birchler was employed by CIBA Vision Corp. and Burroughs Wellcome Pharmaceuticals in various engineering,
 development and commercial positions.

 C. FRANK BENNETT, Ph. D.

 Executive Vice President, Chief Scientific Officer

 Dr. Bennett has served as Ionis' Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr. Bennett was
 promoted to Chief Scientific Officer. From January 2006 to December 2019, Dr. Bennett served as Senior Vice President, Antisense Research. From June 1995 to January 2006, Dr. Bennett served as our Vice President, Research. From March 1993 to June 1995,
 he was Director, Molecular Pharmacology, and from May 1992 to March 1993, he was an Associate Director in our Molecular and Cellular Biology department. Prior to joining Ionis in 1989, Dr. Bennett was employed by SmithKline and French Laboratories in
 various research positions. He is a member of the Board of Directors for Flamingo Therapeutics and an external member of the Hereditary Disease Foundation.

 ONAIZA CADORET-MANIER

 Executive Vice President, Chief Global Product Strategy and Operations Officer

 Ms. Cadoret-Manier has served as Ionis' Executive Vice
 President, Chief Product Strategy and Operations Officer since February 2022. From April 2020 to February 2022, Ms. Cadoret-Manier served as our Executive Vice President, Chief Corporate Development and Commercial Officer. Ms. Cadoret-Manier joined Ionis as Chief Corporate Development and Commercial Officer in January 2020. Prior to joining Ionis, from 2018 to 2019 Ms. Cadoret-Manier was the chief
 commercial officer for Grail Biosciences, an early detection genomics company. Prior to Grail, Ms. Cadoret-Manier was vice president of the Respiratory Franchise at Genentech where she worked from 2011 to 2018. Ms. Cadoret-Manier also has held
 multiple senior management positions overseeing corporate strategy, alliances, and marketing and sales for numerous disease areas for Genentech, Pfizer and Amylin Pharmaceuticals.

 RICHARD S. GEARY, Ph. D.

 Executive Vice President, Chief Development Officer

 Dr. Geary has served as Ionis' Executive Vice President, Chief Development Officer since January 2021. From April 2020 to December 2020,
 Dr. Geary served as our Executive Vice President, Development and from August 2008 to March 2020, was our Senior Vice President, Development. From August 2003 to August 2008, Dr. Geary served as our Vice President, Preclinical Development. From
 November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr. Geary was Senior Research Scientist and Group Leader for the bioanalytical and preclinical pharmacokinetics group
 in the Applied Chemistry Department at Southwest Research Institute.

 ELIZABETH L. HOUGEN

 Executive Vice President, Finance and Chief Financial Officer

 Ms. Hougen has served as Ionis' Executive Vice President and Chief Financial Officer since April 2020. From January 2013 to March 2020,
 Ms. Hougen served as our Senior Vice President, Finance and Chief Financial Officer. From January 2007 to December 2012, Ms. Hougen served as our Vice President, Finance and Chief Accounting Officer and from May 2000 to January 2007, she served as our
 Vice President, Finance. Prior to joining Ionis in 2000, Ms. Hougen was Executive Director, Finance and Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company.

 PATRICK R. O'NEIL, Esq.

 Chief Legal Officer, General Counsel and Corporate Secretary

 Mr. O'Neil has served as Ionis' Chief Legal Officer and General Counsel since September 2021. Mr. O'Neil also serves as our Corporate
 Secretary. From March 2020 to September 2021, Mr. O'Neil served as our Executive Vice President, Legal & General Counsel and Chief Compliance Officer. From January 2013 to March 2020, Mr. O'Neil served as our Senior Vice President, Legal and
 General Counsel. From September 2010 to January 2013, Mr. O'Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel. From October 2001
 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr. O'Neil was an associate at Cooley LLP.

 EUGENE SCHNEIDER, M.D.

 Executive Vice President, Chief Clinical Development and Operations Officer

 Dr. Schneider has served as Ionis' Executive Vice President and Chief Clinical Development and Operations Officer since September 2023.
 From January 2021 to September 2023, Dr. Schneider served as our Executive Vice President and Chief Clinical Development Officer. From August 2018 to December 2020, Dr. Schneider served as our Senior Vice President, Head of Clinical Development. From
 April 2015 to July 2018, Dr. Schneider was our Vice President, Clinical Development, Severe and Rare Diseases. Dr. Schneider joined Ionis in December 2013 as Executive Director, Clinical Development. Dr. Schneider has two decades of experience in
 clinical development primarily in the rare diseases space. Prior to joining Ionis, Dr. Schneider was senior medical director at both Synageva BioPharma and Biovail Technologies Ltd.

 ERIC E. SWAYZE, Ph. D.

 Executive Vice President, Research

 Dr. Swayze has served as Ionis' Executive Vice President, Research since April 2020 and is responsible for leading preclinical antisense
 drug discovery and antisense technology research. In January 2020, Dr. Swayze was promoted to Senior Vice President of Research. Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, overseeing the
 advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis' Generation 2.5 chemistry and LICA technology.

 Item 1A. RISK FACTORS

 Investing in our securities involves a high degree of risk. You should carefully consider the following information
 about the risks described below, together with the other information contained in this report and in our other public filings in evaluating our business. If any of the following risks actually occur, our business could be materially harmed, and our
 financial condition and results of operations could be materially and adversely affected. As a result, the trading price of our securities could decline, and you might lose all or part of your investment.

 Risks Related to the Commercialization of our Medicines

 We have limited experience as a company in commercializing medicines and we will have to continue to invest significant resources to
 develop our capabilities. If we are unable to establish effective marketing, sales, market access, distribution, and related functions, or enter into agreements with third parties to commercialize our medicines, we may not be able to generate revenue
 from our medicines.

 We currently rely on third parties for the commercialization of our marketed medicines, have limited experience as a company in
 commercializing medicines and will have to continue to invest significant financial and management resources to develop the infrastructure required to successfully commercialize our medicines. There are significant risks involved in building and
 managing a sales organization, including our ability to hire, retain and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed
 sales and marketing team. We will also need to continue to scale-up existing internal support functions to aid our commercialization efforts, in particular, regulatory affairs and medical affairs. Any failure to effectively build or maintain the
 infrastructure required to successfully commercialize our medicines, including our sales, marketing, market access, distribution, and related capabilities, or scale-up our existing support functions, could adversely impact the revenue we generate from
 our medicines. In addition, if we choose to rely on third parties to assist us in commercializing our medicines, we may not be able to enter into collaborations or hire consultants or external service providers on acceptable financial terms, or at all.
 If we continue to engage third parties to assist us in the commercialization of our medicines, our product revenues and profitability may be lower than if we commercialized such medicines ourselves.

 If the market does not accept our medicines, including our commercial medicines and our medicines in development, we are not likely to
 generate substantial revenues or become consistently profitable.

 Even if our medicines are authorized for marketing, our success will depend upon the medical community, patients and third-party payers
 accepting our medicines as medically useful, cost-effective, safe and convenient. Even when the FDA or foreign regulatory authorities authorize our or our partners' medicines for commercialization, doctors may not prescribe our medicines to treat
 patients. Furthermore, we and our partners may not successfully commercialize additional medicines.

 Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners cannot agree
 with the government or other third-party payers regarding the price we can charge for our medicines, we may not be able to sell our medicines in that market. Similarly, cost control initiatives by governments or third-party payers could decrease the
 price received for our medicines or increase patient coinsurance to a level that makes our medicines, including our commercial medicines and our medicines in development, economically unviable. If the pricing of any of our medicines decreases for any
 reason, it will reduce our revenue for such medicine. For example, Biogen has in the past disclosed that SPINRAZA revenue decreased in part due to lower pricing in the U.S. and certain rest-of-world markets.

 The degree of market acceptance for our medicines, including our commercial medicines and our medicines in development, depends upon a
 number of factors, including the:

 receipt and scope of marketing authorizations;

 establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over competing products;

 cost and effectiveness of our medicines compared to other available therapies;

 patient convenience of the dosing regimen for our medicines; and

 reimbursement policies of government and third-party payers.

 Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general may not accept
 or use any of the medicines that we or our partners may develop.

 For example, TEGSEDI requires periodic blood and urine monitoring and is available in the U.S. only through a risk evaluation and
 mitigation strategy, or REMS program. In addition, the product label for TEGSEDI in the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis. Our main external competitors in the U.S. market for TEGSEDI are patisiran and vutrisiran,
 both marketed by Alnylam Pharmaceuticals, Inc. Neither patisiran nor vutrisiran has a boxed warning nor does either require use of a REMS program. Additionally, the product label for WAYLIVRA in the European Union, or EU, requires regular blood
 monitoring. In each case, these label requirements have negatively affected our ability to attract and retain patients for these medicines.

 If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including our commercial
 medicines and our medicines in development, our revenue will be limited.

 In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of coverage and
 reimbursement from third-party payers. The majority of patients in the U.S. who would fit within our target patient populations for our medicines have their healthcare supported by a combination of Medicare coverage, other government health programs
 such as Medicaid, managed care providers, private health insurers and other organizations. Coverage decisions may depend upon clinical and economic standards that disfavor new medicines when more established or lower cost therapeutic alternatives are
 already available or subsequently become available. Assuming coverage is approved, the resulting reimbursement payment rates might not be enough to make our medicines affordable. Even if favorable coverage status and adequate reimbursement rates are
 attained, less favorable coverage policies and reimbursement rates may be implemented in the future. Accordingly, our commercial medicines and our medicines in development will face competition from other therapies and medicines for limited financial
 resources. Furthermore, we or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future products to satisfy third-party payers. These studies might require us to commit a significant amount of
 management time and financial and other resources. In addition, third-party payers may never consider our future products as cost-effective and adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels
 sufficient to realize an appropriate return on investment in product development.

 Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated methods of
 controlling healthcare costs. In addition, in the U.S., no uniform policy of coverage and reimbursement for medicines exists among third-party payers. Therefore, coverage and reimbursement for medicines can differ significantly from payer to payer. For
 example, the Affordable Care Act, or ACA, was passed in March 2010, and substantially changed the way healthcare is financed by both governmental and private insurers and continues to significantly impact the U.S. pharmaceutical industry. There have
 been judicial and Congressional challenges to certain aspects of the ACA, as well as efforts to repeal or replace certain aspects of the ACA. It is unclear how future litigation and healthcare reform measures will impact the ACA and our business.

 Further, we believe that future coverage, reimbursement and
 pricing will likely be subject to increased restrictions both in the U.S. and in international markets. In the U.S., recent health reform measures have resulted in reductions in Medicare and other healthcare funding, and there have been several
 recent U.S. Congressional inquiries, legislation and executive orders designed to, among other things, reduce drug prices, increase competition (including by enhancing support for generic and biosimilar drugs), lower out-of-pocket drug costs for
 patients, curtail spread pricing practices by pharmacy benefit managers, and foster scientific innovation to promote better health care and improved health. In addition, the Inflation Reduction Act of 2022, or the IRA, includes key actions aimed at
 reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare and establish a price cap on such drugs. Specifically, in an effort to curb Medicare patients' out-of-pocket costs
 for prescription drugs, the Part D redesign legislation under the IRA requires, among other things, (1) a cap on out-of-pocket drug spending under Part D, (2) drug manufacturers to pay a rebate to the federal government if prices for drugs
 covered under Part D and Part B increase faster than the rate of inflation, and (3) drug manufacturers to contribute to the catastrophic coverage phase for Part D drugs as
 discounts through a manufacturer discount program. The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. These provisions take effect progressively starting in fiscal year 2023.
 On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges. In response to the Biden administration's
 October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve
 quality of care. It is unclear whether the models will be utilized in any health reform measures in the future. Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs using march-in
 rights under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the
 price of a product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework. It is unclear whether or how these
 selected models or similar policy initiatives will impact prescription drug pricing in the future.

 Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private
 payers. Our future product sales may be subject to additional discounts from list price in the form of rebates and discounts provided to covered entities under the Public Health Service Act 340B drug pricing program. Changes to the 340B program or to
 Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.

 At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and
 biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from
 other countries and bulk purchasing. For example, on January 5, 2024, the FDA approved Florida's Section 804 Importation Program, or SIP, proposal to import certain drugs from Canada for specific state healthcare programs. It is unclear how this
 program will be implemented, including which drugs will be chosen, and whether it will be subject to legal challenges in the United States or Canada. Other states have also submitted SIP proposals that are pending review by the FDA. Any such approved
 importation plans, when implemented, may result in lower drug prices for products covered by those programs. Third-party coverage and reimbursement for medicines may not be available or adequate in either the U.S. or international markets, which would
 negatively affect the potential commercial success of our products, our revenue and our profits.

 If we or our partners fail to compete effectively, our medicines, including our commercial medicines and our medicines in development,
 will not generate significant revenues.

 Our competitors engage in drug discovery throughout the world, are numerous, and include, among others, major pharmaceutical companies and
 specialized biopharmaceutical firms. In addition, other companies are engaged in developing RNA-targeted technology. Our competitors may succeed in developing medicines that are:

 priced lower than our medicines;

 reimbursed more favorably by government and other third-party payers than our medicines;

 safer than our medicines;

 more effective than our medicines; or

 more convenient to use than our medicines.

 These competitive developments could make our medicines, including our commercial medicines and our medicines in development, obsolete or
 non-competitive.

 Certain of our partners are pursuing other technologies or developing other medicines either on their own or in collaboration with others,
 including our competitors, to treat some of the same diseases our own collaborative programs target. Competition may negatively impact a partner's focus on and commitment to our medicines and, as a result, could delay or otherwise negatively affect the
 commercialization of our medicines, including our commercial medicines and our medicines in development.

 Many of our competitors have substantially greater financial, technical and human resources than we do. In addition, many of these
 competitors have significantly greater experience than we do in conducting preclinical testing and human clinical studies of new pharmaceutical products, in obtaining FDA and other regulatory authorizations of such products and in commercializing such
 products. Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do or more successfully commercialize their products.

 There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain geographic markets
 of products against targets that are also targets of products in our development pipeline. For example:

 Onasemnogene abeparvovec and risdiplam compete with SPINRAZA;

 Taldefgrobep alfa, Evrysdi + GYM329 and NMD670 could compete with SPINRAZA;

 Patisiran, tafamidis, tafamidis meglumine and vutrisiran compete with TEGSEDI and WAINUA;

 Acoramidis, NTLA-2001 and NNC6019-0001 could compete with TEGSEDI and WAINUA;

 ARO-APOC3 and pegozafermin could compete with WAYLIVRA and olezarsen;

 Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor subcutaneous,
 garadacimab, deucrictibant, NTLA-2002 and STAR-0215 could compete with donidalorsen;

 Olpasiran, zerlasiran, lepodisiran and muvalaplin could compete with pelacarsen;

 NI-005/AP-101 could compete with QALSODY;

 VIR-2218 + PEG-IFN-, VIR-3434 VIR-2218 PEG-IFN-, VIR-2218 + BRII-179, NI-204VIR-2218 + GS-9688 + nivolumab, AB-729, imdusiran + Peg-IFNa-2 + NA, xalnesiran +
 RG6084 + NA, xalnesiran + NA, xalnesiran + pegIFN + NA, xalnesiran + RO7049389 + NA, xalnesiran + ruzotolimod + NA, RO7049389 + ruzotolimod + NA could complete with bepirovirsen; and

 Budesonide, sparsentan, atrasentan, iptacopan, zigakibart, sibeprenlimab, atacicept, ravulizumab, vemircopan, felzartamab, povetacicept, avacincaptad pegol,
 pegcetacoplan, tinlarebant, danicopan, GT005, AVD-104 and ANX007 could compete with IONIS-FB-L Rx.

 SPINRAZA injection for intrathecal use is an antisense medicine indicated for the treatment of SMA patients of all ages approved in over
 50 countries. Specifically, SPINRAZA faces competition from onasemnogene abeparvovec, a gene therapy product that was approved in the U.S. in May 2019 and in the EU in May 2020 for the treatment of SMA, as well as risdiplam, an oral product for the
 treatment of SMA that was approved in the U.S. in August 2020 and in the EU in March 2021. Biogen has in the past disclosed that SPINRAZA revenue decreased due to a reduction in demand as a result of increased competition and that future sales of
 SPINRAZA may be adversely affected by competing products.

 Additionally, companies that are developing medicines that
 target the same patient populations as our medicines in development may compete with us to enroll participants in the clinical trials for such medicines, which could make it more difficult for us to complete enrollment for these clinical trials.

 Our medicines could be subject to regulatory limitations following approval.

 Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding the manufacture,
 marketing and distribution of medicines. Promotional communications regarding prescription medicines must be consistent with the information in the product's approved labeling. We or our partners may not obtain the labeling claims necessary or
 desirable to successfully commercialize our medicines, including our commercial medicines and our medicines in development.

 The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine through the product
 label and on advertising, promotional and distribution activities. For example:

 in the U.S., TEGSEDI's label contains a boxed warning for thrombocytopenia and glomerulonephritis;

 TEGSEDI requires periodic blood and urine monitoring; and

 in the U.S., TEGSEDI is available only through a REMS program.

 Prescription medicines may be promoted only for the approved indication(s) in accordance with the approved label. The FDA and other
 regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

 In addition, when approved, the FDA or a foreign regulatory authority may condition approval on the performance of post-approval
 clinical studies or patient monitoring, which could be time consuming and expensive. For example, in connection with the conditional marketing approval for WAYLIVRA in the EU, we are required to conduct a post-authorization safety study to evaluate the
 safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. If the results of such post-marketing studies are not satisfactory, the FDA, EC or other foreign regulatory authorities may withdraw marketing authorization or may
 condition continued marketing on commitments from us or our partners that may be expensive and time consuming to fulfill.

 If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur subsequent to
 regulatory approval, or if we, our CMOs or our partners fail to comply with regulatory requirements, we or our partners may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to conduct additional
 clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our medicines.

 We depend on our collaborations with Biogen for the development and commercialization of SPINRAZA and QALSODY.

 We have entered into separate collaborative arrangements with Biogen to develop and commercialize SPINRAZA and QALSODY. We entered into
 these collaborations primarily to:

 fund our development activities for SPINRAZA and QALSODY;

 seek and obtain regulatory approvals for SPINRAZA and QALSODY; and

 successfully commercialize SPINRAZA and QALSODY.

 We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA and QALSODY, generate additional clinical data for
 SPINRAZA and QALSODY, manufacture SPINRAZA and QALSODY, and successfully commercialize SPINRAZA and QALSODY. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaborations. If Biogen fails to further develop
 SPINRAZA or QALSODY, obtain additional regulatory approvals for SPINRAZA or QALSODY, manufacture SPINRAZA or QALSODY, or successfully commercialize SPINRAZA or QALSODY, or if Biogen's efforts in any of these respects are ineffective, revenues for
 SPINRAZA or QALSODY would be negatively affected.

 In addition, our collaborations with Biogen may not continue for various reasons. Biogen can terminate our collaborations at any time. If
 Biogen stops developing or commercializing SPINRAZA or QALSODY, we would have to seek or spend additional funding, and SPINRAZA's or QALSODY's commercialization may be harmed.

 We depend on our collaboration with AstraZeneca for the joint development and commercialization of WAINUA.

 We have entered into a collaborative arrangement with AstraZeneca to develop and commercialize WAINUA. Under the terms of the
 collaboration agreement, we and AstraZeneca will co-develop and co-commercialize WAINUA in the U.S. and AstraZeneca will have the sole right to commercialize WAINUA in all other countries. As a company we do not have experience with
 co-commercialization arrangements. We also do not have control over the amount and timing of resources that AstraZeneca devotes to our collaboration, particularly outside of the U.S. If the co-commercialization arrangement for WAINUA is not successful
 for any reason, WAINUA may not meet our commercial objectives and our revenues for WAINUA may be limited.

 In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various subcommittees oversee and
 coordinate the development, manufacturing, commercialization and other exploitation activities for WAINUA in the U.S. by mutual agreement. If any subcommittee cannot reach unanimous agreement on any matter within its respective scope of authority, such
 matter may be referred to the JSC for resolution. If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize WAINUA.

 If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a third party to
 manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our products profitably.

 To successfully commercialize any of our medicines, we need
 to optimize and manage large-scale commercial manufacturing capabilities either on a standalone basis or through a third-party manufacturer. As our drug development and commercial pipeline increases and matures, we will have a greater need for
 clinical trial and commercial manufacturing capacity. While we believe our current capabilities and those we obtain through third-party manufacturers support our
 manufacturing needs now, it will be important to expand our manufacturing infrastructure in the future, which will likely require substantial expenditures. If we are not successful in executing this expansion, it could limit our ability to meet our
 manufacturing requirements and commercial objectives in the future.

 In addition, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our medicines, called
 oligonucleotides, on a commercial scale for the systemic administration of a medicine. There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these suppliers will need
 to increase their scale of production to meet our projected needs for commercial manufacturing. Further, we must continue to improve our manufacturing processes to allow us to reduce our drug costs. We or our partners may not be able to manufacture our
 medicines at a cost or in quantities necessary to make commercially successful products.

 Manufacturers, including us, must adhere to the FDA's cGMP regulations and similar regulations in foreign countries, which the applicable
 regulatory authorities enforce through facilities inspection programs. We, our partners and our contract manufacturers may not comply or maintain compliance with cGMP, or similar foreign regulations. Non-compliance could significantly delay or prevent
 receipt of marketing authorizations for our medicines, including authorizations for our commercial medicines and our medicines in development, or could result in enforcement action after authorization that might limit the commercial success of our
 medicines, including our commercial medicines and our medicines in development.

 We rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and WAINUA and drug product for WAYLIVRA.
 Any delays or disruption to our own or third-party commercial manufacturing capabilities could limit the commercial success of our medicines.

 Risks Related to the Development and Regulatory Approval of our Medicines

 If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for our commercial medicines, we or
 our partners cannot sell them in the applicable markets.

 We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for commercialization. In
 addition, it is possible that our commercial medicines may not be approved in additional markets or for additional indications. We and our partners must conduct time-consuming, extensive and costly clinical studies to demonstrate the safety and
 efficacy of each of our medicines before they can be approved or receive additional approvals for sale. We and our partners must conduct these studies in compliance with FDA regulations and with comparable regulations in other countries.

 We and our partners may not obtain necessary regulatory approvals on a timely basis, if at all, for our medicines. It is possible that
 regulatory authorities will not approve our medicines for marketing or our commercial medicines in additional markets or for additional indications. If the FDA or another regulatory authority believes that we or our partners have not sufficiently
 demonstrated the safety or efficacy of any of our medicines, including our commercial medicines or our medicines in development, the authority will not approve the specific medicine or will require additional studies, which could be time consuming and
 expensive and delay or harm commercialization of the medicine. For example, in August 2018 we received a complete response letter from the FDA regarding the new drug application for WAYLIVRA in which the FDA determined that the safety concerns
 identified with WAYLIVRA in our clinical development program outweighed the expected benefits of triglyceride lowering in patients with FCS. We also received a Notice of Non-Compliance Withdrawal Letter, or Non-W, from Health Canada for WAYLIVRA in
 November 2018.

 The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many reasons, including:

 such authorities may disagree with the design or implementation of our clinical studies;

 we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for any indication;

 such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in countries where the
 standard of care is potentially different from the U.S.;

 we or our partners may be unable to demonstrate that our medicine's clinical and other benefits outweigh its safety risks to support approval;

 such authorities may disagree with the interpretation of data from preclinical or clinical studies;

 such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial supplies for our
 medicines; and

 the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly change in a manner
 rendering our clinical data insufficient for approval.

 Failure to receive marketing authorization for our medicines in development, or failure to receive additional marketing authorizations for
 our commercial medicines, or delays in these authorizations, could prevent or delay commercial introduction of the medicine, and, as a result, could negatively impact our ability to generate revenue from product sales.

 If the results of clinical testing indicate that any of our medicines are not suitable for commercial use, we may need to abandon one or
 more of our drug development programs.

 Drug discovery and drug development have inherent risks and the historical failure rate for drugs is high. Antisense medicines are a
 relatively new approach to therapeutics. If we cannot demonstrate that our medicines are safe and effective for human use in the intended indication(s), we may need to abandon one or more of our drug development programs.

 Even if our medicines are successful in preclinical and human clinical studies, the medicines may not be successful in late-stage clinical
 studies.

 Successful results in preclinical or initial human clinical studies, including the Phase 2 results for some of our medicines in
 development, may not predict the results of subsequent clinical studies. If any of our medicines in Phase 3 clinical studies do not show sufficient efficacy in patients with the targeted indication, or if such studies are discontinued for any other
 reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.

 In the past, we have invested in clinical studies of medicines that have not met the primary clinical endpoints in their Phase 3 studies
 or have been discontinued for other reasons. For example, in October 2021, Biogen reported that QALSODY did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring QALSODY were seen across multiple secondary and
 exploratory measures of disease activity and clinical function. In addition, in March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington's disease based on the results of a
 pre-planned review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee. Similar results could occur in clinical studies for our other medicines.

 There are a number of factors that could cause a clinical study to fail or be delayed, including:

 the clinical study may produce negative or inconclusive results;

 regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements;

 we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on subjects or lack of
 efficacy in the trial;

 we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies;

 enrollment in our clinical studies may be slower than we anticipate;

 we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we rely, may not
 identify, recruit or train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study;

 the institutional review board for a prospective site might withhold or delay its approval for the study;

 people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the
 clinical study process or personal issues;

 a clinical study site may deviate from the protocol for the study;

 the cost of our clinical studies may be greater than we anticipate;

 our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and

 the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed.

 Further, the FDA or other regulatory authorities could request, among other things, additional information or commitments before we can
 start or continue a clinical study, protocol amendments, increased safety monitoring, additional product labeling information, and post-approval commitments. This happened in connection with the conditional marketing approval for WAYLIVRA in the EU, as
 the EC is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. In addition, under accelerated approval the FDA is requiring completion of the
 ongoing Phase 3 trial for QALSODY to confirm the clinical benefit of QALSODY.

 Moreover, our commercial medicines are chemically similar to each other. As a result, a safety observation we encounter with one of our
 medicines could have, or be perceived by a regulatory authority to have, an impact on a different medicine we are developing. This could cause the FDA or other regulators to ask questions or take actions that could harm or delay our ability to develop
 and commercialize our medicines or increase our costs. Any failure or delay in our clinical studies could reduce the commercial potential or viability of our medicines.

 We depend on third parties to conduct clinical studies for our medicines and any failure of those parties to fulfill their obligations
 could adversely affect our development and commercialization plans.

 We depend on independent clinical investigators, contract research organizations and other third-party service providers to conduct our
 clinical studies for our medicines and expect to continue to do so in the future. For example, we use clinical research organizations, such as Icon Clinical Research Limited, Medpace, Inc., Parexel International Corporation, Syneos Health, Inc. and
 Thermo Fisher Scientific Inc. for the clinical studies for our medicines, including WAINUA for the treatment of ATTR-CM, donidalorsen, olezarsen, ulefnersen and zilganersen. We rely heavily on these parties for successful execution of our clinical
 studies, but do not control many aspects of their activities. For example, the investigators are not our employees, but we are responsible for ensuring that such investigators conduct each of our clinical studies in accordance with the general
 investigational plan and approved protocols for the study. Third parties may not complete activities on schedule or may not conduct our clinical studies in accordance with regulatory requirements or our stated protocols. For example, some of our key
 vendors have in the past experienced labor shortages, which impacted their ability to perform services for us for certain of our clinical trials. Subsequent failures of these third parties to carry out their obligations, or a termination of our
 relationship with such third parties, could delay or prevent the development, marketing authorization and commercialization of our medicines.

 In addition, while we do not have any clinical trial sites in Ukraine or Gaza, we do have a limited number of clinical trial sites in
 Russia and Israel that may be materially impacted by the ongoing wars between Russia and Ukraine and military conflicts in Israel and the surrounding areas, as well as related political or economic responses and counter-responses by various global
 actors, or collectively, conflicts in Eastern Europe and the Middle East, and could result in difficulties enrolling or completing our clinical trials in such areas on schedule. Furthermore, the U.S. and its European allies have imposed significant
 sanctions against Russia, including regional embargoes, full blocking sanctions, and other restrictions targeting major Russian financial institutions. The U.S. government has also indicated it will consider imposing additional sanctions and other
 similar measures in the future. Our ability to conduct clinical trials in Russia may become restricted under applicable sanctions laws, which would require us to identify alternative trial sites, and could increase our costs and delay the clinical
 development of certain of our medicines.

 Since corporate partnering is a significant part of our strategy to fund the advancement and commercialization of our development
 programs, if any of our collaborative partners fail to fund our collaborative programs, or if we cannot obtain additional partners, we may have to delay or stop progress on our drug development programs.

 To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add key development
 resources. We plan to continue to rely on additional collaborative arrangements to develop and commercialize some of our unpartnered medicines. However, we may not be able to negotiate favorable collaborative arrangements for these drug programs. If we
 cannot continue to secure additional collaborative partners, our revenues could decrease and the development of our medicines could suffer.

 Our corporate partners are developing and funding many of the medicines in our development pipeline. For example, we are relying on:

 AstraZeneca for the joint development and funding of WAINUA;

 Novartis for development and funding of pelacarsen;

 GSK for development and funding of bepirovirsen; and

 Roche for development and funding of IONIS-FB-L Rx.

 If any of these pharmaceutical companies stops developing and funding these medicines, our business could suffer and we may not have, or
 be willing to dedicate, the resources available to develop these medicines on our own. Our collaborators can terminate their relationships with us under certain circumstances, many of which are outside of our control. For example, in 2022, Pfizer and
 Bayer decided to discontinue the clinical development programs for vupanorsen and fesomersen, respectively.

 Even with funding from corporate partners, if our partners do not effectively perform their obligations under our agreements with them, it
 would delay or stop the progress of our drug development and commercial programs.

 In addition to receiving funding, we enter into collaborative arrangements with third parties to:

 conduct clinical studies;

 seek and obtain marketing authorizations; and

 manufacture and commercialize our medicines.

 Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development programs, such as our
 collaborations with AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we anticipated.

 For example, a collaborator such as AstraZeneca, Biogen, GSK, Novartis, Otsuka or Roche, could determine that it is in its financial
 interest to:

 pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of the collaboration with us;

 pursue higher-priority programs or change the focus of its own development programs; or

 choose to devote fewer resources to our medicines than it does to its own medicines.

 If any of these occur, it could affect our partner's commitment to the collaboration with us and could delay or otherwise negatively
 affect the commercialization of our medicines, including QALSODY, SPINRAZA, WAINUA, bepirovirsen, donidalorsen, IONIS-FB-L Rx and pelacarsen.

 We may not be able to benefit from orphan drug designation for our medicines.

 In the U.S., under the Orphan Drug Act, the FDA may designate a medicine as an orphan drug if it is intended to treat a rare disease or
 condition affecting fewer than 200,000 individuals in the U.S. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process, but it can provide financial incentives, such as tax
 advantages and user-fee waivers, as well as longer regulatory exclusivity periods. The FDA has granted orphan drug designation to olezarsen for the treatment of patients with FCS, to ulefnersen for the treatment of patients with FUS-ALS, and to ION582
 for the treatment of patients with Angelman syndrome. The FDA and EMA have granted orphan drug designation to WAINUA for the treatment of patients with ATTR, to donidalorsen for the treatment of patients with HAE, to TEGSEDI for the treatment of
 patients with ATTRv-PN, to WAYLIVRA for the treatment of patients with FCS, to tominersen for the treatment of patients with HD, and to ION356 for the treatment of patients with Pelizaeus-Merzbacher disease. In addition, the EMA has granted orphan drug
 designation to WAYLIVRA for the treatment of patients with FPL. Even if approval is obtained on a medicine that has been designated as an orphan drug, we may lose orphan drug exclusivity if the FDA or EMA determines that the request for designation was
 materially defective or if we cannot assure sufficient quantity of the applicable medicine to meet the needs of patients with the rare disease or condition, or if a competitor is able to gain approval for the same medicine in a safer or more effective
 form or that makes a major contribution to patient care. If we lose orphan drug exclusivity on any of our medicines, we may face increased competition and lose market share for such medicine.

 Risks Associated with our Businesses as a Whole

 Risks related to our financial condition

 If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.

 Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our programs will
 require significant additional research, development, manufacturing, preclinical and clinical testing, marketing authorizations, preclinical activities and commitment of significant additional resources prior to their successful commercialization. In
 addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue developing the infrastructure required to successfully commercialize our medicines, including the expansion of our manufacturing
 capabilities. All of these activities will require significant cash. As of December 31, 2023, we had cash, cash equivalents and short-term
 investments equal to $2.3 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including our
 commercial medicines, or to license certain medicines and proprietary technologies, we will need additional funding in the future. Our future capital requirements will depend on many factors such as:

 successful commercialization of our commercial medicines;

 the profile and launch timing of our medicines in development;

 changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements;

 continued scientific progress in our research, drug discovery and development programs;

 the size of our programs and progress with preclinical and clinical studies;

 the time and costs involved in obtaining marketing authorizations;

 competing technological and market developments, including the introduction by others of new therapies that address our markets; and

 our manufacturing requirements and capacity to fulfill such requirements.

 If we need additional funds, we may need to raise them through public or private financing. Additional financing may not be available on
 acceptable terms or at all. If we raise additional funds by issuing equity securities, the shares of existing stockholders will be diluted and the price, as well as the price of our other securities, may decline. If adequate funds are not available or
 not available on acceptable terms, we may have to cut back on one or more of our research, drug discovery or development programs, or commercial operations. Alternatively, we may obtain funds through arrangements with collaborative partners or others,
 which could require us to give up rights to certain of our technologies or medicines.

 We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the future.

 Because drug discovery and development require substantial lead-time and money prior to commercialization, our expenses have generally
 exceeded our revenue since we were founded in January 1989. As of December 31, 2023, we had an accumulated deficit of approximately $1.8 billion and stockholders' equity of approximately $0.4
 billion. Most of our income has historically come from collaborative arrangements, including commercial revenue from royalties and R&D revenue, with additional income from research grants and the sale or licensing of our patents, as well as
 interest income. We will now and continuing into the foreseeable future need to invest significant financial resources to develop capabilities to commercialize medicines on our own and expect that our income in the future will be driven primarily by
 commercial sales. If we do not earn substantial revenue from commercial sales, we may incur additional operating losses in the future, which could restrict our ability to successfully develop additional medicines or sustain future profitability.

 We may not be entitled to obtain additional milestone payments under our royalty monetization agreement with Royalty Pharma.

 In January 2023, we entered into a Royalty Purchase Agreement with Royalty Pharma Investments. In addition to the $500 million we received
 at closing, this agreement makes available to us up to an additional $625 million in milestone payments. However, these additional milestone payments are subject to satisfaction of certain conditions related to the regulatory approval or commercial
 sales of pelacarsen, in certain cases by specific deadlines. Should we not satisfy such conditions by the applicable deadlines, or if we fail to meet our obligations or default under this agreement, the actual amount of additional payments to us could
 be substantially less than the maximum amounts available thereunder.

 Risks related to our intellectual property

 If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us.

 Our success depends to a significant degree upon whether we can continue to develop, secure and maintain intellectual property rights to
 proprietary products and services. However, we may not receive issued patents on any of our pending patent applications in the U.S. or in other countries and we may not be able to obtain, maintain or enforce our patents and other intellectual property
 rights, any of which could impact our ability to compete effectively. In addition, the scope of any of our issued patents may not be sufficiently broad to provide us with a competitive advantage. Furthermore, other parties may successfully challenge,
 invalidate or circumvent our issued patents or patents licensed to us so that our patent rights do not create an effective competitive barrier or revenue source.

 We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and courts in
 foreign countries will consider the claims in our patents and applications covering our commercial medicines, or any of our medicines in development, as patentable. Method-of-use patents protect the use of a product for the specified method. This type
 of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the patented method. Moreover, even if competitors do not actively promote their product for our
 targeted indications, physicians may prescribe these products off-label. Although off-label prescriptions may infringe or contribute to the infringement of method-of-use patents, the practice is common and such infringement is difficult to prevent,
 even through legal action.

 If we or any licensor partner loses or cannot obtain patent protection for our commercial medicines or any of our medicines in
 development, it could have a material adverse impact on our business.

 Intellectual property litigation could be expensive and prevent us from pursuing our programs.

 From time to time, we have to defend our intellectual property rights. If we are involved in an intellectual property dispute, we may need
 to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. PTO or the International Trade Commission or foreign patent authorities. Even if resolved in our favor,
 litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public
 announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.

 If a third party claims that our medicines or technology infringe its patents or other intellectual property rights, we may have to
 discontinue an important product or product line, alter our products and processes, pay license fees or cease certain activities. We may not be able to obtain a license to needed intellectual property on favorable terms, if at all. There are many
 patents issued or applied for in the biotechnology industry, and we may not be aware of patents or patent applications held by others that relate to our business. This is especially true since patent applications in the U.S. are filed confidentially
 for the first 18 months. Moreover, the validity and breadth of biotechnology patents involve complex legal and factual questions for which important legal issues remain.

 Risks related to product liability

 We are exposed to potential product liability claims, and insurance against these claims may not be available to us at a reasonable rate
 in the future or at all.

 Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing and sale of
 therapeutic products, including potential product liability claims related to our commercial medicines and our medicines in development. We have clinical study insurance coverage and commercial product liability insurance coverage. However, this
 insurance coverage may not be adequate to cover claims against us, or be available to us at an acceptable cost, if at all. Regardless of their merit or eventual outcome, product liability claims may result in decreased demand for our medicines, injury
 to our reputation, withdrawal of clinical study volunteers and loss of revenues. Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material.

 Risks related to our personnel

 The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult to run our
 business and reduce our likelihood of success.

 We are dependent on the principal members of our management
 and scientific staff, and as we move towards commercializing medicines on our own, we will become increasingly dependent on the principal members of our commercial team. We do not have employment agreements with any of our employees that would
 prevent them from leaving us. The loss of our management, key scientific or commercial employees might slow the achievement of important research and development or commercial goals. It is also critical to our success that we recruit and retain
 qualified scientific personnel to perform research and development work and that we recruit and retain qualified marketing, sales, market access, distribution, and related personnel to commercialize our medicines. We may not be able to attract and
 retain skilled and experienced personnel on acceptable terms because of intense competition for experienced personnel among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to
 succeed in clinical studies or in commercializing our medicines may make it more challenging to recruit and retain qualified personnel.

 Risks related to pandemics, climate change and other events

 Our business may be adversely affected by pandemics, climate change, extreme weather events, earthquakes, wars, civil or political unrest,
 terrorism or other catastrophic events.

 Our business could be adversely affected by health epidemics in regions where we or our partners are commercializing our medicines, have
 concentrations of clinical trial sites or other business operations, and could cause disruption in the operations of third-party manufacturers and contract research organizations upon whom we rely. For example, enrollment in some of our clinical trials
 was delayed due to the COVID-19 pandemic.

 In recent years, extreme weather events and changing weather patterns have become more common. As a result, we are potentially exposed to
 varying natural disaster or extreme weather risks such as hurricanes, tornadoes, fires, droughts, floods, or other events that may result from the impact of climate change on the environment. The potential impacts of climate change may also include
 increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we currently manufacture most of our research and clinical supplies in a manufacturing
 facility located in Carlsbad, California. We manufacture the finished drug product for TEGSEDI, WAINUA and WAYLIVRA at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA and QALSODY. The facilities and the
 equipment we, our partners and our contract manufacturers use to research, develop and manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace.

 Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside our control,
 such as earthquakes, wars, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event,
 our development and commercialization efforts would be delayed. Although we possess property damage and business interruption insurance coverage, this insurance may not be sufficient to cover all of our potential losses and may not continue to be
 available to us on acceptable terms, or at all. In addition, our development and commercialization activities could be harmed or delayed by a shutdown of the U.S. government, including the FDA.

 Risks related to cybersecurity, social media and artificial intelligence

 We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.

 We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to
 operate our business. The multitude and complexity of our computer systems may make them vulnerable to service interruption or destruction, disruption of data integrity, malicious intrusion, or random attacks. Likewise, data privacy or security
 incidents or breaches by employees or others may pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our employees, patients, customers or other business partners may be exposed to unauthorized
 persons or to the public. Cyber-attacks are increasing in their frequency, sophistication and intensity, particularly as companies (including us) moved to more remote work structures during and following the COVID-19 pandemic. In addition, the number
 and frequency of cybersecurity events globally may be heightened during times of geopolitical tension or instability between countries, including, for example, the ongoing conflicts in Eastern Europe and the Middle East.

 Cyber-attacks could include the deployment of harmful malware, denial-of-service, social engineering and other means to affect service
 reliability and threaten data confidentiality, integrity and availability. Our business partners face similar risks and any security breach of their systems could adversely affect our security posture. A security breach or privacy violation that leads
 to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health information, could harm our reputation, delay progress on the development of our medicines, compel us to
 comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness of database contents and otherwise subject us to
 litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue. Moreover, the prevalent use of mobile devices that access confidential
 information increases the risk of data security breaches, which could lead to the loss of confidential information, trade secrets or other intellectual property. While we have invested, and continue to invest, in the protection of our data and
 information technology infrastructure, our efforts may not prevent service interruptions or identify breaches in our systems that could adversely affect our business and operations and result in the loss of critical or sensitive information, which
 could result in financial, legal, business or reputational harm to us.

 The increasing use of social media platforms and artificial intelligence based software presents new risks and challenges.

 Social media is increasingly being used to communicate about our medicines and the diseases our therapies are designed to treat. Social
 media practices in the biopharmaceutical industry continue to evolve and regulations relating to such use are not always clear and create uncertainty and risk of noncompliance with regulations applicable to our business. There is also a risk of
 inappropriate disclosure of sensitive information or negative or inaccurate posts or comments about us on social media. We may also encounter criticism on social media regarding our company, management, or medicines. Our reputation could be damaged by
 negative publicity or if adverse information concerning us is posted on social media platforms or similar mediums, which we may not be able to reverse. If any of these events were to occur or we otherwise fail to comply with applicable regulations, we
 could incur liability, face restrictive regulatory actions or incur other harm to our business.

 Additionally, the use of artificial intelligence, or AI, based software is increasingly being used in the biopharmaceutical industry. Use
 of AI based software may lead to the release of confidential proprietary information, which may impact our ability to realize the benefit of our intellectual property.

 Risks related to our securities and the global credit markets

 If we do not progress in our programs as anticipated, the price of our securities could decrease.

 For planning purposes, we estimate and may disclose the timing of a variety of clinical, regulatory and other milestones, such as when we
 anticipate a certain medicine will enter clinical trials, when we anticipate completing a clinical study, or when we anticipate filing an application for, or obtaining, marketing authorization, or when we or our partners plan to commercially launch a
 medicine. We base our estimates on present facts and a variety of assumptions, many of which are outside of our control. If we do not achieve milestones in accordance with our or our investors' or securities analysts' expectations, including milestones
 related to our commercial medicines and medicines in development, the price of our securities could decrease.

 If the price of our securities continues to be highly volatile, this could make it harder to liquidate your investment and could increase
 your risk of suffering a loss.

 The market price of our common stock, like that of the securities of many other biopharmaceutical companies, has been and is likely to
 continue to be highly volatile. These fluctuations in our common stock price may significantly affect the trading price of our securities. During the 12 months preceding December 31, 2023, the closing market price of our common stock ranged from $52.27 to
 $32.69 per share. Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results,
 announcements of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in
 payers' reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines.

 Broad market factors may materially harm the market price of our common stock irrespective of our operating performance. For example,
 recent events such as the COVID-19 pandemic, the ongoing conflicts in Eastern Europe and the Middle East, and the failure of Silicon Valley Bank have caused disruptions of global financial markets and resulted in increased volatility in the trading
 price of our common stock. In addition, industry factors may materially harm the market price of our common stock. Nasdaq, and the market for biotechnology companies in particular, have historically experienced extreme price and volume fluctuations
 that have often been unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable. A loss of investor confidence in the market
 for biotechnology or pharmaceutical stocks or the stocks of other companies that investors perceive to be similar to us, the opportunities in the biotechnology and pharmaceutical market or the stock market in general, could depress our stock price
 regardless of our business, prospects, financial conditions or results of operations.

 Provisions in our certificate of incorporation, bylaws, convertible notes documents, call spread hedge transaction documents and Delaware
 law may prevent stockholders from receiving a premium for their shares.

 Our certificate of incorporation provides for classified terms for the members of our board of directors. Our certificate also includes a
 provision that requires at least 66 2/3 percent of our voting stockholders to approve a merger or certain other business transactions with, or proposed by, any holder of 15 percent or more of our voting stock, except in cases where certain directors
 approve the transaction or certain minimum price criteria and other procedural requirements are met.

 Our certificate of incorporation also requires that any action required or permitted to be taken by our stockholders must be taken at a
 duly called annual or special meeting of stockholders and may not be taken by written consent. In addition, only our board of directors, chairperson of the board or chief executive officer can call special meetings of our stockholders. We have in the
 past, and may in the future, implement a stockholders' rights plan, also called a poison pill, which could make it uneconomical for a third party to acquire our company on a hostile basis. In addition, our board of directors has the authority to fix
 the rights and preferences of, and issue shares of preferred stock, which may have the effect of delaying or preventing a change in control of our company without action by our stockholders.

 The provisions of our convertible senior notes could make it more difficult or more expensive for a third party to acquire us. Upon the
 occurrence of certain transactions constituting a fundamental change, holders of the notes will have the right, at their option, to require us to repurchase all of their notes or a portion of their notes, which may discourage certain types of
 transactions in which our stockholders might otherwise receive a premium for their shares over the then-current market prices.

 In 2023, we completed a $575 million offering of 1.75% Notes and used $488.2 million of the net proceeds from the issuance of the 1.75%
 Notes to repurchase $504.4 million of our 0.125% Notes. In 2021, we completed a $632.5 million offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0
 million. In 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes,
 and to issue $109.5 million of our 0.125% Notes. Additionally, in connection with the pricing of our 0% Notes and 0.125% Notes, we entered into call spread transactions in which we purchased note hedges and sold warrants. Terminating or unwinding the
 call spread transactions could require us to make substantial payments to the counterparties under those agreements or may increase our stock price. The costs or any increase in stock price that may arise from terminating or unwinding such agreements
 could make an acquisition of our company significantly more expensive to the purchaser.

 These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our agreements, may
 discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over then-current market prices, and may limit the ability of our stockholders to approve transactions that they think may be in their
 best interests.

 Future sales of our common stock in the public market could adversely affect the trading price of our securities.

 Future sales of substantial amounts of our common stock in
 the public market, or the perception that such sales could occur, could adversely affect trading prices of our securities. For example, as of December 31, 2023, we may issue approximately 28.2 million shares of our common stock upon conversion of our
 1.75% Notes, 0% Notes and 0.125% Notes. In connection with the issuance of the 0% Notes and 0.125% Notes, we entered into certain call spread transactions covering 10.9 million shares and 6.6 million shares, respectively, that we expect will
 offset the dilution to holders of common stock upon any conversion of those notes. In addition, o f the shares reserved, 6.1 million shares are reserved for issuance upon conversion of 0.125% Notes that we have repurchased and are currently held by us in treasury (and thus would not be dilutive). As a result, to the extent we elect to
 convert the 0.125% Notes held by us in treasury, we expect we would receive up to 6.1 million shares upon settlement of related convertible note hedges (without any additional dilution caused by the conversion of the 0.125% Notes held in treasury).
 However, the anti-dilutive effect of the convertible note hedges is offset by certain warrant transactions we entered into in connection with the issuance of the 0% Notes and the 0.125% Notes. The addition of any of these shares into the public
 market may have an adverse effect on the price of our securities.

 In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and 0.125% Notes, the
 counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments, including
 over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock. The call spread
 transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes or 0.125% Notes or offset any cash payments we are required to make in excess of the principal amount of the converted
 0% Notes or 0.125% Notes, as the case may be. However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants.

 Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, financial
 condition or stock price.

 The global credit and financial markets have experienced extreme volatility and disruptions recently, including as a result of the
 COVID-19 pandemic, ongoing conflicts in Eastern Europe and the Middle East, and the failure of Silicon Valley Bank. These disruptions can result in severely diminished liquidity and credit availability, declines in consumer confidence, declines in
 economic growth, increases in unemployment rates and uncertainty about economic stability. There can be no assurance that further deterioration in credit and financial markets and confidence in economic conditions will not occur. If the current equity
 and credit markets deteriorate, it may make any necessary debt or equity financing more difficult, more costly and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect
 on our operations, growth plans, financial performance or stock price. In addition, our insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover any or all of our
 losses and may not continue to be available to us on acceptable terms, or at all.

 A variety of risks associated with operating our business and
 marketing our medicines internationally could adversely affect our business. In addition to our U.S. operations, we are commercializing TEGSEDI in the EU, Canada, Latin America and certain Caribbean countries, and WAYLIVRA in the EU, Latin America
 and certain Caribbean countries. We face risks associated with our international operations, including possible unfavorable regulatory, pricing and reimbursement, political, tax and labor conditions, which could harm our business. Because we have
 international operations, we are subject to numerous risks associated with international business activities, including:

 compliance with differing or unexpected regulatory requirements for our medicines and foreign employees;

 complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems;

 difficulties in staffing and managing foreign operations;

 in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic partners;

 foreign government taxes, regulations and permit requirements;

 U.S. and foreign government tariffs, trade and export restrictions, price and exchange controls and other regulatory requirements;

 anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions;

 economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, in particular foreign
 countries or globally;

 fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing business in
 another country;

 compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad;

 workforce uncertainty in countries where labor unrest is more common than in the U.S.; and

 changes in diplomatic and trade relationships.

 Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules
 of other countries in which we operate, including the United Kingdom's Bribery Act 2010. In many other countries, the healthcare providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are
 government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. There is no certainty that all employees and third-party business partners (including our contract research organizations,
 contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be
 liable for their actions. Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial
 condition.

 Risks related to compliance with laws

 Our operations are subject to extensive legal and regulatory requirements affecting the health care industry.

 Our operations are subject to extensive legal and regulatory requirements affecting the health care industry, including federal and state
 anti-kickback laws, false claims laws, transparency laws, such as the federal Sunshine Act, and health information privacy and security laws, which are subject to change at any time. It is possible that governmental authorities will conclude that our
 business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. Penalties for violations of applicable healthcare laws and regulations may include
 significant civil, criminal and administrative penalties, damages, disgorgement, fines, imprisonment, exclusion of products from government funded healthcare programs, such as Medicare and Medicaid, and additional reporting requirements and oversight
 if we enter into a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws. In addition, violations may also result in reputational harm, diminished profits and future earnings.

 Because we use biological materials, hazardous materials, chemicals and radioactive compounds, if we do not comply with laws regulating
 the protection of the environment and health and human safety, our business could be adversely affected.

 Our research, development and manufacturing activities involve the use of potentially harmful biological materials as well as materials,
 chemicals and various radioactive compounds that could be hazardous to human health and safety or the environment. We store most of these materials and various wastes resulting from their use at our facilities in Carlsbad, California pending ultimate
 use and disposal. We cannot completely eliminate the risk of contamination, which could cause:

 interruption of our research, development and manufacturing efforts;

 injury to our employees and others;

 environmental damage resulting in costly clean up; and

 liabilities under federal, state and local laws and regulations governing health and human safety, as well as the use, storage, handling and disposal of these materials
 and resultant waste products.

 In such an event, we may be held liable for any resulting damages, and any liability could exceed our resources. Although we carry
 insurance for pollution liability in amounts and types that we consider commercially reasonable, the coverage or coverage limits of our insurance policies may not be adequate. If our losses exceed our insurance coverage, our financial condition would
 be adversely affected.

 Our business is subject to changing regulations for corporate governance and public disclosure that has increased both our costs and the
 risk of noncompliance.

 Each year we are required to evaluate our internal control systems to allow management to report on, and our Independent Registered Public
 Accounting Firm to attest to, our internal controls as required by Section 404 of the Sarbanes-Oxley Act. As a result, we continue to incur additional expenses and divert our management's time to comply with these regulations. In addition, if we cannot
 continue to comply with the requirements of Section 404 in a timely manner, we might be subject to sanctions or investigation by regulatory authorities, such as the SEC, the Public Company Accounting Oversight Board, or PCAOB, or The Nasdaq Global
 Select Market. Any such action could adversely affect our financial results and the market price of our common stock.

 The SEC and other regulators have continued to adopt new rules and regulations and make additional changes to existing regulations that
 require our compliance. In July 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, was enacted, and in August 2022, the SEC adopted additional rules and regulations under the Dodd-Frank Act related to "say on pay" and
 proxy access. Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead
 to additional compliance costs and impact the manner in which we operate our business.

 Risks related to taxes

 Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.

 Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net operating losses,
 or NOLs, carried over from a prior taxable year. Under the Code, we can carry forward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire. The same is true of other unused tax attributes, such as tax credits.

 Under the current U.S. federal income tax law, U.S. federal NOLs generated in taxable years beginning after December 31, 2017 may be
 carried forward indefinitely, but the deductibility of such U.S. federal NOLs is limited to 80 percent of taxable income. It is uncertain if and to what extent various states will conform to current U.S. federal income tax law, and there may be periods
 during which states suspend or otherwise limit the use of NOLs for state income tax purposes.

 In addition, under Sections 382 and 383 of the Code, and corresponding provisions of state law, if a corporation undergoes an "ownership
 change," which is generally defined as a greater than 50 percentage-point cumulative change, by value, in its equity ownership over a three-year period, the corporation's ability to use its pre-change NOL carryforwards and other pre-change tax
 attributes to offset its post-change income or taxes may be limited. We may experience ownership changes in the future as a result of subsequent shifts in our stock ownership, some of which may be outside of our control. If an ownership change occurs
 and our ability to use our NOL carryforwards or other tax attributes is materially limited, it would harm our future operating results by effectively increasing our future tax obligations. As a result of our merger with Akcea Therapeutics, Inc. in
 2020, or the Akcea Merger, we are subject to the separate return limitation year, or SRLY, rules. Under the SRLY rules, our utilization of Akcea's pre-merger NOL and tax credit carryforwards is limited to the amount of income that Akcea contributes to
 our consolidated taxable income. The Akcea pre-merger tax attributes cannot be used to offset any of the income that Ionis contributes to our consolidated taxable income. In addition, at the state level, there may be periods during which the use of
 NOLs is suspended or otherwise limited, which could accelerate or permanently increase state taxes owed.

 Our future taxable income could be impacted by changes in tax laws, regulations and treaties.

 A change in tax laws, treaties or regulations, or their interpretation, of any country in which we operate could materially affect us.

 We could be subject to additional tax liabilities.

 We are subject to U.S. federal, state, local and foreign
 income taxes, sales taxes in the U.S., withholding taxes and transaction taxes in foreign jurisdictions. Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. During the ordinary course of business,
 there are many activities and transactions for which the ultimate tax determination is uncertain. In addition, our tax obligations and effective tax rates could be adversely affected by changes in the relevant tax, accounting and other laws,
 regulations, principles and interpretations, including those relating to income tax nexus, by recognizing tax losses or lower than anticipated earnings in jurisdictions where we have lower statutory rates and higher than anticipated earnings in
 jurisdictions where we have higher statutory rates, by changes in foreign currency exchange rates, or by changes in the valuation of our deferred tax assets and liabilities. We may be audited in various jurisdictions, and such jurisdictions may
 assess additional taxes, sales taxes and value-added taxes against us. Although we believe our tax estimates are reasonable, the final determination of any tax audits or litigation could be materially different from our historical tax provisions and
 accruals, which could have a material adverse effect on our operating results or cash flows in the period for which a determination is made.

 Item 1B. Unresolved Staff Comments

 Not applicable.

 Item 1C. Cybersecurity

 Risk management and strategy

 We have implemented and maintain various information security processes designed to detect, respond to, recover, and protect our
 technology ecosystem from cybersecurity threats. These processes are designed to identify, assess, and manage material risks that may result from cybersecurity threats and apply to our critical technologies inclusive of networks, third party hosted
 services, communications systems, hardware, software, and critical data, including intellectual property and confidential information that is proprietary, strategic, or competitive in nature.

 Our Information Technology department, led by our Senior Vice President, Information Technology, helps to detect, respond to, and manage
 cybersecurity threats and risks by monitoring and evaluating our threat environment using various manual and automated tools in certain environments and systems and other methods including, for example:

 analyzing reports of certain threats and actors;

 conducting scans of the threat environment;

 evaluating our and our industry's risk profile;

 evaluating certain threats reported to us;

 conducting internal and external audits;

 conducting threat assessments for certain internal and external threats; and

 conducting vulnerability assessments to identify vulnerabilities.

 Depending on the environment and system, we have implemented and maintain various technical, physical, and organizational measures,
 processes, standards, and policies designed to manage and mitigate material risks from cybersecurity threats to our critical technologies, including, for example:

 incident response plan;

 disaster recovery/business continuity plans;

 risk assessments;

 encryption of certain data;

 network security and access controls for certain systems;

 physical security;

 asset management, tracking and disposal;

 systems monitoring; and

 employee training.

 Our assessment and management of material risks from cybersecurity threats are integrated into the Company's overall
 risk management processes. For example, cybersecurity risk is assessed as a component of the Company's enterprise risk management program. In addition, we have developed a process whereby our senior management will evaluate material risks from
 cybersecurity threats against our overall business objectives and will report certain cybersecurity incidents to the Audit Committee of the Board of Directors, which evaluates our overall enterprise risk.

 We use third-party service providers to perform various functions throughout our business, such as application
 providers and hosting companies. We use third-party service providers to assist us from time to time to identify, assess, and manage material risks from cybersecurity threats, including, for example, legal counsel, cybersecurity consultants,
 cybersecurity software providers, penetration testing firms, and forensic investigators.

 For a description of the risks from cybersecurity threats that may materially affect the Company and how they may do so, see our risk
 factors under Part 1. Item 1A. Risk Factors in this Annual Report on Form 10-K, including the risk factor titled " We are dependent on information
 technology systems, infrastructure and data, which exposes us to data security risks."

 Governance

 Our Board of Directors addresses the Company's cybersecurity risk management as part of its general oversight
 function. The Audit Committee of the Board of Directors is responsible for overseeing the Company's cybersecurity risk management processes, including oversight and mitigation of risks from cybersecurity threats.

 Our cybersecurity risk assessment and management processes are implemented and maintained by our Senior Vice
 President, Information Technology, who is an information technology professional with healthcare and digital certifications and has over 25 years of relevant experience, and other employees in our Information Technology department who are certified
 security professionals and have relevant experience.

 Our Senior Vice President, Information Technology is responsible for hiring appropriate personnel, helping to
 integrate cybersecurity risk considerations into the Company's overall risk management strategy, communicating key priorities to relevant personnel, helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security
 assessments and other security-related reports.

 Our cybersecurity incident response plan is designed to escalate cybersecurity incidents, depending on the circumstances, to our senior
 management team and Audit Committee of the Board of Directors. As part of such process, the Audit Committee of the Board of Directors receives regular reports from our Senior Vice President, Information Technology concerning the Company's significant
 cybersecurity threats and risks and the processes the Company has implemented to address them.

 Item 2. Properties

 As of February 15, 2024, the
 following are the primary facilities in which we operate:

 Property Description

 Location

 Square

 Footage

 Owned

 or Leased

 Initial Lease

 Term End Date

 Lease

 Extension Options

 Laboratory and office space facility

 176,300

 2037

 Two, five-year options to extend

 Office and meeting space facility

 74,000

 2037

 Two, five-year options to extend

 Manufacturing facility

 26,800

 Owned

 Manufacturing support facility

 25,800

 2026

 One, five-year option to extend

 Office space facility

 Boston, MA

 14,300

 2029

 One, five-year option to extend

 Office space facility

 5,800

 2027

 None

 Warehouse facility

 4,200

 2028

 None

 Office space facility

 Dublin, Ireland

 3,900

 2025

 None

 331,100

 We believe that our current and future facilities will be adequate for the foreseeable future. Refer to Part IV, Section 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated
 Financial Statements for details on real estate transactions.

 Item 3. Legal Proceedings

 For details of legal proceedings, refer to Part IV, Item 15, Note 11, Legal Proceedings, in the Notes to the Consolidated Financial Statements.

 Item 4. Mine Safety Disclosures

 Not applicable.

 Item 5. Market for Registrant ' s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities

 Market Information and Dividends

 Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol "IONS." As of February 15, 2024, there were approximately 476 stockholders of record of our common stock. Because many of our shares are held by brokers and other
 institutions on behalf of stockholders, we are unable to estimate the total number of stockholders represented by these record holders.

 We have never paid dividends and do not anticipate paying any dividends in the foreseeable future.

 Performance Graph (1)

 Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 2018 in our common
 stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index. The total return assumes reinvestment of dividends.

 * $100 invested on December 31, 2018 in stock or index, including reinvestment of dividends. Fiscal year ending December 31.

 COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN

 Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index,

 and the Nasdaq Biotechnology Index

 Dec-18

 Dec-19

 Dec-20

 Dec-21

 Dec-22

 Dec-23

 Ionis Pharmaceuticals, Inc.

 $

 100.00

 $

 111.75

 $

 104.59

 $

 56.29

 $

 69.87

 $

 93.58

 Nasdaq Composite Index

 $

 100.00

 $

 136.69

 $

 198.10

 $

 242.03

 $

 163.28

 $

 236.17

 Nasdaq Biotechnology Index

 $

 100.00

 $

 125.11

 $

 158.17

 $

 158.20

 $

 142.19

 $

 148.72

 ___________

 (1)

 This section is not "soliciting material," is not deemed "filed" with the SEC, is not subject to the liabilities of Section 18 of the Exchange Act and is not to be
 incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.

 Item 6. Reserved

 Item 7. Management ' s Discussion and Analysis of Financial Condition and Results of Operations

 This financial review presents our operating results for each of the two years in the period ended December 31, 2023, and our financial condition as of December 31, 2023.
 Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021. Except for the historical information contained herein, the
 following discussion contains forward-looking statements that are subject to known and unknown risks, uncertainties and other factors that may cause our actual results to differ materially from those expressed or implied by such forward-looking
 statements. We discuss such risks, uncertainties and other factors throughout this report and specifically under Item 1A of Part I of this report, Risk
 Factors. In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements included in Item 8 of Part II of
 this report.

 Overview

 As noted in our Business Overview in Part I of this report, for three decades, we have invented medicines that we believe bring better futures to people with serious diseases. Today, as a pioneer in RNA-targeted medicines, we continue to drive innovation in RNA therapies. We currently have five
 marketed medicines: SPINRAZA, QALSODY, WAINUA, TEGSEDI and WAYLIVRA. We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and other areas of
 high patient need. We currently have nine medicines in Phase 3 development and multiple additional medicines in early and mid-stage development. Refer to Part I, Item 1, Business, for further details on our business and key developments in our medicines.

 Results of Operations

 Below we have included our results of operations for 2023 compared to 2022. Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021. The following table provides selected summary information from our consolidated statements of operations for 2023 and 2022 (in millions):

 2023

 2022

 Total revenue

 $

 787.6

 $

 587.4

 Total operating expenses

 $

 1,141.4

 $

 997.6

 Loss from operations

 $

 (353.7

)

 $

 (410.2

)

 $

 (366.3

)

 $

 (269.7

)

 Cash, cash equivalents and short-term investments

 $

 2,331.2

 $

 1,986.9

 Revenue

 Total revenue for 2023 was $787.6 million compared to $587.4 million in 2022 and was comprised of the following (in millions):

 2023

 2022

 Revenue:

 Commercial revenue:

 SPINRAZA royalties

 $

 240.4

 $

 242.3

 Other commercial revenue:

 TEGSEDI and WAYLIVRA revenue, net

 34.9

 30.1

 Licensing and other royalty revenue

 33.3

 31.0

 Total other commercial revenue

 68.2

 61.1

 Total commercial revenue

 308.6

 303.4

 R&D revenue:

 Amortization from upfront payments

 125.3

 68.6

 Milestone payments

 100.5

 74.0

 License fees

 116.8

 37.0

 Other services

 10.0

 27.6

 Collaborative agreement revenue

 352.6

 207.2

 WAINUA joint development revenue

 126.4

 76.8

 Total R&D revenue

 479.0

 284.0

 Total revenue

 $

 787.6

 $

 587.4

 Commercial revenues in 2023 were relatively consistent compared to 2022. Commercial revenue for 2023 included $240 million from SPINRAZA
 royalties, which were relatively consistent compared to 2022. Our commercial revenue in 2023 also included royalties from QALSODY U.S. product sales.

 Our R&D revenue increased in 2023 compared to 2022 primarily due to continued success with our pipeline and technology. As a result,
 we earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from our new collaborations with Otsuka, Roche and
 Novartis.

 WAINUA (Eplontersen) Collaboration with AstraZeneca

 Our financial results for the years ended December 31, 2023 and 2022 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and
 commercialize WAINUA for the treatment of ATTR. Under the terms of the collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading and
 conducting the Phase 3 development program, we are recognizing as R&D revenue the 55 percent of cost-share funding AstraZeneca is responsible for, net of our share of AstraZeneca's development expenses, in the same period we incur the related
 development expenses.

 As AstraZeneca is responsible for the majority of the medical affairs and commercial costs in the U.S. and all costs associated with
 bringing WAINUA to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling,
 general and administrative, or SG&A, expenses, respectively. We expect our medical affairs and commercialization expenses to increase as WAINUA advances toward the market under our collaboration with AstraZeneca.

 The following table sets forth information on revenue and expenses under this collaboration (in millions):

 2023

 2022

 WAINUA joint development revenue

 $

 126.4

 $

 76.8

 Research and development expenses related to Phase 3 development expenses for WAINUA

 150.8

 147.1

 Medical affairs expenses for WAINUA

 4.1

 2.0

 Commercialization expenses for WAINUA

 15.6

 2.6

 Our WAINUA joint development revenue in 2023 includes a $50 million milestone payment from AstraZeneca that we earned when the FDA
 approved WAINUA for ATTRv-PN in the U.S.

 Operating Expenses

 The following table sets forth information on operating expenses (in millions):

 2023

 2022

 Operating expenses, excluding non-cash compensation expense related to equity awards

 $

 1,035.7

 $

 897.3

 105.7

 100.3

 Total operating expenses

 $

 1,141.4

 $

 997.6

 Our operating expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022, primarily
 due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee we paid to Vect-Horus. Our R&D expenses increased as we advanced our pipeline, which included an increase in the costs associated with our
 clinical studies as most of our Phase 3 studies were either fully enrolled or approaching full enrollment at the end of 2023. Our SG&A expenses increased due to expenses related to our launch preparation activities for WAINUA, olezarsen and
 donidalorsen.

 To analyze and compare our results of operations to other similar companies, we believe it is important to exclude non-cash compensation
 expense related to equity awards from our operating expenses. We believe non-cash compensation expense related to equity awards is not indicative of our operating results or cash flows from our operations. Further, we internally evaluate the
 performance of our operations excluding it.

 Cost of Sales

 Our cost of sales is comprised of costs related to our commercial revenue, which consisted of manufacturing costs, including certain fixed
 costs, transportation and freight, indirect overhead costs associated with the manufacturing and distribution of TEGSEDI and WAYLIVRA and certain associated period costs.

 The following table sets forth information on cost of sales (in millions):

 2023

 2022

 Cost of sales, excluding non-cash compensation expense related to equity awards

 $

 8.7

 $

 13.4

 0.4

 0.7

 Total cost of sales

 $

 9.1

 $

 14.1

 Research, Development and Patent Expenses

 Our research, development and patent expenses consist of expenses for drug discovery, drug development, medical affairs, manufacturing and
 development chemistry and R&D support expenses.

 The following table sets forth information on research, development and patent expenses (in millions):

 2023

 2022

 Research, development and patent expenses, excluding non-cash compensation expense related to equity awards

 $

 821.7

 $

 759.4

 77.9

 73.7

 Total research, development and patent expenses

 $

 899.6

 $

 833.1

 Drug Discovery

 We use our proprietary technologies to generate information about the function of genes and to determine the value of genes as drug
 discovery targets. We use this information to direct our own drug discovery research, and that of our partners. Drug discovery is also the function that is responsible for advancing our core technology. This function is also responsible for making
 investments in complementary technologies to expand the reach of our technologies.

 The following table sets forth information on drug discovery expenses (in millions):

 2023

 2022

 Drug discovery expenses, excluding non-cash compensation expense related to equity awards

 $

 125.6

 $

 181.3

 16.2

 16.2

 Total drug discovery expenses

 $

 141.8

 $

 197.5

 Drug discovery expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022. In 2022, we
 recognized $80 million for licensing Metagenomi's gene editing technologies.

 Drug Development

 The following table sets forth drug development expenses, including expenses for our marketed medicines and those in Phase 3 development
 for which we have incurred significant costs (in millions):

 2023

 2022

 WAINUA

 $

 115.5

 $

 103.9

 TEGSEDI and WAYLIVRA

 8.1

 10.6

 Olezarsen

 138.3

 68.1

 Donidalorsen

 24.9

 14.1

 Zilganersen

 8.4

 5.6

 Ulefnersen

 10.8

 8.4

 Other development projects

 101.0

 123.5

 Development overhead expenses

 123.3

 92.0

 Total drug development, excluding non-cash compensation expense related to equity awards

 530.3

 426.2

 34.5

 31.5

 Total drug development expenses

 $

 564.8

 $

 457.7

 Our development expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily
 due to our advancing late-stage pipeline and full or nearly full enrollment of many of our Phase 3 studies.

 We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the various indications we may be
 studying. Furthermore, as we obtain results from trials, we may elect to discontinue clinical trials for certain drug candidates in certain indications in order to focus our resources on more promising drug candidates or indications. Our Phase 1 and
 Phase 2 programs are clinical research programs that fuel our Phase 3 pipeline. When our medicines are in Phase 1 or Phase 2 clinical trials, they are in a dynamic state in which we may adjust the development strategy for each medicine. Although we may
 characterize a medicine as "in Phase 1" or "in Phase 2," it does not mean that we are conducting a single, well-defined study with dedicated resources. Instead, we allocate our internal resources on a shared basis across numerous medicines based on
 each medicine's particular needs at that time. This means we are constantly shifting resources among medicines. Therefore, what we spend on each medicine during a particular period is usually a function of what is required to keep the medicines
 progressing in clinical development, not what medicines we think are most important. For example, the number of people required to start a new study is large, the number of people required to keep a study going is modest and the number of people
 required to finish a study is large. However, such fluctuations are not indicative of a shift in our emphasis from one medicine to another and cannot be used to accurately predict future costs for each medicine. Because we always have numerous
 medicines in preclinical and varying stages of clinical research, the fluctuations in expenses from medicine to medicine, in large part, offset one another. If we partner a medicine, it may affect the size of a trial, its timing, its total cost and the
 timing of the related costs.

 Medical Affairs

 Our medical affairs function is responsible for funding and coordinating investigator-sponsored trials, communicating scientific and
 clinical information to healthcare providers, medical professionals and patients, and managing publications.

 The following table sets forth information on medical affairs expenses (in millions):

 2023

 2022

 Medical affairs expenses, excluding non-cash compensation expense related to equity awards

 $

 19.5

 $

 15.9

 3.4

 2.0

 Total medical affairs expenses

 $

 22.9

 $

 17.9

 Medical affairs expenses, excluding non-cash compensation
 expense related to equity awards, increased in 2023 compared to 2022 as we continued advancing our late-stage pipeline.

 Manufacturing and Development Chemistry

 Expenditures in our manufacturing and development chemistry function consist primarily of personnel costs, specialized chemicals for
 oligonucleotide manufacturing, validation batches to support regulatory approvals, laboratory supplies and outside services. Our manufacturing and development chemistry function is responsible for providing drug supplies to drug development and our
 collaboration partners. Our manufacturing procedures include testing to satisfy good laboratory and good manufacturing practice requirements.

 The following table sets forth information on manufacturing and development chemistry expenses (in millions):

 2023

 2022

 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards

 $

 65.3

 $

 76.2

 8.8

 9.9

 Total manufacturing and development chemistry expenses

 $

 74.1

 $

 86.1

 Manufacturing and development chemistry expenses, excluding
 non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022. In 2022, we manufactured higher quantities of API to support launch preparation activities for WAINUA, olezarsen and donidalorsen. Refer to the section
 titled, Manufacturing, in Part I, Item 1, Business, for further details on the activities and types of costs we incur
 in our manufacturing process.

 R&D Support

 In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for buildings and
 equipment, utilities, depreciation of laboratory equipment and facilities, amortization of our intellectual property, information technology costs, procurement costs and waste disposal costs. We call these costs R&D support expenses.

 The following table sets forth information on R&D support expenses (in millions):

 2023

 2022

 Personnel costs

 $

 27.2

 $

 21.2

 Occupancy

 28.7

 19.2

 Consulting

 4.8

 0.8

 Patent expenses

 4.3

 4.7

 Insurance

 3.6

 3.8

 Computer software and licenses

 2.7

 1.9

 Other

 9.7

 8.2

 Total R&D support expenses, excluding non-cash compensation expense related to equity awards

 81.0

 59.8

 15.0

 14.1

 Total R&D support expenses

 $

 96.0

 $

 73.9

 R&D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022. The
 increase was primarily related to increased occupancy, personnel and consulting costs to support advancing our pipeline and our technology. In October 2022, we executed a sale and leaseback transaction for our headquarters in Carlsbad, California. As a
 result, beginning in the fourth quarter of 2022, our occupancy costs increased because we began incurring rent expense for these facilities.

 Selling, General and Administrative Expenses

 SG&A expenses include personnel and outside costs associated with the pre-commercialization and commercialization activities for our
 medicines and costs to support our company, our employees and our stockholders including, legal, human resources, investor relations and finance. Additionally, we include in SG&A expenses such costs as rent, repair and maintenance of buildings and
 equipment, depreciation and utilities costs that we need to support the corporate functions listed above. We also include fees we owe under our in-licensing agreements related to SPINRAZA and QALSODY.

 The following table sets forth information on SG&A expenses (in millions):

 2023

 2022

 Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards

 $

 205.1

 $

 124.4

 27.5

 25.9

 Total selling, general and administrative expenses

 $

 232.6

 $

 150.3

 SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to
 increased expenses related to our go-to-market activities for WAINUA, olezarsen and donidalorsen. In addition, we recorded a one-time expense of $20 million when we terminated a build-to-suit lease agreement in August 2023. Refer to Part IV, Item 15,
 Note 7, Long-Term Obligations and Commitments, in the Notes to the
 Consolidated Financial Statements for further details on the lease termination.

 Investment Income

 Investment income for 2023
 was $89.0 million compared to $25.3
 million for 2022. The increase in investment income was primarily due to an increase in interest rates associated with our investments in debt
 securities and an increase in our cash available for investment during 2023 compared to 2022. Our cash balance increased due to the $500.0 million upfront payment we received in January 2023 from our royalty purchase agreement with Royalty Pharma
 Investments, or Royalty Pharma, net proceeds we received from the debt offering in June 2023 and payments from partners. These increases were partially offset by the repurchase of $504.4 million in principal of our 0.125% Notes during 2023.

 Interest Expense

 The following table sets forth information on interest expense (in millions):

 2023

 2022

 Convertible senior notes:

 Non-cash amortization of debt issuance costs

 $

 5.9

 $

 5.3

 Interest expense payable in cash

 6.4

 0.7

 Interest on mortgage for primary R&D and manufacturing facilities

 0.4

 2.1

 Total interest expense

 $

 12.7

 $

 8.1

 In 2023, we completed a $575.0 million offering of our 1.75% Notes and repurchased $504.4 million in principal of our 0.125% Notes. As a
 result, beginning in the second quarter of 2023, our interest expense related to our convertible notes increased because we began incurring interest expense for our 1.75% Notes.

 Interest Expense Related to Sale of Future Royalties

 We recorded $ 68.8 million of interest expense related to the sale of future royalties in 2023 as a result of the
 Royalty Pharma transaction, in which we sold a minority interest in our future SPINRAZA and pelacarsen royalties to Royalty Pharma for a $500 million upfront payment and $625 million of potential future payments. Refer to Part IV, Item 15,
 Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details.

 Loss on Investments

 We recorded a $1.9 million and
 $7.3 million loss on investments for 2023 and 2022, respectively. The period-over-period fluctuation in our loss on investments was primarily
 driven by changes in the fair value of our investments in publicly traded and privately held biotechnology companies.

 Gain on Sale of Real Estate

 In 2022, we closed a purchase and sale agreement with a real estate investor in which we sold and leased back the facilities at our
 headquarters location in Carlsbad, California for a total purchase price of $263.4 million and recorded a gain of $150.1 million in 2022, resulting in income tax expense of $8.8 million. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, for further details on this transaction.

 Other Income (Expense)

 In 2023, we completed a $575.0 million offering of our 1.75%
 Notes and used $488.2 million of the net proceeds to repurchase $504.4 million in principal of our 0.125% Notes. As a result of these repurchases, we recorded a $13.4 million gain on early retirement of debt in 2023, which reflects the difference
 between the amounts we paid to repurchase portions of our 0.125% Notes and the net carrying balance of the liability at the time that we repurchased the debt. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further
 details regarding our convertible debt.

 Income Tax Expense (Benefit)

 We recorded an income tax expense of $32.3 million for 2023 compared to $11.7 million for 2022.

 The primary drivers of our income tax expense despite our full year pretax loss relate to the requirement for taxpayers to amortize
 research and development expenditures over five years pursuant to Internal Revenue Code, or IRC, Section 174 beginning in 2022 under the Tax Cuts and Jobs Act of 2017, or TCJA, and the impact of the royalty purchase agreement with Royalty Pharma, which
 we reflected as a taxable sale which required us to include the proceeds from the sale, net of currently deductible issuance costs, as taxable income in 2023. The resulting tax liability is partially offset by the utilization of our R&D tax
 credits.

 The increase in income tax expense for 2023 compared to 2022 relates primarily to the impact of the Royalty Pharma transaction.

 We continue to maintain a full valuation allowance on all our net deferred tax assets.

 Net Loss and Net Loss per Share

 We generated a net loss of $366.3
 million for 2023 compared to $269.7
 million for 2022. Our net loss increased for 2023 compared to 2022 primarily due to factors discussed in the sections above. Basic and diluted net loss per share for 2023 were $2.56 compared to $1.90 for 2022.

 Liquidity and Capital Resources

 We have financed our operations primarily from research and
 development collaborative agreements. We also financed our operations from commercial revenue from SPINRAZA and QALSODY royalties and TEGSEDI and WAYLIVRA commercial revenue. In addition, we expect to receive commercial revenue from WAINUA
 royalties beginning in 2024. From our inception through December 31, 2023,
 we have earned approximately $7.2 billion in revenue. We have also
 financed our operations through the sale of our equity securities, the issuance of long-term debt and the sale of future royalties. From the time we were founded through December 31, 2023, we have raised net proceeds of approximately $ 2.1 billion from the sale of our equity securities. Additionally, from our inception through December 31, 2023, we have borrowed approximately $ 2.7 billion under long-term debt arrangements and received proceeds of $0.5
 billion from the sale of future royalties to finance a portion of our operations.

 Our cash, cash equivalents and short-term investments, working capital and long-term obligations increased from 2022 to 2023. As discussed
 above, in 2023, we repurchased $504.4 million in principal of our 0.125% Notes. In the third quarter of 2023, we closed a real estate transaction and received $32.4 million. In the second quarter of 2023, we issued $575.0 million of 1.75% Notes (due in
 June 2028). In the first quarter of 2023, we received an upfront payment of $500.0 million when we entered into a royalty purchase agreement with Royalty Pharma and recorded a corresponding long-term liability related to the sale of future royalties.

 The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of December 31, 2023. The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our
 debt in Part IV, Item 15, Note 7, Long-Term Obligations and
 Commitments, in the Notes to the Consolidated Financial Statements.

 Contractual Obligations

 Payments Due by Period

 (in millions)

 (selected balances described below)

 Total

 Less than 1 year

 More than 1 year

 1.75% Notes (principal and interest payable)

 $

 620.3

 $

 10.1

 $

 610.2

 0% Notes (principal payable)

 632.5

 —

 632.5

 0.125% Notes (principal and interest payable)

 44.6

 44.6

 —

 Building mortgage payments (principal and interest payable)

 10.2

 0.5

 9.7

 Operating leases

 279.5

 20.4

 259.1

 Other obligations (principal and interest payable)

 0.8

 0.1

 0.7

 Total

 $

 1,587.9

 $

 75.7

 $

 1,512.2

 Our contractual obligations consist primarily of our convertible debt. In addition, we also have a facility mortgage, facility leases,
 equipment financing arrangements and other obligations. We believe our cash, cash equivalents and short-term investments, as well as plans for cash in the future, will be sufficient to fund our planned operations and these obligations. We have not
 entered into, nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules).

 Convertible Debt and Call Spread

 Refer to our Convertible Debt and Call Spread accounting
 policies in Part IV, Item 15, Note 1, Organization and Significant Accounting Policies, and Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for the significant terms of each convertible debt instrument.

 Operating Facilities

 Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated
 Financial Statements for further details on our operating facilities.

 Operating Leases

 Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated
 Financial Statements for further details on our operating leases.

 Royalty Revenue Monetization

 In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and
 pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements
 for further details on this agreement.

 Other Obligations

 In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2023 for the purchase of services, capital equipment and materials as part of our normal course of business.

 We may enter into additional collaborations with partners which could provide for additional revenue to us and we may incur additional
 cash expenditures related to our obligations under any of the new agreements we may enter into. We currently intend to use our cash, cash equivalents and short-term investments to finance our activities. However, we may also pursue other financing
 alternatives, like issuing additional shares of our common stock, issuing debt instruments, refinancing our existing debt, securing lines of credit or executing royalty monetization agreements. Whether we use our existing capital resources or choose to
 obtain financing will depend on various factors, including the future success of our business, the prevailing interest rate environment and the condition of financial markets generally.

 Critical Accounting Estimates

 We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S. As such, we make
 certain estimates, judgments and assumptions that we believe are reasonable, based upon the information available to us. These judgments involve making estimates about the effect of matters that are inherently uncertain and may significantly impact our
 quarterly or annual results of operations and financial condition. Each quarter, our senior management reviews the development, selection and disclosure of such estimates with the audit committee of our board of directors. In the following paragraphs,
 we describe the specific risks associated with these critical accounting estimates and we caution that future events rarely develop exactly as one may expect, and that best estimates may require adjustment. Our significant accounting policies are
 outlined in Part IV, Item 15, Note 1, Organization and Significant
 Accounting Policies, in the Notes to the Consolidated Financial Statements.

 The following are our significant accounting estimates, which we believe are the most critical to aid in fully understanding and
 evaluating our reported financial results:

 Assessing the propriety of revenue recognition and associated deferred revenue;

 Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities; and

 Assessing the appropriate estimate of anticipated future royalty payments under our royalty purchase agreement

 The following are descriptions of our critical accounting estimates.

 Revenue Recognition

 We earn revenue from several sources. The judgements and estimates we make vary between each source of our revenue. At contract inception,
 we analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the
 commercial success of such activities and therefore within the scope of Accounting Standards Codification, or ASC, Topic 808, Collaborative Arrangements,
 or ASC 808. For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and are therefore within the scope of ASC 606, Revenue from Contracts with Customers. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we consistently
 apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.

 The following is a summary of the critical accounting estimates we make with respect to our revenue.

 Research and development revenue under collaborative agreements

 We recognize R&D revenue from numerous collaboration agreements. Our collaboration agreements typically contain multiple elements, or
 performance obligations, including technology licenses or options to obtain technology licenses, R&D services, and manufacturing services. Upon entering into a collaboration agreement, we are required to make the following judgements:

 Identifying the performance obligations contained in the agreement

 Our assessment of what constitutes a separate performance
 obligation requires us to apply judgement. Specifically, we have to identify which goods and services we are required to provide under the contract are distinct.

 Determining the transaction price, including any variable consideration

 To determine the transaction price, we review the amount of consideration we are eligible to earn under the agreement. We do not typically
 include any payments we may receive in the future in our initial transaction price since the payments are typically not probable because they are contingent upon certain future events. We reassess the total transaction price at each reporting period to
 determine if we should include additional payments in the transaction price that have become probable.

 Allocating the transaction price to each of our performance obligations

 When we allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone selling
 price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. The estimate of the relative stand-alone selling price requires us in some cases to make significant judgements. For example, when we
 deliver a license at the start of an agreement, we use valuation methodologies, such as the relief from royalty method, to value the license. Under this method we are required to make estimates including: future sales, royalties on future product
 sales, contractual milestones, expenses, income taxes and discount rates. Additionally, when we estimate the selling price for R&D services, we make estimates, including: the number of internal hours we will spend on the services, the cost of work
 we and third parties will perform and the cost of clinical trial material we will use.

 The R&D revenue we recognize each period is comprised of several types of revenue, including amortization from upfront payments,
 milestone payments, license fees and other services that are recognized immediately or amortized over the period in which we satisfy our performance obligation. Each of these types of revenue require us to make various judgements and estimates.

 R&D Services with Upfront Payments

 We recognize revenue from the amortization of upfront payments as we perform R&D services. We use an input method to estimate the
 amount of revenue to recognize each period. This method requires us to make estimates of the total costs we expect to incur to complete our R&D services performance obligation or the total amount of effort it will take us to complete our R&D
 services performance obligation. If we change our estimates, we may have to adjust our revenue.

 Milestone Payments

 When recognizing revenue related to milestone payments, we typically make the following judgements and estimates:

 Whether a milestone payment is probable (discussed in detail above under "Determining the
 transaction price, including any variable consideration");

 Whether a milestone payment relates to services we are performing or if our partner is performing the services;

 If we are performing services, we recognize revenue over our estimated period of performance in a similar manner to the amortization of upfront payments (discussed above
 under "R&D Services with Upfront Payments"); and

 Conversely, we recognize in full those milestone payments that we earn based on our partners' activities when our partner achieves the milestone event and we do not have
 a performance obligation.

 License Fees

 When we grant a license for a medicine in clinical
 development, we generally recognize as R&D revenue the total amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. Refer to Part IV, Item 15, Note 1, Organization and Significant Accounting Policies, in the Notes to the Consolidated Financial Statements for our revenue recognition policy. We discuss
 the estimates we make related to the relative stand-alone selling price of a license in detail above under "Allocating the transaction price to each of our performance obligations."

 Estimated Liability for Clinical Development Costs

 We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
 basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
 third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
 determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
 settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.

 As of December 31, 2023, a
 hypothetical 10 percent increase in our liability for preclinical and clinical development costs would have resulted in an increase in our loss before income tax benefit and accrued liabilities of approximately $10.6 million.

 Liability Related to Sale of Future Royalties

 In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and
 pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively. Under our agreement with Royalty Pharma, we calculate the liability related to the sale of future royalties, effective interest rate and the related
 interest expense using our current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the
 medicines. The amount that Royalty Pharma will receive under the agreement is based on sales of SPINRAZA, our currently commercialized medicine, and pelacarsen, a product candidate that is not currently commercialized. As such, the repayment amounts
 that we estimate related to projections of future pelacarsen revenues contain more subjective estimation which we believe could lead to larger changes in estimates in the future. If there is a material change in our estimate, we will prospectively
 adjust the effective interest rate and the related interest expense.

 There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of future royalty
 payments, particularly those from Novartis for pelacarsen, and could result in changes to our estimate of future royalty payments to Royalty Pharma. Such factors include, but are not limited to, the regulatory approval and commercial sales of
 pelacarsen, competing products or other significant events. These factors and other events or circumstances could result in reduced royalty payments from sales of pelacarsen, which would result in a reduction of our non-cash royalty revenue and
 non-cash interest expense over the life of the agreement. Conversely, if sales of pelacarsen are more than amounts we estimated, the non-cash royalty revenue and non-cash interest expense we record would be greater over the life of the arrangement.

.

 Item 7A. Quantitative and Qualitative Disclosures About Market Risk

 We are exposed to changes in interest rates primarily from
 our investments in certain short-term investments. We primarily invest our excess cash in highly liquid short-term investments of the U.S. Treasury and reputable financial institutions, corporations, and U.S. government agencies with strong credit
 ratings. We typically hold our investments for the duration of the term of the respective instrument. We do not utilize derivative financial instruments, derivative commodity instruments or other market risk sensitive instruments, positions or
 transactions to manage exposure to interest rate changes. Accordingly, we believe that, while the securities we hold are subject to changes in the financial standing of the issuer of such securities, we were not subject to any material risks arising
 from changes in interest rates, foreign currency exchange rates, commodity prices, equity prices or other market changes that affect market risk sensitive instruments as of December 31, 2023 and will not be subject to any material risks arising from these changes in the foreseeable future.

 Item 8. Financial Statements and Supplementary Data

 We filed our consolidated financial statements and supplementary data required by this item as exhibits hereto, and listed them under Item
 15(a)(1) and (2), and incorporate them herein by reference.

 Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure

 None.

 Item 9A. Controls and Procedures

 Disclosure Controls and Procedures

 We maintain disclosure controls and procedures (as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, as
 amended, or Exchange Act) that are designed to ensure that information we are required to disclose in our Exchange Act reports is recorded, processed, summarized and reported within the time periods specified in the SEC's rules and forms, and that such
 information is accumulated and communicated to our management, including our Chief Executive Officer and Chief Financial Officer, as appropriate, to allow timely decisions regarding required disclosure. We designed and evaluated our disclosure controls
 and procedures recognizing that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance and not absolute assurance of achieving the desired control objectives.

 As of the end of the period covered by this report on Form 10-K, we carried out an evaluation of our disclosure controls and procedures
 under the supervision of, and with the participation of our management, including our Chief Executive Officer and Chief Financial Officer. Based on our evaluation, our Chief Executive Officer and Chief Financial Officer concluded that our disclosure
 controls and procedures were effective as of December 31, 2023.

 Management ' s Report on Internal Control over Financial Reporting

 Our management is responsible for establishing and maintaining adequate internal control over financial reporting, as defined in Exchange
 Act Rules 13a-15(f). Our internal control over financial reporting is a process designed under the supervision of our Chief Executive Officer and Chief Financial Officer to provide reasonable assurance regarding the reliability of financial reporting
 and the preparation of our financial statements for external purposes in accordance with U.S. generally accepted accounting principles.

 As of December 31, 2023, we
 assessed the effectiveness of our internal control over financial reporting based on the criteria for effective internal control over financial reporting under the 2013 "Internal Control—Integrated Framework," issued by the Committee of Sponsoring
 Organizations, or COSO, of the Treadway Commission, under the supervision of, and with the participation of our management, including our Chief Executive Officer and Chief Financial Officer. Based on that assessment, our management concluded that we
 maintained effective internal control over financial reporting as of December 31, 2023.

 Ernst & Young LLP, an independent registered public accounting firm, audited the effectiveness of our internal control over financial
 reporting as of December 31, 2023, as stated in their attestation report, which is included elsewhere herein.

 Changes in Internal Control over Financial Reporting

 The above assessment did not identify any change in our internal control over financial reporting that occurred during our latest fiscal
 quarter and that has materially affected, or is reasonably likely to materially affect, our internal control over financial reporting.

 REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM

 To the Stockholders and Board of Directors of Ionis Pharmaceuticals, Inc.

 Opinion on Internal Control over Financial Reporting

 We have audited Ionis Pharmaceuticals, Inc.'s internal control over financial reporting as of December 31, 2023, based on criteria
 established in Internal Control—Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) (the COSO criteria). In our opinion, Ionis Pharmaceuticals, Inc. (the Company) maintained, in all
 material respects, effective internal control over financial reporting as of December 31, 2023, based on the COSO criteria.

 We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the
 consolidated balance sheets of the Company as of December 31, 2023 and 2022, the related consolidated statements of operations, comprehensive loss, stockholders' equity and cash flows for each of the three years in the period ended December 31, 2023,
 and the related notes and our report dated February 21, 2024 expressed an unqualified opinion thereon.

 Basis for Opinion

 The Company's management is responsible for maintaining effective internal control over financial reporting and for its assessment of the
 effectiveness of internal control over financial reporting included in the accompanying Management's Report on Internal Control over Financial Reporting. Our responsibility is to express an opinion on the Company's internal control over financial
 reporting based on our audit. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the
 Securities and Exchange Commission and the PCAOB.

 We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to
 obtain reasonable assurance about whether effective internal control over financial reporting was maintained in all material respects.

 Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness
 exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable
 basis for our opinion.

 Definition and Limitations of Internal Control Over Financial Reporting

 A company's internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of
 financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company's internal control over financial reporting includes those policies and procedures that (1)
 pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit
 preparation of financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3)
 provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company's assets that could have a material effect on the financial statements.

 Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections
 of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.

 /s/ Ernst & Young LLP

 San Diego, California

 Item 9B. Other Information

 Trading Plans

 During the quarter ended December 31, 2023, our
 officers and directors (as defined in Rule 16a-1(f) under the Exchange Act), or Section 16 officers and directors, adopted or terminated contracts, instructions or written plans for the purchase or sale of our securities as noted in the table below.

 *

 Contract, instruction or written plan intended to satisfy the affirmative defense conditions of Rule 10b5-1(c) under the Exchange Act.

 **

 "Non-Rule 10b5-1 trading arrangement" as defined in item 408(c) of Regulation S-K under the Exchange Act.

 Action

 Date

 Trading Arrangement

 Total Shares

 to be Sold

 Expiration Date

 Rule 10b5-1*

 Non-Rule 10b5-1 **

 Joseph Wender, Board Member

 Adoption

 November 30, 2023

 X

 104,079

 February 28, 2025

 Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections

 Not applicable.

 Item 10. Directors, Executive Officers and Corporate Governance

 We incorporate by reference the information required by this
 Item with respect to directors and the Audit Committee from the information under the caption "ELECTION OF DIRECTORS," including in particular the information under "Nominating, Governance and Review Committee" and "Audit Committee," contained in our
 definitive Proxy Statement, which we will file with the Securities and Exchange Commission within 120 days after the end of the fiscal year ended December 31, 2023, or the Proxy Statement.

 We include information concerning our executive officers in the section titled, Information about our Executive Officers, in this report on the Form 10-K in Item 1 titled "Business."

 We incorporate by reference the required information concerning our Code of Ethics from the information under the caption "Code of Ethics
 and Business Conduct" contained in the Proxy Statement. Our Code of Ethics and Business Conduct is posted on our website at www.ionispharma.com (1). We intend to make all required disclosures regarding any amendments to, or waivers from,
 provisions of our Code of Ethics and Business conduct on our website.

 ___________

 (1)

 Any information that is included on or linked to our website is not part of this Form 10-K.

 Delinquent Section 16(a) Reports

 Item 1, Part I of this Report contains information concerning our executive officers. We incorporate by reference the information required
 by this Item concerning compliance with Section 16(a) of the Exchange Act from the information under the caption "Delinquent Section 16(a) Reports" contained in the Proxy Statement.

 Item 11. Executive Compensation

 We incorporate by reference the information required by this item to the information under the caption "EXECUTIVE COMPENSATION,"
 "Compensation Committee Interlocks and Insider Participation" and "COMPENSATION COMMITTEE REPORT" contained in the Proxy Statement.

 Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters

 We incorporate by reference the information required by this item to the information under the captions "SECURITY OWNERSHIP OF CERTAIN
 BENEFICIAL OWNERS AND MANAGEMENT" contained in the Proxy Statement.

 Securities Authorized for Issuance under Equity Compensation Plans

 The following table sets forth information regarding outstanding options and shares reserved for future issuance under our equity
 compensation plans as of December 31, 2023.

 Plan Category

 Number of Shares to

 be Issued Upon Exercise

 of Outstanding Options

 Weighted Average

 Exercise Price of

 Outstanding Options

 Number of Shares

 Remaining Available

 for Future Issuance

 Equity compensation plans approved by stockholders (a)

 14,090,732

 $

 48.43

 9,976,286

 (b)

 Total

 14,090,732

 $

 48.43

 9,976,286

 ________________

 (a)

 Consists of five Ionis plans: 1989 Stock Option Plan, Amended and Restated 2002 Non-Employee Directors' Stock Option Plan, 2011 Equity Incentive Plan, 2020 Equity
 Incentive Plan and Employee Stock Purchase Plan, or ESPP.

 (b)

 Of these shares, 386,792 were available for purchase under the ESPP as of December 31, 2023.

 For additional details about our equity compensation plans, including a description of each plan, refer to Part IV, Item 15, Note 8, Stockholders' Equity, in the Notes to the Consolidated Financial Statements.

 Item 13. Certain Relationships and Related Transactions, and Director Independence

 We incorporate by reference the information required by this item to the information under the captions "Information Regarding the Board
 and Corporate Governance" and "Certain Relationships and Related Transactions" contained in the Proxy Statement.

 Item 14. Principal Accountant Fees and Services

 We incorporate by reference the information required by this item to the information under the caption "Ratification of Selection of
 Independent Auditors" contained in the Proxy Statement.

 Item 15. Exhibits, Financial Statement Schedules

 (a)(1) Index to Financial Statements

 We submitted the consolidated financial statements required by this item in a separate section beginning on page F-1 of this Report.

 (a)(2) Index to Financial Statement Schedules

 We omitted these schedules because they are not required, or are not applicable, or the required information is shown in the consolidated
 financial statements or notes thereto.

 (a)(3) Index to Exhibits

 INDEX TO EXHIBITS

 Exhibit Number

 Description of Document

 2.1

 Agreement and Plan of Merger, dated as of August 30, 2020, among Akcea Therapeutics, Inc., Ionis Pharmaceuticals, Inc. and Avalanche Merger Sub, Inc., filed as an exhibit to the Registrant's Current Report on Form 8-K filed August 31, 2020 and incorporated herein by reference.

 3.1

 Amended and Restated Certificate of Incorporation filed June 19, 1991,
 filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.

 3.2

 Certificate of Amendment to Restated Certificate of Incorporation, filed
 as an exhibit to the Registrant's Notice of Annual Meeting and Proxy Statement, for the 2014 Annual Meeting of Stockholders, filed on April 25, 2014 and incorporated herein by reference.

 3.3

 Certificate of Amendment to Restated Certificate of Incorporation, filed as an
 exhibit to the Registrant's Current Report on Form 8-K filed December 18, 2015 and incorporated herein by reference.

 3.4

 Amended and Restated Bylaws, filed as an exhibit to the
 Registrant's Current Report on Form 8-K filed March 29, 2021 and incorporated herein by reference.

 4.1

 Description of the Registrant's Securities, filed as an exhibit to the
 Registrant's Annual Report on Form 10-K for the year ended December 31, 2021 and incorporated herein by reference.

 4.2

 Certificate of Designation of the Series C Junior Participating Preferred Stock, filed as an exhibit to Registrant's Current Report on Form 8-K filed December 13, 2000 and incorporated herein by reference.

 4.3

 Specimen Common Stock Certificate, filed as an exhibit to the
 Registrant's Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.

 4.4

 Indenture, dated as of December 19, 2019, by and between the Registrant and U.S. Bank National Association, as trustee, including Form of 0.125 percent
 Convertible Senior Note due 2024, filed as an exhibit to the Registrant's Current Report on Form 8-K filed December 23, 2019 and incorporated herein by
 reference.

 4.5

 Form of Exchange and/or Subscription Agreement for Convertible Senior Notes due 2024, filed as an exhibit to the Registrant's Current Report on Form 8-K filed December 12, 2019 and incorporated herein by reference.

 4.6

 Form of Convertible Note Hedge Transactions Confirmation for Convertible
 Senior Notes due 2024, filed as an exhibit to the Registrant's Current Report on Form 8-K filed December 12, 2019 and incorporated herein by reference.

 4.7

 Form of Warrant Transactions Confirmation for Convertible Senior Notes due
 2024, filed as an exhibit to the Registrant's Current Report on Form 8-K filed December 12, 2019 and incorporated herein by reference.

 4.8

 Indenture, dated as of April 12, 2021, by and between the Registrant and U.S. Bank National Association, as trustee, including Form of 0 percent
 Convertible Senior Note due 2026, filed as an exhibit to the Registrant's Current Report on Form 8-K filed April 13, 2021 and incorporated herein by reference.

 4.9

 Form of Warrant Confirmation for Convertible Senior Notes due 2026,
 filed as an exhibit to the Registrant's Current Report on Form 8-K filed April 13, 2021 and incorporated herein by reference.

 4.10

 Form of Convertible Note Hedge Confirmation for Convertible Senior Notes due 2026, filed as an exhibit to the Registrant's Current Report on Form 8-K filed April 13, 2021 and incorporated herein by reference.

 4.11

 Indenture, dated as of June 12, 2023, by and between the Registrant and U.S. Bank Trust Company, a National Association, as trustee, including Form of
 1.75 percent Global Note due in 2028, filed as an exhibit to the Registrant's Current Report on Form 8-K filed June 12, 2023 and incorporated herein by
 reference.

 10.1*

 Second Amended Non-Employee Director Compensation Policy, filed as an exhibit
 to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2023 and incorporated herein by reference.

 10.2*

 Registrant's Amended and Restated Severance Benefit Plan dated March 17, 2022, filed as an exhibit to the Registrant's Quarterly Report on form 10-Q for the quarter ended March 31, 2022 and incorporated herein by reference.

 10.3

 Form of Indemnity Agreement entered into between the Registrant and its Directors and Executive Officers with related schedule

 10.4

 Form of Employee Confidential Information and Inventions Agreement, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year
 ended December 31, 2017 and incorporated herein by reference.

 10.5*

 Registrant's Amended and Restated 2000 Employee Stock Purchase Plan, filed as
 an exhibit to Registrant's Current Report on Form 8-K filed on March 26, 2019 and incorporated herein by reference.

 10.6*

 Registrant's Amended and Restated 2002 Non-Employee Directors' Stock Option Plan, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2023 and incorporated herein by reference.

 10.7 *

 Form of Option Agreement for Options granted under the Ionis Pharmaceuticals, Inc. Amended and Restated 2002 Non-Employee Directors' Stock Option Plan, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference.

 10.8*

 Forms of Restricted Stock Unit Grant Notice and Restricted Stock Unit Agreement for Restricted Stock Units granted under the Ionis Pharmaceuticals, Inc.
 Amended and Restated 2002 Non-Employee Directors' Stock Option Plan, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter
 ended March 31, 2023 and incorporated herein by reference.

 10.9*

 Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan, filed as an exhibit to the Registrant's Notice of 2021 Annual Meeting of Stockholders and Proxy Statement filed on April 23, 2021 and incorporated herein by reference.

 10.10 *

 Form of Option Agreement under the 2011 Equity Incentive Plan, filed
 as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference.

 10.11 *

 Form of Time-Vested Restricted Stock Unit Agreement for Restricted Stock Units granted under the 2011 Equity Incentive Plan, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference.

 10.12*

 Forms of Performance Based Restricted Stock Unit Grant Notice and Performance Based Restricted Stock Unit Agreement for Performance Based Restricted
 Stock Units granted prior to January 1, 2023 under the 2011 Equity Incentive Plan, filed as an exhibit to the Registrant's Annual Report on Form 10-K for
 the year ended December 31, 2021 and incorporated herein by reference.

 10.13 *

 Forms of Performance Based Restricted Stock Unit Grant Notice and Performance Based Restricted Stock Unit Agreement for Performance Based Restricted
 Stock Units granted beginning January 1, 2023 under the 2011 Equity Incentive Plan, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the
 year ended December 31, 2022 and incorporated herein by reference.

 10.14*

 Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, filed as
 an exhibit to the Registrant's Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference.

 10.15*

 Form of Global Option Agreement for options granted under the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, filed as an exhibit to the Registrant's Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference.

 10.16*

 Form of Global Restricted Stock Unit Agreement for restricted stock units granted under the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive
 Plan, filed as an exhibit to the Registrant's Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference.

 10.17*

 Forms of Restricted Stock Unit Grant Notice, Stock Option Grant Notice and Stock Option Exercise Notice for options granted under the Ionis
 Pharmaceuticals, Inc. 2020 Equity Incentive Plan, filed as an exhibit to the Registrant's Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference.

 10.18

 Loan Agreement between Ionis Faraday, LLC and UBS AG dated July 18, 2017,
 filed as an exhibit to the Registrant's Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.

 10.19

 Guaranty between the Registrant and UBS AG dated July 18, 2017, filed as an
 exhibit to the Registrant's Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference.

 10.20

 Purchase and Sale Agreement between Ionis Gazelle, LLC and 2850 2855 & 2859 Gazelle Owner (DE) LLC dated as of October 20, 2022, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit
 have been omitted because they are both (i) not material and (ii) is the type that the Registrant treats as private or confidential.

 10.21

 Purchase and Sale Agreement between the Registrant and Oxford I Asset Management USA Inc. dated as of October 20, 2022, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because
 they are both (i) not material and (ii) is the type that the Registrant treats as private or confidential.

 10.22

 First Amendment dated June 15, 2023 to the Purchase and Sale Agreement by and between the Registrant and Oxford I Asset Management USA Inc. dated as of
 October 20, 2022, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 and incorporated herein by
 reference.

 10.23

 Lease Agreement dated October 20, 2022 between the Registrant and 2850 2855 & 2859 Gazelle Owner (DE) LLC, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because
 they are both (i) not material and (ii) is the type that the Registrant treats as private or confidential.

 10.24

 Amended and Restated Lease Agreement between the Registrant and Lots 21 & 22 Owner (DE) LLC dated as of August 21, 2023, filed as an exhibit to the
 Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted
 because they are both (i) not material and (ii) is the type that the Registrant treats as private or confidential.

 10.25

 First Amendment dated as of November 6, 2023 to Amended and Restated Lease Agreement between the Registrant and Lots 21 & 22 Owner (DE) LLC dated
 as of August 21, 2023.

 10.26

 Defeasance Pledge and Security Agreement dated as of October 20, 2022 by and among Ionis Gazelle, LLC, Wells Fargo Bank, National Association, as
 Trustee for the Benefit of the Registered Holders of UBS Commercial Mortgage Trust 2017-C3, Commercial Mortgage Pass-Through Certificates, Series 2017-C3, and U.S. Bank Trust Company, National Association, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because
 they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.27

 Defeasance Assignment, Assumption and Release Agreement dated as of October 20, 2022 by and among Ionis Gazelle, LLC, DHC UBSCM 17 C3 Successor
 Borrower-R, LLC, Wells Fargo Bank, National Association, as Trustee for the Benefit of the Registered Holders of UBS Commercial Mortgage Trust 2017-C3, Commercial Mortgage Pass-Through Certificates, Series 2017-C3, Midland Loan Services, a
 division of PNC Bank, National Association, and U.S. Bank Trust Company, National Association, filed as an exhibit to the Registrant's Annual Report on Form 10-K
 for the year ended December 31, 2022 and incorporated herein by reference.

 10.28

 Defeasance Account Agreement dated as of October 20, 2022 by and among Ionis Gazelle, LLC, U.S. Bank Trust Company, National Association, U.S. Bank
 National Association, as Trustee for the Benefit of the Registered Holders of UBS Commercial Mortgage Trust 2017-C3, Commercial Mortgage Pass-Through Certificates, Series 2017-C3, and Midland Loan Services, a division of PNC Bank, National
 Association, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference.
 Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.29

 Exclusive License Agreement between the Registrant and the University of Massachusetts dated January 14, 2010, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted and separately
 filed with the SEC with a request for confidential treatment.

 10.30

 Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated March 30, 2010, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2010 and incorporated herein by reference. Portions of this exhibit have been omitted and
 separately filed with the SEC with a request for confidential treatment.

 10.31

 Amendment #1 to the Research, Development and License Agreement dated May 11, 2011 by and between the Registrant and Glaxo Group Limited, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2011 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.32

 Amendment #2 to the Research, Development and License Agreement by and between the Registrant and Glaxo Group Limited dated October 30, 2012, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2012 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.33

 Amendment No. 3 to the Research, Development and License Agreement by and between the Registrant and Glaxo Group Limited dated July 10, 2013, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.34

 Amendment #4 to the Research, Development and License Agreement by and between the Registrant and Glaxo Group Limited dated April 10, 2014, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.35

 Amendment #5 to the Research, Development and License Agreement by and between the Registrant, Glaxo Group Limited and GlaxoSmithKline Intellectual Property
 Development Limited dated June 27, 2014, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and
 incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.36

 Amendment #6 to Research, Development and License Agreement by and between the Registrant, Glaxo Group Limited and GlaxoSmithKline Intellectual Property
 Development Limited dated September 2, 2015, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and
 incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.37

 Amendment #7 to the Research, Development and License Agreement by and between the Registrant, Glaxo Group Limited and GlaxoSmithKline Intellectual Property
 Development Limited dated March 4, 2016, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2016 and
 incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.38

 Amendment #8 to the Research, Development and License Agreement by and between the Registrant, Glaxo Group Limited and Glaxosmithkline Intellectual Property
 Development Limited, dated July 29, 2019, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and
 incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.39

 Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring Harbor Laboratory dated October 26, 2011, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference. Portions of this
 exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.40

 Amendment to Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring Harbor Laboratory dated March 14, 2014, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and incorporated herein by reference. Portions of this
 exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.41

 Development, Option and License Agreement between the Registrant and Biogen Idec International Holding Ltd. dated January 3, 2012, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2012 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.42

 Amendment #1 to the Development, Option and License Agreement between the Registrant and Biogen Idec International Holding Ltd. dated December 15, 2014, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2014 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.43

 Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated December 7, 2012, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2012 and incorporated herein by reference. Portions of this exhibit have been omitted and
 separately filed with the SEC with a request for confidential treatment.

 10.44

 Amendment #1 to Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated August 13, 2013, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2013 and incorporated herein by reference. Portions of this
 exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.45

 Amendment No.2 to the Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated October 15, 2014, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2014 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.46

 Amendment No.3 to the Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated January 18, 2016, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2016 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.47

 Amendment No. 4 to the Collaboration, License and Development Agreement by and between the Registrant and AstraZeneca AB, dated October 18, 2018, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.48

 HTT Research, Development, Option and License Agreement among the Registrant, F. Hoffmann-La Roche Ltd and Hoffman-La Roche Inc. dated April 8,
 2013, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2023 and incorporated herein by reference. Portions
 of this exhibit have been omitted because they are both (i) not material and (ii) is the type that the Registrant treats as private or confidential.

 10.49

 Amendment #1 to HTT Research, Development, Option and License Agreement between the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. dated
 January 9, 2015, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and incorporated herein by reference.
 Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.50

 Second Amended and Restated Strategic Collaboration and License Agreement between the Registrant and Alnylam Pharmaceuticals, Inc. dated January 8, 2015, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.51

 Amendment Number One to the Second Amended and Restated Strategic Collaboration and License Agreement between the Registrant and Alnylam Pharmaceuticals, Inc.
 dated July 13, 2015, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by
 reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.52

 Strategic Collaboration Agreement between the Registrant and AstraZeneca AB dated July 31, 2015, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with
 the SEC with a request for confidential treatment.

 10.53

 Amendment No. 1 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB, dated October 18, 2018, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated herein by reference. Portions of this exhibit
 have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.54

 Amendment No. 2 dated April 30, 2020 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB dated July 31, 2015, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not
 material and (ii) is the type that the Registrant treats as private or confidential.

 10.55

 Amendment No. 3 dated December 17, 2020 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB dated July 31, 2015, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both
 (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.56

 Strategic Collaboration, Option and License Agreement by and among Akcea Therapeutics, Inc. and Novartis Pharma AG, dated January 5, 2017,
 filed as an exhibit to Akcea Therapeutics, Inc.'s Form S-1 filed March 27, 2017 and incorporated herein by reference.

 10.57

 Amendment No. 1 to the Strategic Collaboration, Option and License Agreement between Akcea Therapeutics, Inc. and Novartis Pharma AG dated February
 22, 2019, filed as an exhibit to Akcea Therapeutics, Inc.'s Quarterly Report on Form 10-Q for the quarter ended March 30, 2019 and incorporated herein by reference.

 10.58

 Stock Purchase Agreement among the Registrant, Akcea Therapeutics, Inc. and Novartis Pharma AG dated January 5, 2017, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 and incorporated herein by reference.

 10.59

 Research Collaboration, Option and License Agreement between the Registrant and Biogen MA Inc. dated December 19, 2017, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference. Portions of this exhibit have been omitted and
 separately filed with the SEC with a request for confidential treatment.

 10.60

 New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc., dated April 19, 2018, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2018 and incorporated herein by reference.
 Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.61

 Amendment No. 1 to the New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement between the Registrant and Biogen MA
 Inc., dated August 16, 2019, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and incorporated
 herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.62

 Side Letter dated December 31, 2020 to the New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc. dated April 19,
 2018, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2020 and incorporated herein by
 reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.63

 Factor B Development Collaboration, Option and License Agreement by and between the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc.,
 dated October 9, 2018, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated herein by
 reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.64

 First Amendment dated July 8, 2022 to Factor B Development, Collaboration, Option and License Agreement by and between the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., dated October 9, 2018, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2022. Portions of this exhibit have been
 omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.65

 Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant
 and Biogen MA Inc., dated October 17, 2018, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2018 and
 incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment.

 10.66

 Letter Agreement between the Registrant and Biogen MA Inc. dated October 28, 2016, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2016 and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a
 request for confidential treatment.

 10.67

 Amendment No. 1 to Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between
 the Registrant and Biogen MA Inc., dated May 2, 2019, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2019
 and incorporated herein by reference.

 10.68

 Collaboration and License Agreement by and between the Registrant and Novartis Pharma AG dated as of August 2, 2023, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.69

 Research, Development, and License Agreement by and among the Registrant, F. Hoffmann-La Roche Ltd., and Hoffmann-La Roche Inc. dated as of September 26, 2023, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.70

 Side Letter dated June 11, 2020 to the Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc.
 dated October 17, 2018, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2020 and incorporated
 herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.71

 Collaboration and License Agreement by and between the Registrant and BicycleTX Limited dated July 9, 2021, filed as an exhibit to the Registrant's
 Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.72

 Amendment No. 1 dated December 17, 2021 to the Collaboration and License Agreement by and between the Registrant and BicycleTX Limited dated July 9, 2021, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2021 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.73

 Amendment No. 2 dated July 28, 2022 to the Collaboration and License Agreement by and between the Registrant and BicycleTx Limited dated July 9, 2021, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.74

 Amendment No. 3 dated April 27, 2023 to the Collaboration and License Agreement by and between the Registrant and BicycleTx Limited dated July 9, 2021, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.75

 Amended and Restated Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc.
 dated July 12, 2021, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and incorporated herein by
 reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.76

 Collaboration and License Agreement by and between Akcea Therapeutics, Inc. and AstraZeneca AB dated December 6, 2021, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2021 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.77

 Letter Agreement dated June 29, 2023 in reference to the Collaboration and License Agreement dated December 6, 2021 by and between Akcea Therapeutics, Inc.
 and AstraZeneca AB, filed as an exhibit to the Registrant's Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 and incorporated herein by
 reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.78

 Collaboration and License Agreement between the Registrant and Metagenomi, Inc. dated November 10, 2022, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both
 (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.79

 Royalty Purchase Agreement by and between the Registrant, Akcea Therapeutics, Inc. and Royalty Pharma Investments 2019 ICAV dated as of January 9, 2023, filed as an exhibit to the Registrant's Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit
 have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 10.80

 License Agreement by and between the Registrant and Otsuka Pharmaceuticals Co., LTD. dated as of December 15, 2023. Portions of this exhibit have
 been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential.

 21.1

 List of Subsidiaries for the Registrant.

 23.1

 Consent of Independent Registered Public Accounting Firm.

 24.1

 Power of Attorney – Included on the signature page of this Annual Report on Form 10-K.

 31.1

 Certification by Chief Executive Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of the Sarbanes-Oxley Act of 2002.

 31.2

 Certification by Chief Financial Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of the Sarbanes-Oxley Act of 2002.

 32.1+

 Certification Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.

 Registrant's Amended and Restated Clawback Policy

 (iii) consolidated statements of comprehensive income (loss), (iv) consolidated statements of stockholders' equity (v) consolidated statements of cash flows, and (vi) notes to consolidated financial statements (detail tagged).

 *

 Indicates management compensatory plans and arrangements as required to be filed as exhibits to this Report pursuant to Item 14(c).

 +

 This certification is deemed not filed for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liability of that
 section, nor shall it be deemed incorporated by reference into any filing under the Securities Act of 133, as amended, or the Securities Exchange Act of 1934, as amended.

 SIGNATURES

 Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the Registrant has duly caused this report on
 Form 10-K to be signed on its behalf by the undersigned, thereunto duly authorized on the 21 st day of February, 2024.

 By:

 /s/ BRETT P. MONIA

 Brett P. Monia, Ph. D.

 Chief Executive Officer (Principal executive officer)

 POWER OF ATTORNEY

 KNOW ALL MEN BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Brett P. Monia and Elizabeth L.
 Hougen, or any of them, his or her attorney-in-fact, each with the power of substitution, for him or her in any and all capacities, to sign any amendments to this Report, and to file the same, with exhibits thereto and other documents in connection
 therewith, with the Securities and Exchange Commission, hereby ratifying and confirming all that each of said attorneys-in-fact, or his or her substitute or substitutes, may do or cause to be done by virtue hereof.

 Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf
 of the Registrant and in the capacities and on the dates indicated.

 Signatures

 Title

 Date

 /s/ BRETT P. MONIA

 Director and Chief Executive Officer

 Brett P. Monia, Ph. D.

 (Principal executive officer)

 /s/ ELIZABETH L. HOUGEN

 Executive Vice President, Finance and Chief Financial Officer

 Elizabeth L. Hougen

 (Principal financial and accounting officer)

 /s/ JOSEPH LOSCALZO

 Chairman of the Board

 Joseph Loscalzo, M.D., Ph. D.

 /s/ SPENCER R. BERTHELSEN

 Spencer R. Berthelsen, M.D.

 /s/ ALLENE M. DIAZ

 Allene M. Diaz

 /s/ MICHAEL HAYDEN

 Michael Hayden, CM OBC MB ChB PhD FRCP(C) FRSC

 /s/ JOAN E. HERMAN

 Joan E. Herman

 /s/ JOSEPH KLEIN

 Joseph Klein, III

 /s/ B. LYNNE PARSHALL

 B. Lynne Parshall, J.D.

 /s/ JOSEPH H. WENDER

 Lead Independent Director

 Joseph H. Wender

 /s/ MICHAEL YANG

 Michael Yang

 INDEX TO CONSOLIDATED FINANCIAL STATEMENTS

 Page

 Report of Independent Registered Public Accounting Firm (PCAOB ID 42)

 Consolidated Balance Sheets at December 31, 2023 and 2022

 Consolidated Statements of Operations for the years ended December 31, 2023, 2022 and 2021

 Consolidated Statements of Comprehensive Loss for the years ended December 31, 2023, 2022 and 2021

 Consolidated Statements of Stockholders' Equity for the years ended December 31, 2023, 2022 and 2021

 Consolidated Statements of Cash Flows for the years ended December 31, 2023, 2022 and 2021

 Notes to the Consolidated Financial Statements

 REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM

 To the Stockholders and Board of Directors of Ionis Pharmaceuticals, Inc.

 Opinion on the Financial Statements

 We have audited the accompanying consolidated balance sheets of Ionis Pharmaceuticals, Inc. (the Company) as of December 31, 2023 and 2022, the related
 consolidated statements of operations, comprehensive loss, stockholders' equity and cash flows for each of the three years in the period ended December 31, 2023, and the related notes (collectively referred to as the "consolidated financial
 statements"). In our opinion, the consolidated financial statements present fairly, in all material respects, the financial position of the Company at December 31, 2023 and 2022, and the results of its operations and its cash flows for each of the
 three years in the period ended December 31, 2023, in conformity with U.S. generally accepted accounting principles.

 We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the Company's internal
 control over financial reporting as of December 31, 2023, based on criteria established in Internal Control—Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework), and our report dated
 February 21, 2024 expressed an unqualified opinion thereon.

 Basis for Opinion

 These financial statements are the responsibility of the Company's management. Our responsibility is to express an opinion on the Company's financial
 statements based on our audits. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the
 Securities and Exchange Commission and the PCAOB.

 We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable
 assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether due to error
 or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the financial statements. Our audits also included evaluating the accounting
 principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion.

 Critical Audit Matters

 The critical audit matters communicated below are matters arising from the current period audit of the financial statements that were communicated or
 required to be communicated to the audit committee and that: (1) relate to accounts or disclosures that are material to the financial statements and (2) involved our especially challenging, subjective or complex judgments. The communication of critical
 audit matters does not alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, by communicating the critical audit matters below, providing separate opinions on the critical audit matters or on the
 accounts or disclosures to which they relate.

 Estimated Liability for Clinical Development Costs

 Description of the Matter

 As of December 31, 2023, the Company accrued $106 million for clinical development expenses. As discussed in Note 1 to the consolidated financial
 statements, the Company records costs for clinical trial activities based upon estimates of costs incurred through the balance sheet date that have yet to be invoiced related to third-party clinical management costs, laboratory and analysis
 costs, toxicology studies and investigator grants. The Company estimates its liability using assumptions about study and patient activities and the related expected expenses for those activities based on the contracted fees with service
 providers.

 Auditing the Company's accruals for clinical and contract research organization costs is especially complex as the information necessary to estimate
 the accruals is accumulated from multiple sources. In addition, in certain circumstances, the determination of the nature and level of services that have been received during the reporting period requires judgment because the timing and pattern
 of vendor invoicing does not correspond to the level of services provided and there may be delays in invoicing from vendors.

 How We Addressed the Matter in Our Audit

 We obtained an understanding and evaluated the design and tested the operating effectiveness of controls over the accounting for accrued clinical
 development expenses. This included controls over management's assessment of the assumptions and accuracy of data underlying the accrued clinical development expenses estimate.

 To test the accuracy of the Company's accrued clinical development expenses, we performed audit procedures that included, among other procedures,
 obtaining supporting evidence of the research and development activities performed for significant clinical trials. We corroborated the status of significant clinical development expenses through meetings with accounting and clinical project
 managers. We compared the costs for a sample of transactions against the related invoices and contracts, and examined a sample of subsequent payments to evaluate the accuracy of the accrued clinical development expenses and compared the results
 to the current year accrual.

 Accounting for the Royalty Pharma Sale of Future Royalties Transaction

 Description of the Matter

 As discussed in Note 7 to the consolidated financial statements, in January 2023, the Company entered into a royalty purchase agreement to monetize a
 portion of future SPINRAZA and pelacarsen royalties that the Company is entitled to under existing agreements. As a result, the Company received an upfront payment of $500 million. The Company accounted for the sale of future royalties as a
 liability. The Company determines the effective interest rate used to record interest expense based on the estimate of future royalty payments over the term of the agreement. The carrying value of the liability related to the sale of future
 royalties at December 31, 2023 was $514 million.

 Auditing the Company's liability related to the sale of future royalties was complex due to the subjective judgments required to forecast the
 expected royalty payments subject to the agreement and due to the nature and extent of audit effort required to address these matters. Specifically, as it related to pelecarsen, a product candidate that is not currently commercialized, these
 estimates include significant assumptions such as market penetration, probability of success, and sales price, among others, that are affected by expectations about future market conditions.

 How We Addressed the Matter in Our Audit

 We obtained an understanding, evaluated the design, and tested the operating effectiveness of controls over the Company's processes for estimating
 the amount and timing of future royalty payments.

 To test the liability balance and the amount of interest expense recognized, our audit procedures included, among others, evaluating the methodology
 used and assessing the significant assumptions and the underlying data used by the Company in its effective interest model. We compared the significant assumptions in the estimate of future royalty payments to current industry and market
 trends. We recalculated the current year interest expense based on the amortization schedules and estimates of royalties using the effective interest method, and performed sensitivity analyses to evaluate the changes in the effective interest
 rate, and associated interest expense, that would result from changes in the assumptions.

 /s/ Ernst & Young LLP

 We have served as the Company's auditor since 1989.

 San Diego, California

 CONSOLIDATED BALANCE SHEETS

 (In thousands, except share data)

 2023

 2022

 ASSETS

 Current assets:

 Cash and cash equivalents

 $

 399,266

 $

 276,472

 Short-term investments

 1,931,935

 1,710,397

 Contracts receivable

 97,778

 25,538

 Inventories

 28,425

 22,033

 Other current assets

 184,449

 168,254

 Total current assets

 2,641,853

 2,202,694

 Property, plant and equipment, net

 71,043

 74,294

 Right-of-use assets

 171,896

 181,544

 Deposits and other assets

 105,280

 75,344

 Total assets

 $

 2,990,072

 $

 2,533,876

 LIABILITIES AND
 STOCKHOLDERS ' EQUITY

 Current liabilities:

 Accounts payable

 $

 26,027

 $

 17,921

 Accrued compensation

 67,727

 49,178

 Accrued liabilities

 147,894

 140,101

 Income taxes payable

 2,151

 6,249

 0.125 percent
 convertible senior notes, net

 44,332

 —

 Current portion of deferred contract revenue

 151,128

 90,577

 Other current liabilities

 8,831

 7,535

 Total current liabilities

 448,090

 311,561

 Long-term deferred contract revenue

 241,184

 287,768

 1.75 percent
 convertible senior notes, net

 562,285

 —

 0 percent
 convertible senior notes, net

 625,380

 622,242

 0.125 percent
 convertible senior notes, net

 —

 544,504

 Liability related to sale of future royalties, net

 513,736

 —

 Long-term lease liabilities

 170,875

 178,941

 Long-term obligations

 41,836

 15,973

 Total liabilities

 2,603,386

 1,960,989

 Stockholders' equity:

 Common stock, $ 0.001
 par value; 300,000,000 shares authorized, 144,340,526 and 142,057,736 shares issued and outstanding at December 31,
 2023 and December 31, 2022,
 respectively

 Additional paid-in capital

 2,215,098

 2,059,850

 Accumulated other comprehensive loss

 ( 32,645

)

 ( 57,480

)

 Accumulated deficit

 ( 1,795,911

)

 ( 1,429,625

)

 Total stockholders' equity

 386,686

 572,887

 Total liabilities and stockholders' equity

 $

 2,990,072

 $

 2,533,876

 CONSOLIDATED STATEMENTS OF OPERATIONS

 (In thousands, except for per share amounts)

 2023

 2022

 2021

 Revenue:

 Commercial revenue:

 SPINRAZA royalties

 $

 240,379

 $

 242,314

 $

 267,776

 Other commercial revenue

 68,212

 61,044

 74,619

 Total commercial revenue

 308,591

 303,358

 342,395

 Research and development revenue:

 Collaborative agreement revenue

 352,657

 207,222

 468,061

 WAINUA joint development revenue

 126,399

 76,787

 —

 Total research and development revenue

 479,056

 284,009

 468,061

 Total revenue

 787,647

 587,367

 810,456

 Expenses:

 Cost of sales

 9,133

 14,116

 10,842

 Research, development and patent

 899,625

 833,147

 643,453

 Selling, general and administrative

 232,619

 150,295

 186,347

 Total operating expenses

 1,141,377

 997,558

 840,642

 Loss from operations

 ( 353,730

)

 ( 410,191

)

 ( 30,186

)

 Other income (expense):

 Investment income

 89,041

 25,331

 10,044

 Interest expense

 ( 12,660

)

 ( 8,122

)

 ( 9,349

)

 Interest expense related to sale of future royalties

 ( 68,797

)

 —

 —

 Gain (loss) on investments

 ( 1,914

)

 ( 7,333

)

 10,103

 Gain (loss) on sale of real estate assets

 ( 161

)

 149,604

 —

 Other income (expense)

 14,256

 ( 7,274

)

 ( 9,760

)

 Loss before income tax benefit (expense)

 ( 333,965

)

 ( 257,985

)

 ( 29,148

)

 Income tax benefit (expense)

 ( 32,321

)

 ( 11,737

)

 $

)

 $

)

 $

)

 Basic and diluted net loss per share

 $

 ( 2.56

)

 $

 ( 1.90

)

 $

 ( 0.20

)

 Shares used in computing basic and diluted net loss per share

 143,190

 141,848

 141,021

 CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS

 (In thousands)

 2023

 2022

 2021

 $

)

 $

)

 $

)

 Unrealized gains (losses) on investments, net of tax

 24,484

 ( 24,395

)

 ( 11,486

)

 Currency translation adjustment

 ( 417

)

 ( 111

)

 Comprehensive loss

 $

 ( 341,451

)

 $

 ( 294,534

)

 $

 ( 40,194

)

 CONSOLIDATED STATEMENTS OF STOCKHOLDERS ' EQUITY

 (In thousands)

 Common Stock

 Additional

 Accumulated Other

 Accumulated

 Total Ionis

 Stockholders '

 Description

 Shares

 Amount

 Paid in Capital

 Comprehensive Loss

 Deficit

 Equity

 Balance at December 31, 2020

 140,366

 $

 $

 1,895,519

 $

 ( 21,071

)

 $

 ( 1,131,306

)

 $

 743,282

 —

 —

 —

 —

)

)

 Change in unrealized losses, net of tax

 —

 —

 —

 ( 11,486

)

 —

 ( 11,486

)

 Foreign currency translation

 —

 —

 —

 ( 111

)

 —

 ( 111

)

 Issuance of common stock in connection with employee stock plans

 1,132

 11,563

 —

 —

 11,564

 Issuance of warrants

 —

 —

 89,752

 —

 —

 89,752

 Purchase of note hedges

 —

 —

 ( 136,620

)

 —

 —

 ( 136,620

)

 Stock-based compensation expense

 —

 —

 120,678

 —

 —

 120,678

 Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options

 ( 288

)

 —

 ( 16,725

)

 —

 —

 ( 16,725

)

 Balance at December 31, 2021

 141,210

 $

 $

 1,964,167

 $

 ( 32,668

)

 $

 ( 1,159,903

)

 $

 771,737

 —

 —

 —

 —

)

)

 Change in unrealized losses, net of tax

 —

 —

 —

 ( 24,395

)

 —

 ( 24,395

)

 Foreign currency translation

 —

 —

 —

 ( 417

)

 —

 ( 417

)

 Issuance of common stock in connection with employee stock plans

 1,194

 6,372

 —

 —

 6,373

 Stock-based compensation expense

 —

 —

 100,264

 —

 —

 100,264

 Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options

 ( 346

)

 —

 ( 10,953

)

 —

 —

 ( 10,953

)

 Balance at December 31, 2022

 142,058

 $

 $

 2,059,850

 $

 ( 57,480

)

 $

 ( 1,429,625

)

 $

 572,887

 —

 —

 —

 —

)

)

 Change in unrealized gains, net of tax

 —

 —

 —

 24,484

 —

 24,484

 Foreign currency translation

 —

 —

 —

 —

 Issuance of common stock in connection with employee stock plans

 2,283

 49,439

 —

 —

 49,441

 Stock-based compensation expense

 —

 —

 105,809

 —

 —

 105,809

 Balance at December 31, 2023

 144,341

 $

 $

 2,215,098

 $

 ( 32,645

)

 $

 ( 1,795,911

)

 $

 386,686

 CONSOLIDATED STATEMENTS OF CASH FLOWS

 (In thousands)

 2023

 2022

 2021

 Operating activities:

 $

)

 $

)

 $

)

 Adjustments to reconcile net loss to net cash provided by (used in) operating activities:

 Depreciation

 10,292

 14,328

 15,487

 Amortization of right-of-use operating lease assets

 9,647

 5,362

 1,721

 Amortization of other assets

 2,559

 2,415

 2,352

 Amortization of premium (discount) on investments, net

 ( 28,885

)

 7,389

 17,776

 Amortization of debt issuance costs

 6,330

 5,373

 4,958

 Non-cash royalty revenue related to sale of royalties

 ( 44,628

)

 —

 —

 Non-cash interest related to sale of future royalties

 68,238

 —

 —

 Stock-based compensation expense

 105,809

 100,264

 120,678

 Loss (gain) on early retirement of debt

 ( 13,389

)

 —

 8,627

 Non-cash losses related to disposal of property, plant and equipment

 16,649

 —

 Loss (gain) on sale of real estate assets

 ( 150,135

)

 —

 Loss (gain) on investments

 1,589

 ( 1,092

)

 Non-cash losses related to other assets

 1,661

 2,030

 2,707

 Changes in operating assets and liabilities:

 Contracts receivable

 ( 72,059

)

 36,358

 14,308

 Inventories

 ( 6,392

)

 2,773

 ( 2,841

)

 Other current and long-term assets

 ( 29,840

)

 ( 24,682

)

 ( 877

)

 Accounts payable

 8,119

 1,094

 ( 6,000

)

 Income taxes

 ( 4,098

)

 6,213

 ( 280

)

 Accrued compensation

 18,549

 10,368

 ( 26,918

)

 Accrued liabilities and other current liabilities

 ( 5,506

)

 46,695

 ( 8,381

)

 Deferred contract revenue

 13,967

 ( 71,248

)

 ( 82,829

)

 Net cash provided by (used in) operating activities

 ( 307,513

)

 ( 274,370

)

 30,799

 Investing activities:

 Purchases of short-term investments

 ( 1,770,814

)

 ( 1,485,772

)

 ( 1,124,193

)

 Proceeds from sale of short-term investments

 1,584,676

 989,152

 1,344,185

 Purchases of property, plant and equipment

 ( 23,805

)

 ( 15,721

)

 ( 11,955

)

 Proceeds from sale of real estate assets

 254,083

 —

 Acquisition of licenses and other assets, net

 ( 4,206

)

 ( 4,378

)

 ( 5,946

)

 Purchases of strategic investments

 —

 —

 ( 7,185

)

 Net cash provided by (used in) investing activities

 ( 214,127

)

 ( 262,636

)

 194,906

 Financing activities:

 Proceeds from equity, net

 49,442

 6,373

 11,565

 Payments of tax withholdings related to vesting of employee stock awards and exercise of employee stock options

 —

 ( 10,953

)

 ( 16,725

)

 Proceeds from issuance of 1.75 percent convertible senior notes

 575,000

 —

 —

 1.75 percent
 convertible senior notes issuance costs

 ( 14,175

)

 —

 —

 Repurchase of $ 504.4
 million principal amount of 0.125 percent convertible senior notes

 ( 487,943

)

 —

 —

 Proceeds from sale of future royalties

 500,000

 —

 —

 Payments of transaction costs related to sale of future royalties

 ( 10,434

)

 ( 29

)

 —

 Proceeds from real estate transaction

 32,352

 —

 —

 Proceeds from the issuance of 0 percent convertible senior notes

 —

 —

 632,500

 0 percent
 convertible senior notes issuance costs

 —

 —

 ( 15,609

)

 Repurchase of $ 247.9
 million principal amount of 1 percent convertible senior notes

 —

 —

 ( 256,963

)

 Repayment of remaining principal amount of 1 percent convertible senior notes at maturity

 —

 —

 ( 61,967

)

 Proceeds from issuance of warrants

 —

 —

 89,752

 Purchase of note hedges

 —

 —

 ( 136,620

)

 Principal payments on debt

 ( 160

)

 ( 50,686

)

 —

 Net cash provided by (used in) financing activities

 644,082

 ( 55,295

)

 245,933

 Effects of exchange rates on cash

 ( 418

)

 ( 111

)

 Net increase (decrease) in cash and cash equivalents

 122,794

 ( 592,719

)

 471,527

 Cash and cash equivalents at beginning of year

 276,472

 869,191

 397,664

 Cash and cash equivalents at end of year

 $

 399,266

 $

 276,472

 $

 869,191

 Supplemental disclosures of cash flow information:

 Interest paid

 $

 6,512

 $

 2,898

 $

 4,778

 Income taxes paid

 $

 48,334

 $

 5,010

 $

 Supplemental disclosures of non-cash investing and financing activities:

 Right-of-use assets obtained in exchange for lease liabilities

 $

 —

 $

 168,931

 $

 6,641

 Amounts accrued for capital and patent expenditures

 $

 $

 4,767

 $

 NOTES TO CONSOLIDATED FINANCIAL STATEMENTS

 1. Organization and Significant Accounting Policies

 Basis of Presentation

 In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results of our
 wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries ("we", "us" or "our").

 Organization and Business Activity

 We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation in April 1991. We
 were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc.

 Use of Estimates

 We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the United States, or
 U.S., that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial statements and accompanying notes. Actual results could differ from our estimates.

 Revenue Recognition

 We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting the resulting
 receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include
 the amounts within deferred revenue in our consolidated balance sheets.

 At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities
 performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808, Collaborative Arrangements, or ASC 808. ASC 808 does not address the recognition and measurement of collaborative arrangements and instead refers companies to use other authoritative accounting literature. For collaboration arrangements within the scope of ASC 808 that contain multiple elements, we first determine which elements of the collaboration
 reflect a vendor-customer relationship and therefore are within the scope of ASC 606, Revenue from Contracts with Customers. When we determine elements of a collaboration do not reflect a vendor-customer relationship, we
 consistently apply the reasonable and rational policy election we made by analogizing to authoritative accounting literature.

 We evaluate the income statement classification for presentation of amounts due from or owed to other participants associated with
 multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our WAINUA collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development activities as revenue; while
 we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-medical affairs activities as selling, general and administrative, or SG&A, expense and research and development, or R&D, expense,
 respectively.

 Steps to Recognize Revenue

 For elements of our contractual relationships that we account for under ASC 606, we use a five-step process to determine the amount of
 revenue we should recognize and when we should recognize it. The five-step process is as follows:

 1.

 Identify the contract

 Accounting rules require us to first determine if we have a contract with our partner, including confirming that we have met each of the
 following criteria:

 We and our partner approved the contract and we are both committed to perform our obligations;

 We have identified our rights, our partner's rights and the payment terms;

 We have concluded that the contract has commercial substance, meaning that the risk, timing, or amount of our future cash flows is expected to change as a result of the
 contract; and

 We believe collectability of the consideration is probable.

 2.

 Identify the performance obligations

 We next identify our performance obligations, which represent the distinct goods and services we are required to provide under the
 contract.

 We may enter into a collaboration agreement in which we
 provide our partner with an option to license a medicine in the future. We may also provide our partner with an option to request that we provide additional goods or services in the future, such as active pharmaceutical ingredient, or API. We
 evaluate whether these options are material rights at the inception of the agreement. If we determine an option is a material right, we will consider the option a separate performance obligation. When a partner exercises its option to license a
 medicine that was not previously determined to be a material right at the inception of the agreement or requests additional goods or services, then we identify a new performance obligation for that item.

 In some cases, we deliver a license at the start of an agreement. If we determine that our partner has full use of the license and we do
 not have any additional material performance obligations related to the license after delivery, then we consider the license to be a separate performance obligation.

 3.

 Determine the transaction price

 We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the collaboration
 agreement, including any variable consideration. Under our collaboration agreements, consideration typically includes fixed consideration in the form of an upfront payment and variable consideration in the form of potential milestone payments,
 license fees and royalties. At the start of an agreement, our transaction price usually consists of only the upfront payment. We do not typically include any payments we may receive in the future in our initial transaction price because the payments
 are not probable and are contingent on certain future events. We reassess the total transaction price at each reporting period to determine if we should include additional payments in the transaction price.

 Milestone payments are our most common type of variable consideration. We recognize milestone payments using the most likely amount method
 because we will either receive the milestone payment or we will not, which makes the potential milestone payment a binary event. The most likely amount method requires us to determine the likelihood of earning the milestone payment. We include a
 milestone payment in the transaction price once it is probable that we will achieve the milestone event. Most often, we do not consider our milestone payments probable until we or our partner achieve the milestone event because the majority of our
 milestone payments are contingent upon events that are not within our control and/ or are usually based on scientific progress which is inherently uncertain.

 4.

 Allocate the transaction price

 Next, we allocate the transaction price to each of our
 performance obligations. When we have to allocate the transaction price to more than one performance obligation, we make estimates of the relative stand-alone
 selling price of each performance obligation because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each performance obligation based on the relative stand-alone selling price. We do
 not reallocate the transaction price after the start of an agreement to reflect subsequent changes in stand-alone selling prices.

 We may engage a third party, independent valuation specialist to assist us with determining a stand-alone selling price for collaborations in which we deliver a license at the start of an agreement. We estimate the
 stand-alone selling price of these licenses using valuation methodologies, such as the relief from royalty method. Under this method, we estimate the amount of income, net of taxes, for the license. We then discount the projected income to present
 value. The significant inputs we use to determine the projected income of a license could include:

 Estimated future product sales;

 Estimated royalties we may receive from future product sales;

 Estimated contractual milestone payments we may receive;

 Estimated expenses we may incur;

 Estimated income taxes; and

 A discount rate.

 We typically estimate the selling price of R&D services by using our internal estimates of the cost to perform the specific services.
 The significant inputs we use to determine the selling price of our R&D services include:

 The estimated number of internal hours we will spend performing these services;

 The estimated cost of work we will perform;

 The estimated cost of work that we will contract with third parties to perform; and

 The estimated cost of API we will use.

 For purposes of determining the stand-alone selling price of the R&D services we perform and the API we will deliver, accounting
 guidance requires us to include a markup for a reasonable profit margin.

 5.

 Recognize revenue

 We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are executing on our
 performance obligation over time and our partner receives benefit over time. For example, we recognize revenue over time when we provide R&D services. We recognize revenue at a point in time when our partner receives full use of an item at a
 specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner.

 For R&D services that we recognize over time, we measure our progress using an input method. The input methods we use are based on the
 effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period,
 relative to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the transaction price to determine the amount of revenue we recognize each period. This approach requires us to make
 numerous estimates and use significant judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and amount of revenue that we recognize in the current and future periods.

 We recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue, which
 in certain cases may require us to estimate our royalty revenue.

 Under our distribution agreements with Swedish Orphan Biovitrum AB, or Sobi, we concluded that our performance obligation is to provide
 services to Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi. We are also responsible for maintaining the marketing authorization for TEGSEDI and WAYLIVRA in major markets and for leading the global
 commercial strategy for each medicine. We view this performance obligation as a series of distinct activities that are substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished
 goods inventory to Sobi. We also recognize distribution fee revenue based on Sobi's net sales of TEGSEDI and WAYLIVRA. Under our agreements with Sobi, Sobi does not generally have a right of return.

 Amendments to Agreements

 From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items to determine the
 accounting for the amendment:

 1)

 If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and

 2)

 If the goods and/or services are sold at a stand-alone selling price.

 If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original agreement and at
 a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining goods or services are
 distinct from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the remaining transaction price from the original agreement and the additional transaction price from the amendment
 to the remaining goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction price for our single performance obligation and recognize any change in our estimated revenue as a
 cumulative-effect adjustment.

 Multiple agreements

 From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such agreements to
 determine whether we should account for them individually as distinct arrangements or whether the separate agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the agreements:

 Whether the agreements were negotiated together with a single objective;

 Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or

 Whether the goods and/or services promised under the agreements are a single performance obligation.

 Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that accounting
 guidance requires us to account for them as a combined arrangement.

 Refer to Note 4, Collaborative
 Arrangements and Licensing Agreements, for further discussion of our 2018 Strategic Neurology collaboration with Biogen that included multiple agreements which we negotiated concurrently and in contemplation of one another.

 Contracts Receivable

 Our contracts receivable balance represents the amounts we
 have billed our partners or customers and that are due to us unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment terms based on the passage of time, we consider the contracts
 receivable to be unconditional. We typically receive payment within one quarter of billing our partner or customer.

 As of December 31, 2023,
 approximately 87.8 percent of our contracts receivables were from one significant customer. As of December 31, 2022, approximately 82.5 percent of our contracts receivables were from one
 significant customer.

 Unbilled SPINRAZA Royalties

 Our unbilled SPINRAZA royalties represent our right to receive consideration from Biogen in advance of when we are eligible to bill Biogen
 for SPINRAZA royalties. We include these unbilled amounts in other current assets in our consolidated balance sheets.

 Deferred Revenue

 We are often entitled to bill our customers and receive
 payment from our customers in advance of our obligation to provide services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue in our consolidated balance sheets. During the years ended December 31, 2023 and 2022, we recognized $ 78.2 million and $ 73.5 million of revenue from
 amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue recognition policy above.

 Cost of Sales

 Our cost of sales is comprised of costs related to our commercial revenue, including manufacturing costs, transportation and freight costs
 and indirect overhead costs associated with the manufacturing and distribution of our products. We also may include certain period costs related to manufacturing services and inventory adjustments in cost of sales.

 Research, Development and Patent Expenses

 Our research, development and patent expenses include wages, benefits, facilities, supplies, external services, clinical trial and
 manufacturing costs, patents and other expenses that are directly related to our R&D operations. We expense R&D costs as we incur them. When we make payments for R&D services prior to the services being rendered, we record those amounts as
 prepaid assets in our consolidated balance sheets and we expense them as the services are provided. A portion of the costs included in R&D expenses are costs associated with our partner agreements. In 2023, 2022 and 2021, patent expenses were $ 4.3 million, $ 4.7 million and $ 5.3 million, respectively.

 Income Taxes

 We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities
 for the expected future tax consequences of events that have been recognized in our financial statements or tax returns. In addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development
 credit carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be realized.

 We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial recognition and
 measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight
 of available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit
 as the largest amount that is more than 50 percent likely to be realized upon ultimate settlement.

 We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for income taxes.
 Although we believe our reserves are reasonable, we can provide no assurance that the final tax outcome of these matters will not be different from that which we have reflected in our historical income tax provisions and accruals. We adjust these
 reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the final tax outcome of these matters is different than the amounts recorded, such differences may impact the
 provision for income taxes in the period in which we make such determination.

 We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax assets. In
 assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We
 base our estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from
 our estimates, the amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be
 realized.

 Basic and Diluted Net Loss per Share

 Basic net loss per share

 We compute basic net loss per share by dividing our net loss by our weighted-average number of common shares outstanding during the
 period.

 Diluted net loss per share

 For the years ended December 31, 2023,
 2022 and 2021, we incurred a net
 loss; therefore, we did not include dilutive common equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common stock from the following would have had an anti-dilutive effect on net loss
 per share:

 0 percent convertible senior notes, or 0 % Notes;

 Note hedges related to the 0 % Notes;

 0.125 percent convertible senior notes, or 0.125 % Notes;

 Note hedges related to the 0.125 % Notes;

 Dilutive stock options;

 Unvested restricted stock units, or RSUs;

 Unvested performance restricted stock units, or PRSUs; and

 Employee Stock Purchase Plan, or ESPP.

 For the year ended December 31, 2023, common stock underlying the 1.75 percent convertible senior notes, or 1.75 % Notes, would also have had an
 anti-dilutive effect on net loss per share.

 Additionally as of December 31, 2023, 2022 and 2021, we had warrants related to our 0 % Notes and 0.125 % Notes outstanding. We will include the
 shares issuable under these warrants in our calculation of diluted earnings per share when the average market price per share of our common stock for the reporting period exceeds the strike price of the warrants.

 Stock-Based Compensation Expense

 We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, PRSUs and stock
 purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service
 period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time of grant and revise in subsequent periods if actual forfeitures differ from those estimates.

 We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP using the accelerated
 multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as though the award
 were in substance multiple awards, which results in the expense being front-loaded over the vesting period.

 Stock Options and Stock Purchase Rights:

 We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our ESPP. On the grant
 date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair value of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the
 awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options granted represents the period of time that we expect them to be outstanding. Historically, we estimated the expected term of options granted
 based on historical exercise patterns. In 2021, our Compensation Committee approved an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the 2020 Equity Incentive Plan, or 2020 Plan, that increased the contractual term of stock options
 granted under these plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected life of stock options granted to employees following this
 change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the expected life of stock options granted to employees in the years ended
 December 31, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional historical information, we will transition to calculating our
 expected term based on our historical exercise patterns.

 RSU's:

 The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to employees vest
 annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over a four-year period. RSUs we granted to our board of directors after June 2020 fully vest after one year.

 PRSU's:

 Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Beginning in 2022, we added
 PRSU awards to the compensation for our other Section 16 officers. Under the terms of the PRSUs we granted in 2020 through 2022, one third
 of the PRSUs may vest at the end of three separate performance periods spread over the three years following the date of grant (i.e., the one-year period commencing on the
 date of grant and ending on the first anniversary of the date of grant; the two-year period commencing on the date of grant and ending on the
 second anniversary of the date of grant; and the three-year period commencing on the date of grant and ending on the third anniversary of the
 date of grant) based on our relative total shareholder return, or TSR, as compared to a peer group of companies, and as measured, in each case, at the end of the applicable performance period. Under the terms of the grants no number of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero to 150 percent of the target number
 depending on our relative TSR. These PRSU awards also included an alternative three-year payout mechanism, or the Alternative Calculation, under
 which we must calculate an alternative payout at the end of the final three-year measurement period assuming the only measurement period for all
 shares under the award was the three-year period. If the Alternative Calculation is greater than payouts under the sum of the three years, then such PRSU award will pay out to achieve the number of shares payable under the Alternative Calculation.

 Under the terms of the PRSUs we granted in 2023, 100 percent of the PRSUs may vest at the end of the three-year performance period
 based on our relative TSR as compared to a peer group of companies and as measured at the end of the performance period. Under the terms of the grants, no
 number of PRSUs is guaranteed to vest and the actual number of PRSUs that will vest at the end of each performance period may be anywhere from zero
 to 200 percent of the target number depending on our relative TSR.

 We determined the fair value of the PRSUs using a Monte Carlo model because the performance target is based on our relative TSR, which
 represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation expense using the accelerated multiple-option approach over the vesting period.

 Refer to Note 8, Stockholders' Equity,
 for additional information regarding our stock-based compensation plans.

 Concentration of Credit Risk

 Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-term
 investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions,
 corporations, and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody's, Standard & Poor's, or S&P, or Fitch, respectively. We have established guidelines relative to
 diversification and maturities that maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates without compromising safety and liquidity.

 Fair Value Measurements

 We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts payable and
 accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their estimated fair value based on quoted market prices for identical or similar instruments.

 We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 1,
 defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly
 traded biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly observable, which includes our fixed income securities and commercial paper classified as available-for-sale
 securities; and Level 3, defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We classify most of our securities as Level 2. We obtain the fair value of our Level 2 investments
 from our custodian bank or from a professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the custodian banks or professional pricing service provider and comparing that fair value
 to the fair value based on observable market prices.

 Cash, Cash Equivalents and Investments

 We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. Our short-term
 investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt investments as "available-for-sale" and carry them at fair market value based upon prices on the last day of the fiscal period for
 identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income (loss) and include net realized gains and losses in gain (loss) on investments in our consolidated statements of
 operations. We use the specific identification method to determine the cost of securities sold.

 We also have equity investments of less than 20 percent ownership in public and private biotechnology companies that we received as part
 of a technology license or partner agreement. At December 31, 2023, we held equity investments in three publicly traded companies and seven privately held companies.

 We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our consolidated
 statements of operations. We account for our equity investments in publicly traded companies at their listed stock price. We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting
 from observable price changes in orderly transactions for the identical or similar investment of the same issuer.

 Inventories

 We reflect our inventory in our consolidated balance sheets at the lower of cost or net realizable value under the first-in, first-out
 method, or FIFO. We capitalize the costs of raw materials that we purchase for use in producing our medicines because until we use these raw materials, they have alternative future uses, which we refer to as clinical raw materials. We include in
 inventory raw material costs for medicines that we manufacture for our partners under contractual terms and that we use primarily in our clinical development activities and drug products. We can use each of our raw materials in multiple products and,
 as a result, each raw material has future economic value independent of the development status of any single medicine. For example, if one of our medicines failed, we could use the raw materials for that medicine to manufacture our other medicines. We
 expense these costs as R&D expenses when we begin to manufacture API for a particular medicine if the medicine has not been approved for marketing by a regulatory agency. Our raw materials- commercial inventory includes API for our commercial
 medicines. We capitalize material, labor and overhead costs as part of our raw materials- commercial inventory.

 We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to their estimated
 net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in estimating the net realizable value, including shelf life of our inventory, alternative uses for our medicines in development and historical
 write-offs.

 Property, Plant and Equipment

 We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life,
 which we determine as the following (in years):

 Useful Lives

 Computer software, laboratory, manufacturing and other equipment

 3 to 10

 Building, building improvements and building systems

 15 to 40

 Land improvements

 Leasehold improvements

 5 to 15

 Furniture and fixtures

 5 to 10

 We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term. We evaluate long-lived
 assets, which include property, plant and equipment, for impairment on at least a quarterly basis and whenever events or changes in circumstances indicate that we may not be able to recover the carrying amount of such assets.

 Accrued Liabilities

 We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a quarterly
 basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to
 third-party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and patient activities and the related expected expenses for those activities
 determined based on the contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve inherent uncertainties and the application of our judgment. Upon
 settlement, these costs may differ materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual amounts.

 Convertible Debt

 We account for each of our convertible debt instruments as a
 single unit of accounting, a liability, because we concluded that the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not issue our convertible debt instruments at a substantial premium. We record debt
 issuance costs as contra-liabilities in our consolidated balance sheets at issuance and amortize them over the contractual term of the convertible debt instrument using the effective interest rate. The balances of our convertible senior notes presented in our consolidated balance sheets represent the principal balance of each convertible debt instrument less debt issuance costs.

 As of December 31, 2023, we
 had three outstanding convertible senior notes, our 1.75 % Notes, which mature in June 2028, our 0 % Notes, which mature in April 2026, and
 our 0.125 % Notes, which mature in December 2024. Refer to Note 7, Long-Term Obligations and Commitments, for further details on our convertible senior notes.

 Call Spread

 In conjunction with the issuance of our 0 %
 Notes and 0.125 % Notes in April 2021 and December 2019, respectively, we entered into call spread transactions, which were comprised of
 purchasing note hedges and selling warrants. We account for the note hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting. We determined that the note hedges and warrants do not
 meet the definition of a liability using the guidance contained in ASC Topic 480; therefore, we account for the note hedges and warrants using the Derivatives

 and Hedging – Contracts in Entity's Own Equity accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a derivative, are indexed to our stock and meet the criteria to be classified
 in shareholders' equity. We recorded the aggregate amount paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance sheets. We reassess our ability to continue to classify the
 note hedges and warrants in shareholders' equity at each reporting period.

 Liability Related to Sale of Future Royalties

 In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion of
 our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and Novartis, respectively. Refer to Note 7, Long-Term
 Obligations and Commitments, for further details on the agreement.

 Under our agreement with Royalty Pharma, we record upfront payments and milestone payments we receive from the sale of future royalties as
 a liability, net of transaction costs. We record royalty payments made to Royalty Pharma as a reduction of the liability or accrued interest and amortize the transaction costs over the estimated life of the royalty stream. We account for the associated
 interest expense under the effective interest rate method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue.

 We calculate the liability related to the sale of future royalties, effective interest rate and the related interest expense using our
 current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal projections and information from our partners who are responsible for commercializing the medicines. If there is a material
 change in our estimate, we will prospectively adjust the effective interest rate and the related interest expense.

 Leases

 We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a right-of-use
 operating lease asset and associated short- and long-term operating lease liability in our consolidated balance sheets for operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for the lease term
 and our lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use operating lease assets and lease liabilities based on the present value of the future minimum lease payments we
 will pay over the lease term. We determine the lease term at the inception of each lease, and in certain cases our lease term could include renewal
 options if we conclude we are reasonably certain to exercise the renewal option. When we exercise a lease option that was not previously included in the initial lease term, we reassess our right-of-use asset and lease liabilities for the new lease
 term.

 As our leases do not provide an interest rate implicit in the lease, we use our incremental borrowing rate, based on the information
 available as of the lease inception date or at the lease option extension date in determining the present value of future payments. We recognize rent expense for our minimum lease payments on a straight-line basis over the expected term of our lease.
 Our leases do not include material variable or contingent lease payments. We recognize period expenses, such as common area maintenance expenses, in the period we incur the expense.

 Segment Information

 We operate as a single segment, Ionis operations, because our chief decision maker reviews operating results on an aggregate basis and
 manages our operations as a single operating segment.

 Recently Issued Accounting Standards

 In November 2023, the Financial Accounting Standards Board, or FASB, issued updated guidance on segment reporting. The guidance requires
 public companies with a single reportable segment to provide all disclosures required under ASC 280, Segment Reporting. In addition, the guidance
 requires public companies to include in interim reports all disclosures related to a reportable segment's profit or loss and assets that are currently required in annual reports. This update is effective for annual periods beginning after December 15,
 2023 and interim periods beginning after December 15, 2024. The guidance is applied on a retrospective basis for all periods presented in the financial statements, unless it is impracticable. Early adoption of this guidance is permitted. We currently
 plan to adopt the annual reporting requirements in our 2024 Annual Report on Form 10-K. We plan to adopt the interim reporting requirements in our Quarterly Report on Form 10-Q in the first quarter of 2025.

 In December 2023, the FASB issued updated guidance on income tax disclosures. The new guidance requires companies to provide additional
 disaggregation of information related to the income tax rate reconciliation and income tax payments. In addition, the guidance eliminates certain existing disclosure requirements related to uncertain tax positions and unrecognized deferred tax
 liabilities. This update is effective for annual periods beginning after December 15, 2024. Early adoption of this guidance is permitted. We currently plan to adopt this guidance in our 2025 Annual Report on Form 10-K.

 We do not expect any other recently issued accounting standards to have a material impact to our financial results.

 2. Supplemental Financial Data

 Inventories

 Our inventory consisted of the following (in thousands):

 2023

 2022

 Raw materials:

 Raw materials- clinical

 $

 20,985

 $

 17,061

 Raw materials- commercial

 1,809

 2,699

 Total raw materials

 22,794

 19,760

 Work in process

 5,477

 2,109

 Finished goods

 Total inventory

 $

 28,425

 $

 22,033

 Property, Plant and Equipment

 Our property, plant and equipment consisted of the following (in thousands):

 2023

 2022

 Computer software, laboratory, manufacturing and other equipment

 $

 79,885

 $

 74,351

 Building, building improvements and building systems

 41,228

 41,158

 Leasehold improvements

 28,276

 28,357

 Furniture and fixtures

 9,844

 9,575

 159,233

 153,441

 Less: Accumulated depreciation

 ( 96,759

)

 ( 87,716

)

 62,474

 65,725

 Land

 8,569

 8,569

 Total

 $

 71,043

 $

 74,294

 Accrued Liabilities

 Our accrued liabilities consisted of the following (in thousands):

 2023

 2022

 Clinical expenses

 $

 105,967

 $

 116,460

 In-licensing expenses

 7,454

 7,945

 Commercial expenses

 4,875

 3,498

 Other miscellaneous expenses

 29,598

 12,198

 Total accrued liabilities

 $

 147,894

 $

 140,101

 3. Revenues

 During the years ended December 31, 2023, 2022 and 2021, our revenues were comprised of the following (in
 thousands):

 2023

 2022

 2021

 Revenue:

 Commercial revenue:

 SPINRAZA royalties

 $

 240,379

 $

 242,314

 $

 267,776

 Other commercial revenue:

 TEGSEDI and WAYLIVRA revenue, net

 34,913

 30,051

 55,500

 Licensing and other royalty revenue

 33,299

 30,993

 19,119

 Total other commercial revenue

 68,212

 61,044

 74,619

 Total commercial revenue

 308,591

 303,358

 342,395

 Research and development revenue:

 Collaborative agreement revenue

 352,657

 207,222

 468,061

 WAINUA joint development revenue

 126,399

 76,787

 —

 Total research and development revenue

 479,056

 284,009

 468,061

 Total revenue

 $

 787,647

 $

 587,367

 $

 810,456

 Revenue Sources

 The following are sources of revenue and when we typically recognize revenue.

 Commercial Revenue: SPINRAZA royalties and Licensing and other royalty revenue

 We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA. We earn royalty revenue on net sales of
 QALSODY which is included in Licensing and other royalty revenue.

 Commercial Revenue: TEGSEDI and WAYLIVRA revenue, net

 We earn commercial revenue from TEGSEDI and WAYLIVRA sales
 under our distribution agreements with Sobi. In addition, we receive royalties from PTC Therapeutics International Limited, or PTC, for TEGSEDI and WAYLIVRA
 sales. Refer to Note 4, Collaborative Arrangements and Licensing Agreements, for details on our commercialization partnerships with Sobi and PTC.

 Research and development revenue under collaboration agreements

 We enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our collaboration
 agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&D services and manufacturing services.

 Upfront payments: When we enter into a collaboration agreement and receive an upfront payment, we typically record the entire upfront payment as deferred revenue if our only performance obligation
 is for R&D services we will provide in the future. We amortize the upfront payment into revenue as we perform the R&D services.

 Milestone payments: We include variable consideration in the transaction price when it is probable. We typically include milestone payments for R&D services in the transaction price when they are
 achieved. We include these milestone payments when they are achieved because typically there is considerable uncertainty in the research and development processes that trigger these payments. Similarly, we include approval milestone payments in the
 transaction price once the medicine is approved by the applicable regulatory agency. We will recognize sales-based milestone payments in the period in which we achieve the milestone under the sales-based royalty exception allowed under accounting
 rules.

 We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For example, when we
 achieve a milestone payment from a partner for advancing a clinical study under a collaboration agreement, we add the milestone payment to the transaction price if the milestone relates to an ongoing R&D services performance obligation and
 recognize revenue related to the milestone payment over our estimated period of performance. If we have partially completed our performance obligation, then we record a cumulative-effect adjustment in the period we add the milestone payment to the
 transaction price.

 Conversely, we recognize in full those milestone payments that we earn based on our partners' activities when our partner achieves the
 milestone event and we do not have a performance obligation.

 License fees: We recognize as revenue the total amount we determine to be the relative stand-alone selling price of a license when we deliver the license to our partner who has full use of the
 license and we do not have any additional performance obligations related to the license after delivery.

 Sublicense fees: We recognize sublicense fee revenue in the period in which a party, who has already licensed our technology, further licenses the technology to another party because we do not
 have any performance obligations related to the sublicense.

 WAINUA (Eplontersen) Collaboration with AstraZeneca

 In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize WAINUA
 for the treatment of transthyretin amyloidosis, or ATTR. We jointly developed and are preparing to commercialize WAINUA with AstraZeneca in the U.S. We initially granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S., except for
 certain Latin American countries. In July 2023, we expanded those rights to include Latin America. Under the terms of the agreement, we received a $ 200
 million upfront payment in 2021.

 We evaluated our WAINUA collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca are performing, (iii) the co-commercialization activities
 that we and AstraZeneca are performing and (iv) the co-medical affairs activities that we and AstraZeneca are performing.

 We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to AstraZeneca and as a
 result we had one performance obligation. For our sole performance obligation, we determined the transaction price was the $ 200 million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have any remaining performance obligations
 after we delivered the license to AstraZeneca.

 We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs activities are within
 the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration and therefore do not have a vendor-customer relationship. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading the Phase 3 development program, we made an
 accounting policy election to recognize as non-customer revenue the cost-share funding from AstraZeneca, net of our share of AstraZeneca's development expenses, in the same period we incur the related development expenses. As AstraZeneca is responsible
 for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S., we made an accounting policy election to recognize cost-share funding we receive from AstraZeneca related
 to commercial and medical affairs activities as reductions of our SG&A expense and R&D expense, respectively.

 4. Collaborative Arrangements and Licensing Agreements

 Strategic Partnership

 Biogen

 We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of neurological
 disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat people with spinal muscular atrophy, or SMA. Under our 2013 strategic neurology collaboration, Biogen developed QALSODY (tofersen), our medicine that received
 accelerated approval in the U.S. to treat patients with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS. In addition, we and Biogen are currently developing numerous other investigational medicines to treat neurodegenerative diseases,
 including medicines in development to treat people with amyotrophic lateral sclerosis, or ALS, SMA, Angelman Syndrome, or AS, Alzheimer's disease, or AD, and Parkinson's disease, or PD. In addition to these medicines, our collaborations with Biogen
 include a substantial research pipeline that addresses a broad range of neurological diseases. From inception through December 31, 2023, we
 have received nearly $ 3.8 billion from our Biogen collaborations, including payments to purchase our stock.

 Spinal Muscular Atrophy Collaborations

 In 2012, we entered into a collaboration agreement with
 Biogen to develop and commercialize SPINRAZA. From inception through December 31, 2023, we earned more than $2.1 billion in total revenue under our SPINRAZA collaboration, including more than $1.6 billion in revenue from SPINRAZA royalties and more than $425 million in R&D revenue. We are receiving tiered royalties ranging from
 11 percent to 15 percent on net sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from
 Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of SPINRAZA. Biogen is responsible for all global development,
 regulatory and commercialization activities and costs for SPINRAZA. We completed our performance obligations under our collaboration in 2016.

 In 2023, we entered into a royalty purchase agreement with Royalty Pharma in which Royalty Pharma receives 25 percent of our SPINRAZA royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $ 1.5 billion in annual sales. Royalty
 Pharma's royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $ 475 million or $ 550 million, depending on the timing and occurrence of the U.S. Food and Drug Administration, or FDA, approval of pelacarsen, which Novartis is developing.
 Refer to Note 7, Long-Term Obligations and Commitments, for further discussion of this agreement.

 New Antisense Medicines for the Treatment of SMA

 In 2017, we entered into a collaboration agreement with
 Biogen to identify new antisense medicines for the treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical
 studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization activities and costs for such therapies.

 At the commencement of this
 collaboration, we received a $ 25 million upfront payment from Biogen. In 2021, Biogen
 exercised its option to license ION306, a drug we
 discovered under this collaboration, for which we earned a $60 million license fee payment. We recognized this payment as revenue in full because Biogen had full use of the license without any continuing involvement from us. Biogen is
 solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this collaboration. We will receive development and regulatory milestone payments from Biogen if new medicines, including ION306, advance towards marketing approval.

 Over the term of the collaboration, we are eligible to receive up to $ 555 million if Biogen advances ION306, which is comprised of up to $ 45 million in
 development milestone payments, up to $ 110 million in regulatory milestone payments and up to $ 400 million in sales milestone payments. In addition, we are eligible to receive tiered royalties from the mid-teens to mid- 20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2023, we received $ 85 million in payments under this collaboration. We will achieve the next payment of up to $ 45 million for the initiation of a Phase 3 trial under this collaboration.

 Neurology Collaborations

 2018 Strategic Neurology

 In 2018, we and Biogen entered into a strategic collaboration
 to develop novel antisense medicines for a broad range of neurological diseases. We also entered into a Stock Purchase Agreement, or SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop
 therapies for these diseases for 10 years. We are
 responsible for the identification of antisense drug candidates based on selected targets. In most cases, Biogen will be responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen has the option to license the selected medicine after it completes the IND-enabling toxicology study. If
 Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

 At the commencement of this collaboration, we received $ 1 billion from Biogen, comprised of $ 625 million to purchase our stock at an approximately 25 percent cash premium and $ 375 million in an upfront payment.

 For each medicine under this collaboration, w e are eligible to receive up to $270 million, which is comprised of a $15 million license fee, up to $105 million in development milestone payments and up to $150 million in regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. W e are currently
 advancing multiple programs under this collaboration. From inception through December 31, 2023, we have received nearly $ 1.1 billion in payments under this collaboration, including payments to purchase our stock. We will achieve the next payment of up to $ 15 million if Biogen licenses a medicine under this collaboration.

 We considered that the collaboration agreement and SPA were
 negotiated concurrently and in contemplation of one another. Based on these facts and circumstances, we concluded that we should evaluate the provisions of the agreements on a combined basis. W e identified one performance obligation, which was to perform R&D services for Biogen. We determined our
 transaction price to be $552 million, comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our common
 stock. We determined the fair value of the premium we received by using the stated premium in the SPA and applying a lack of marketability discount. We included a lack of marketability discount in our valuation of the premium because Biogen
 received restricted shares of our common stock. We allocated the transaction price to our single performance obligation.

 From inception through December 31, 2023,
 we have included $ 623 million in upfront and milestone payments in
 the transaction price for our R&D services performance obligation under this collaboration, including a $7.5 million milestone payment we achieved in the fourth quarter of 2023. This milestone payment did not create a new performance obligation because it is part of our original R&D services
 performance obligation. Therefore, we included this amount in our transaction price for our R&D services performance obligation in the period we achieved the milestone payment. We are recognizing revenue for our R&D services performance
 obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the end of
 the contractual term in June 2028.

 2013 Strategic Neurology

 In 2013, we and Biogen entered into a strategic relationship focused on applying antisense technology to advance the treatment of
 neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting from this collaboration. In
 most cases, we are responsible for drug discovery and early development of antisense medicines and Biogen has the option to license antisense medicines after Phase 2 proof-of-concept. In 2016, we expanded our collaboration to include additional
 research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.

 We are currently advancing four
 investigational medicines in development under this collaboration, including a medicine for Parkinson's disease (ION859), two medicines for ALS (QALSODY and ION541) and a
 medicine for multiple system atrophy (ION464). In 2018, Biogen exercised its option to license QALSODY, our medicine that received accelerated approval in April 2023 from the FDA for the treatment of adult patients with SOD1-ALS. As a result, Biogen is
 responsible for global development, regulatory and commercialization activities and costs for QALSODY.

 Under the terms of the agreement, we received an upfront payment of $ 100 million and are eligible to receive milestone payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the
 modality of the molecule advanced by Biogen.

 Over the term of the collaboration for QALSODY, we are eligible to receive nearly $ 110 million, which is comprised of a $ 35 million license fee we received when Biogen
 licensed QALSODY from us in 2018, $ 18 million in development milestone payments and up to $ 55 million in regulatory milestone payments. In addition, we are eligible to receive tiered royalties ranging from 11 percent to 15 percent on net sales of QALSODY. We will achieve the next milestone
 payment for QALSODY of $ 20 million if the European Medicines Agency, or EMA, approves Biogen's Marketing Authorization Application, or MAA,
 filing of QALSODY.

 For each of the other antisense molecules that are chosen for drug discovery and development under this collaboration, we are eligible to
 receive up to approximately $ 260 million, which is comprised of a $ 70 million license fee, up to $ 60 million in development milestone payments and up to $ 130 million in regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product
 that Biogen successfully commercializes under this collaboration. From inception through December 31, 2023, we have received more than $ 325 million in payments under our 2013 strategic neurology collaboration. We will achieve the next payment of $ 70 million if Biogen licenses a medicine under this collaboration.

 At the commencement of our 2013 strategic neurology collaboration, we identified one performance obligation, which was to perform R&D services for Biogen. At inception, we determined the transaction price to be the $ 100 million upfront payment we received and allocated it to our single performance obligation. As we achieve milestone payments for our R&D services, we include these amounts in our
 transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our
 performance obligation. During 2020, we completed our remaining R&D services and
 recognized the remaining revenue related to this performance obligation. From inception through the completion of our R&D services performance obligation in 2020, we included $ 145 million in total payments in the transaction price for our R&D services performance obligation.

 Under this collaboration, we have also generated additional
 payments that we concluded were not part of our R&D services performance obligation. We recognized each of these payments in full in the respective period we generated the payment because we did not have any performance obligations for the
 respective payment. For example, in 2023, we earned a $ 16 million

 milestone payment from Biogen when the FDA approved Biogen's New Drug Application, or NDA, for QALSODY, which we recognized in full because we did not have any remaining performance obligations related to this milestone payment.

 2012 Neurology

 In 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense medicines to treat
 neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the programs through
 the completion of the first Phase 2 study for each program. Under this collaboration, Biogen is conducting the IONIS-MAPT Rx study for AD and we are currently advancing ION582 for AS. If Biogen exercises its option to license a medicine, it
 will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In 2019, Biogen exercised its option to license IONIS-MAPT Rx and as a result Biogen is responsible for global development,
 regulatory and commercialization activities and costs for IONIS-MAPT Rx.

 Under the terms of the agreement, we received an upfront
 payment of $30 million. For each program under this
 collaboration, we are eligible to receive up to $210
 million, which is comprised of a license fee of up to $70
 million, up to $10 million in development milestone
 payments and up to $130 million in regulatory milestone
 payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from each of the two programs. From inception through December 31, 2023, we have received more than $230 million in payments under this collaboration, including $39 million in milestone payments we received from Biogen for advancing ION582
 during 2023 and a $10 million milestone payment we received
 from Biogen when Biogen advanced IONIS-MAPT Rx during 2022. We will achieve the next payment of $70 million if Biogen licenses ION582 under this collaboration.

 When we commenced development for IONIS-MAPT Rx and ION582, we identified two separate performance obligations as our development work for each medicine. We recognized revenue as we performed services based on our effort to satisfy our performance obligation relative
 to the total effort expected to satisfy our performance obligations. In 2022, we completed our R&D services performance obligation for IONIS-MAPT Rx. From inception through December 31, 2023, we have included $ 57 million in the transaction price for our
 IONIS-MAPT Rx development performance obligation, including $ 19.5 million of milestone payments we earned from Biogen in 2020 when we
 advanced IONIS-MAPT Rx. From inception through December 31, 2023, we have included $ 68 million in milestone payments in the transaction price for our ION582 development performance obligation, including $ 39 million in milestone payments we received from Biogen for advancing ION582 during 2023.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our relationship with Biogen (in thousands, except percentage amounts):

 2023

 2022

 2021

 Revenue from our relationship with Biogen

 $

 350,146

 $

 366,696

 $

 428,784

 %

 %

 %

 Our consolidated balance sheets at December 31, 2023 and 2022 included deferred
 revenue of $307.4 million and $351.2 million, respectively, related to our relationship with Biogen.

 Joint Development and Commercialization Arrangement

 WAINUA (Eplontersen) Collaboration

 In 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and commercialize eplontersen for
 the treatment of ATTR. In December 2023, the FDA approved eplontersen with the brand name, WAINUA, in the U.S. for ATTRv-PN. We are jointly developing and commercializing WAINUA with AstraZeneca in the U.S. We initially granted AstraZeneca exclusive
 rights to commercialize WAINUA outside the U.S., except for certain Latin American countries. In July 2023, we expanded those rights to include Latin America.

 Over the term of the collaboration, we are eligible to
 receive up to $3.6 billion, which is comprised of a $200 million upfront payment, a $20 million license fee, up to $485 million in development and approval milestone payments and up to $2.9 billion in sales milestone payments. The agreement includes territory-specific development,
 commercial and medical affairs cost-sharing provisions. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties ranging from mid to high teens for sales outside the U.S. From inception through December 31, 2023, we have received nearly $360 million in payments under this collaboration. We will achieve the next payment of $30 million upon regulatory approval of WAINUA for ATTRv-PN in the EU under this
 collaboration.

 We evaluated our WAINUA collaboration under ASC 808 and identified four material components: (i) the license we granted to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization activities
 that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform.

 We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to AstraZeneca and as a
 result we had one performance obligation. For our sole performance obligation, we determined the transaction price was the $ 200 million upfront payment we received in 2021. In 2023, we earned a $ 20 million license fee payment when we licensed rights to Latin America for WAINUA to AstraZeneca. We recognized these payments in full because we did not have any remaining performance
 obligations after we delivered the licenses to AstraZeneca.

 We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs activities are within
 the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the activities under the collaboration. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading the Phase 3 development program, we recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible
 for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S., we recognize cost-share funding we receive from AstraZeneca related to these activities as a reduction of
 our commercial and medical affairs expenses. In 2023, we earned a $ 50 million milestone payment when the FDA approved WAINUA for ATTRv-PN in the
 U.S. We recognized this milestone payment in full as joint development revenue because we did not have any remaining performance obligations related to the milestone payment.

 Research and Development Partners

 In addition to our collaboration for WAINUA, we have a collaboration with AstraZeneca focused on discovering and developing treatments for
 cardiovascular, renal and metabolic diseases, which we formed in 2015. Under our collaboration, AstraZeneca has licensed multiple medicines from us. AstraZeneca is responsible for global development, regulatory and commercialization activities and
 costs for each of the medicines it has licensed from us.

 Over the term of the collaboration, we are eligible to receive up to $ 3.4 billion, which is comprised of a $ 65 million upfront payment, up to $ 290 million in license fees, up to $ 865 million
 in development milestone payments and up to $ 2.2 billion in regulatory milestone payments. In addition, we are eligible to receive tiered
 royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From inception through December 31, 2023, we have received more than $ 300 million in payments under this
 collaboration. We will achieve the next payment of $ 10 million if AstraZeneca advances a medicine under this collaboration.

 At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for AstraZeneca. We determined the transaction price to be the $ 65 million upfront payment we received and we allocated it to our single performance obligation. We recognized revenue for our R&D services performance obligation as we performed services
 based on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our performance obligation
 in 2021. As we achieved milestone payments for our R&D services, we included these amounts in our transaction price for our R&D services performance obligation. From inception through the completion of our performance obligation, we
 have included $ 90 million in payments in the transaction price for our R&D services performance obligation.

 Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance
 obligation. We recognized each of these payments in full in the respective period we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. For example, in 2023, we earned a
 $ 36 million payment when AstraZeneca licensed ION826 from us. We recognized this payment in full in 2023 because we did not have any remaining
 performance obligations after we delivered the license to AstraZeneca.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our relationship with AstraZeneca (in thousands, except percentage amounts):

 2023

 2022

 2021

 Revenue from our relationship with AstraZeneca

 $

 202,236

 $

 79,160

 $

 254,591

 %

 %

 %

 We did no t have any
 deferred revenue from our relationship with AstraZeneca at December 31, 2023 and 2022.

 GSK

 In 2010, we entered into a collaboration with GSK using our antisense drug discovery platform to discover and develop new medicines
 against targets for serious and rare diseases, including infectious diseases. Upon initiating the collaboration, we received an upfront payment of $ 35
 million. Under our collaboration, GSK is developing bepirovirsen for the treatment of chronic hepatitis B virus infection, or HBV, infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global
 development, regulatory and commercialization activities and costs for the HBV program.

 Over the term of the collaboration, we are eligible to receive nearly $ 260 million, which is comprised of a $ 25 million license fee, up to $ 42.5 million in development milestone payments, up to $ 120
 million in regulatory milestone payments and up to $ 70 million in sales milestone payments if GSK successfully develops and commercializes
 bepirovirsen. In addition, we are eligible to receive tiered royalties up to the low-teens on net sales of bepirovirsen. From inception through December 31, 2023, we have received more than $ 105 million in an upfront payment and payments related to the HBV program.

 We completed our R&D services performance obligations in 2015, therefore we do not have any remaining performance obligations under
 our collaboration with GSK. However, we can still earn additional payments and royalties as GSK advances the HBV program. In 2023, we earned a $ million milestone payment when GSK initiated a Phase 3 program of
 bepirovirsen. We recognized this milestone payment as R&D revenue in full in 2023 because we did not have any remaining performance obligations related to the milestone payment. We will achieve the next payment of $15 million if the FDA accepts an NDA filing of bepirovirsen for review.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our relationship with GSK (in thousands, except percentage amounts):

 2023

 2022

 2021

 Revenue from our relationship with GSK

 $

 15,000

 $

 —

 $

 —

 %

 %

 %

 We did no t have any
 deferred revenue from our relationship with GSK at December 31, 2023 and 2022.

 Pelacarsen Collaboration

 In 2017, we initiated a collaboration with Novartis to
 develop and commercialize pelacarsen. Novartis is responsible for conducting and funding development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study that Novartis initiated in 2019.

 Over the term of the collaboration, we are eligible to receive up to $ 900 million, which is comprised of a $ 75 million upfront payment, a $ 150 million license fee, a $ 25 million
 development milestone payment, up to $ 290 million in regulatory milestone payments and up to $ 360 million in sales milestone payments. We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. From inception through December 31, 2023, we have received more than $275 million in payments under this collaboration. We will achieve the next payment of $50 million if the FDA accepts an NDA filing for pelacarsen.

 In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6 million shares of our common stock for $ 100
 million in 2017.

 At the commencement of this collaboration, we identified four separate performance obligations:

 R&D services for pelacarsen;

 R&D services for olezarsen;

 API for pelacarsen; and

 API for olezarsen.

 We determined that the R&D services for each medicine and the API for each medicine were distinct performance obligations.

 We determined our transaction price to be $ 108.4
 million, comprised of the following:

 $ 75 million from the upfront payment;

 $ 28.4 million for the premium paid by Novartis for its purchase
 of our common stock at a premium in 2017; and

 $ 5.0 million for the potential premium Novartis would have paid
 if they purchased our common stock in the future.

 We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:

 $64.0 million for the R&D services for pelacarsen;

 $ 40.1 million for the R&D services for olezarsen;

 $ 1.5
 million for the delivery of pelacarsen API; and

 $ 2.8
 million for the delivery of olezarsen API.

 We completed our R&D services performance obligations for olezarsen and pelacarsen in 2019. As such, we recognized all
 revenue we allocated to the olezarsen and pelacarsen R&D services as of the end of 2019.

 We recognized revenue related to the R&D services for
 pelacarsen and olezarsen performance obligations as we performed services based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations.

 As described in the Biogen SPINRAZA
 section above, in January 2023, we entered into a royalty purchase agreement with Royalty Pharma. Under the agreement, in addition to a minority interest in SPINRAZA royalties, Royalty Pharma will receive 25 percent of any future royalty payments on pelacarsen. Refer to Note 7, Long-Term

 Obligations and Commitments, for further discussion of this agreement.

 New Medicine for the Treatment of Lp(a)-Driven Cardiovascular Disease

 In August 2023, we entered into a collaboration and license agreement with Novartis for the discovery, development and commercialization
 of a novel medicine for patients with Lp(a)-driven cardiovascular disease, or CVD. Novartis is solely responsible for the development, manufacturing and potential commercialization of the next generation Lp(a) therapy.

 Over the term of the collaboration, we are eligible to receive up to $ 730 million, which is comprised of a $ 60 million upfront payment, up to $ 155 million in development milestone payments, up to $ 105
 million in regulatory milestone payments and up to $ 410 million in sales milestone payments. In addition, we are eligible to receive tiered
 royalties ranging from 10 percent to 20 percent
 on net sales. From inception through December 31, 2023, we have received $ 60 million from the upfront payment we received under this collaboration. We will achieve the next payment of $ 5 million if we designate a development candidate under this collaboration.

 At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Novartis. We determined the transaction price to be the $ 60 million upfront payment we received in the fourth quarter 2023. We allocated the transaction price to our single performance obligation. We are recognizing revenue for our R&D services
 performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation at the
 end of the research term in June 2024.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our relationship with Novartis (in thousands, except percentage amounts):

 2023

 2022

 2021

 Revenue from our relationship with Novartis

 $

 30,194

 $

 $

 25,526

 %

 Less than 1 %

 %

 Our consolidated balance sheet at December 31, 2023 included deferred revenue of $ 30.0 million related to our relationship with Novartis. We did no t have any deferred revenue from our relationship with Novartis at December 31, 2022.

 Roche

 Huntington's Disease

 In 2013, we entered into an agreement with Hoffmann-La Roche Inc and F. Hoffmann-La Roche Ltd, collectively Roche, to develop treatments
 for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in people with
 early-stage HD. In 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen. As a result, Roche is responsible for all global development, regulatory and commercialization activities and costs for tominersen.

 Over the term of the collaboration, we are eligible to receive up to $ 395 million, which is comprised of a $ 30 million upfront payment, a $ 45 million license fee, up to $ 70 million in
 development milestone payments, up to $ 170 million in regulatory milestone payments and up to $ 80 million in sales milestone payments as tominersen advances. In addition, we are eligible to receive up to $ 136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on net sales of any product
 resulting from this collaboration. From inception through December 31, 2023, we have received more than $ 150 million in payments under this collaboration. We will achieve the next payment of $ 17.5
 million if Roche advances a medicine under this collaboration.

 At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Roche. We determined the transaction price to be the $ 30 million upfront payment we received and allocated it to our single performance obligation. As we achieved milestone payments for our R&D services, we included these amounts in our
 transaction price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation over our period of performance, which ended in 2017.

 Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services performance
 obligation. We recognized each of these payments in full in the respective period in which we generated the payment because the payments were distinct and we did not have any performance obligations for the respective payment. In 2021, Roche decided to
 discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the results of a pre-planned review of data from the Phase 3 study conducted by an unblinded independent data monitoring committee, or iDMC.

 In January 2023, Roche initiated the Phase 2, GENERATION HD2, study of tominersen in patients with prodromal or early manifest HD. Roche
 is focusing on early-stage and younger patients based on the post-hoc analyses from the GENERATION HD1 study that suggested tominersen may benefit these patient groups. We do not have any remaining performance obligations related to tominersen under
 this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen.

 IONIS-FB-L Rx for Complement-Mediated Diseases

 In 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-L Rx for the treatment of complement-mediated diseases. We are currently conducting multiple studies in two disease indications for IONIS-FB-L Rx, one for the treatment of patients with immunoglobulin A, or IgA, nephropathy, or IgAN, and one for the treatment of patients with GA, the advanced stage of dry AMD. In April 2023, Roche initiated a Phase 3 study of IONIS-FB-L Rx in patients with IgAN.

 After positive data from a Phase 2 clinical study in patients
 with IgAN, Roche licensed IONIS-FB-L Rx in 2022 for $35 million. As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for IONIS-FB-L Rx, except for the open label Phase 2 study in patients with IgAN and the Phase 2 study in patients with GA, both of which we are conducting and funding. In 2022, we amended our
 IONIS-FB-L Rx collaboration agreement with Roche. The amendment changed future potential milestone payments we could receive under the collaboration. We
 determined there were no changes that would require adjustments to revenue we previously recognized.

 Over the term of the collaboration, we are eligible to
 receive more than $810 million, which is comprised of a $75 million upfront payment, a $35 million license fee, up to $145 million in development milestone payments, up to $279 million in regulatory milestone payments and up to $280 million in sales milestone payments. In addition, we are also eligible to receive tiered royalties from the high
 teens to 20 percent on net sales. From inception through December 31, 2023,
 we have received more than $ 135 million in payments under this collaboration. We will achieve the next payment of up to $90 million if Roche advances IONIS-FB-L Rx under this collaboration.

 At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services for Roche. From inception through December 31, 2023, we have included $ 97 million in upfront and milestone payments in
 the transaction price for our R&D services performance obligation under this collaboration, including $ 22 million of milestone payments we
 achieved in 2022. We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligation in the fourth quarter
 of 2024.

 RNA-Targeting Medicines for Alzheimer's Disease and Huntington's Disease

 In September 2023, we entered into an agreement with Roche to develop two undisclosed early-stage programs for RNA-targeting investigational medicines for the treatment of AD and HD. Under the agreement, we are responsible for advancing the two programs through preclinical studies and Roche is responsible for clinical development, manufacturing and commercialization of the medicines if they
 receive regulatory approval.

 Over the term of the collaboration, we are eligible to receive up to $ 625 million, which is comprised of a $ 60 million upfront payment, up to $ 167 million in development milestone payments and up to $ 398
 million in sales milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through December 31, 2023, we have received $ 60 million from the upfront payment we received under this collaboration. We will achieve the next
 payment of $ 7.5 million if we advance a medicine under this collaboration.

 We identified two performance
 obligations under this new agreement, comprised of R&D services for each of the two separate programs. We determined the transaction price
 to be the $ 60 million upfront payment we received in the fourth quarter 2023. We allocated the transaction price based on the estimated
 stand-alone selling price of each performance obligation as follows:

 $ 45 million for the R&D services for the investigational
 medicine for AD; and

 $15 million for the R&D services for t he investigational medicine for HD.

 We are recognizing revenue for our R&D services performance obligations as we perform services based on our effort to satisfy our
 performance obligations relative to our total effort expected to satisfy our performance obligations. We currently estimate we will satisfy our performance obligations at the end of the research terms of March 2024 and March 2025 for the
 investigational medicines for AD and HD, respectively.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our relationship with Roche (in thousands, except percentage amounts):

 2023

 2022

 2021

 Revenue from our relationship with Roche

 $

 48,838

 $

 67,202

 $

 17,241

 %

 %

 %

 Our consolidated balance sheets at December 31, 2023 and 2022 included deferred
 revenue of $36.7 million and $22.4 million related to our relationship with Roche, respectively.

 Commercialization Partnerships

 Otsuka

 In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize donidalorsen in Europe.
 We are responsible for the ongoing development of donidalorsen. We retained the rights to commercialize donidalorsen in the U.S. and in the rest of the world assuming regulatory approval.

 Over the term of the collaboration, we are eligible to receive up to $ 185 million, which is comprised of a $ 65 million upfront payment, up to $ 50 million in regulatory milestone payments and up to $ 70
 million in sales milestone payments. In addition, we are eligible to receive tiered royalties ranging from 20 percent to 30 percent on net sales. From inception through December 31, 2023, we have received $ 65 million from the upfront payment we received under this collaboration. We will achieve the next
 payment of $ 15 million if the EMA accepts a MAA filing for donidalorsen in the EU under this collaboration.

 We identified two performance
 obligations under this new agreement, comprised of our license of donidalorsen to Otsuka and R&D services for donidalorsen. We determined the transaction price to be the $ 65 million upfront payment we received in the fourth quarter 2023. We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows:

 $ 56 million for the license of donidalorsen; and

 $ 9 million for the R&D services for donidalorsen.

 We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to satisfy our
 performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we will satisfy our performance obligations in March 2026.

 During the year ended December 31, 2023, we earned the following revenue from our relationship with Otsuka (in thousands, except percentage amount):

 2023

 Revenue from our relationship with Otsuka

 $

 56,480

 %

 Our consolidated balance sheets at December 31, 2023 included deferred revenue of $8.5
 million related to our relationship with Otsuka.

 PTC Therapeutics

 In 2018, we entered into an exclusive license agreement with
 PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-20 percent range on net sales for each medicine. In December 2021 and September 2023, we started receiving
 royalties from PTC for TEGSEDI and WAYLIVRA sales, respectively.

 Swedish Orphan Biovitrum AB (Sobi)

 In 2021, we began commercializing TEGSEDI and WAYLIVRA in
 Europe and TEGSEDI in North America through distribution agreements with Sobi. Under our distribution agreements, Sobi is responsible for commercializing TEGSEDI and WAYLIVRA in Europe and TEGSEDI in North America, respectively. We are
 responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. Under our agreements with Sobi, Sobi does not generally have a right of return. We recognize as revenue the price Sobi
 pays us for the inventory when we deliver the finished goods inventory to Sobi. In addition, we earn a distribution fee on net sales from Sobi for each medicine.

 In October 2023, our distribution agreement for TEGSEDI in North America was terminated. As a result, we are currently transitioning
 responsibilities from Sobi to us in order to continue serving the impacted patient community. In February 2024, we began the process to withdraw the TEGSEDI NDA.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our distribution agreement with Sobi for TEGSEDI in North America (in thousands, except percentage amounts):

 2023

 2022

 2021

 TEGSEDI revenue from our distribution agreement with Sobi in North America

 $

 2,646

 $

 4,004

 $

 7,443

 Less than 1 %

 %

 %

 Technology Enhancement Collaborations

 Bicycle Therapeutics

 In 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology to potentially
 increase the delivery capabilities of our LICA medicines. In 2021, we paid $ 42 million when we exercised our option to license Bicycle's
 technology, which included an equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricted our ability to trade our Bicycle shares for one year. In 2021, we recorded a $ 7.2 million equity investment for the shares we
 received in Bicycle. We recognized the remaining $ 34.8 million as R&D expense in 2021.

 Metagenomi

 In 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize investigational
 medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four additional genetic targets using gene editing technologies. As a result, we paid $ 80 million to license Metagenomi's technologies and will pay Metagenomi certain fees for the selection of genetic targets. We recorded the $ 80 million payment as R&D expense in 2022 upon receiving a license from Metagenomi for intellectual property that is in research with no current alternate use. In addition, we will pay
 Metagenomi milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events. We will also reimburse Metagenomi for certain of its costs in conducting its research and drug discovery activities
 under the collaboration.

 Other Agreements

 Alnylam Pharmaceuticals, Inc.

 Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate relating to
 antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alnylam gave us a
 technology access fee, participation in fees from Alnylam's partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited
 number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide
 chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi therapeutics
 targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained exclusive
 license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting
 mechanism and target-specific intellectual property for oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific
 intellectual property for oligonucleotides against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new
 platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for
 double-stranded RNAi therapeutics.

 During the years ended December 31, 2023, 2022 and 2021, we earned the following revenue from our relationship with Alnylam (in thousands, except percentage amounts):

 2023

 2022

 2021

 Revenue from our relationship with Alnylam

 $

 28,426

 $

 21,389

 $

 —

 %

 %

 %

 We did no t have any
 deferred revenue from our relationship with Alnylam at December 31, 2023 and 2022.

 5. Investments

 The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2023:

 One year
 or less

 %

 After one year
 but within two years

 %

 After two years
 but within three and a half years

 %

 Total

 %

 As illustrated above, at December 31, 2023,
 92 percent of our available-for-sale securities had a maturity of less than two years.

 All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of these
 securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the balance sheet date.

 We invest in debt securities with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Standard &
 Poor's, Moody's or Fitch, respectively.

 At December 31, 2023, we had an ownership interest of less than 20 percent in seven
 private companies and three public companies with which we conduct business.

 The following is a summary of our investments (in thousands):

 Amortized

 Gross Unrealized

 December 31, 2023

 Cost

 Gains

 Available-for-sale securities:

 Corporate debt securities (1)

 $

 559,967

 $

 $

 ( 2,625

)

 $

 557,499

 224,711

 ( 611

)

 224,164

 Debt securities issued by the U.S. Treasury (1)

 513,784

 ( 1,889

)

 512,047

 Debt securities issued by states of the U.S. and political subdivisions of the states

 17,757

 ( 113

)

 17,686

 Total securities with a maturity of one year or less

 1,316,219

 ( 5,238

)

 1,311,396

 Corporate debt securities

 243,151

 1,270

 ( 692

)

 243,729

 110,138

 ( 21

)

 110,664

 Debt securities issued by the U.S. Treasury

 294,873

 1,239

 ( 480

)

 295,632

 Debt securities issued by states of the U.S. and political subdivisions of the states

 3,466

 ( 4

)

 3,469

 Total securities with a maturity of more than one year

 651,628

 3,063

 ( 1,197

)

 653,494

 Total available-for-sale securities

 $

 1,967,847

 $

 3,478

 $

 ( 6,435

)

 $

 1,964,890

 Equity securities:

 Publicly traded equity securities included in other current assets (2)

 $

 11,897

 $

 $

 ( 5,832

)

 $

 6,301

 Privately held securities included in deposits and other assets (3)

 23,115

 25,001

 ( 5,125

)

 42,991

 Total equity securities

 $

 35,012

 $

 25,237

 $

 ( 10,957

)

 $

 49,292

 Total available-for-sale and equity securities

 $

 2,002,859

 $

 28,715

 $

 ( 17,392

)

 $

 2,014,182

 Amortized

 Gross Unrealized

 December 31, 2022

 Cost

 Gains

 Available-for-sale securities:

 Corporate debt securities (1)

 $

 513,790

 $

 $

 ( 4,365

)

 $

 509,448

 133,585

 —

 ( 1,829

)

 131,756

 Debt securities issued by the U.S. Treasury (1)

 512,655

 ( 5,124

)

 507,554

 Debt securities issued by states of the U.S. and political subdivisions of the states

 57,484

 ( 686

)

 56,816

 Other municipal debt securities

 6,008

 —

 ( 14

)

 5,994

 Total securities with a maturity of one year or less

 1,223,522

 ( 12,018

)

 1,211,568

 Corporate debt securities

 227,631

 ( 10,143

)

 217,502

 34,339

 —

 ( 1,040

)

 33,299

 Debt securities issued by the U.S. Treasury

 245,030

 —

 ( 4,109

)

 240,921

 Debt securities issued by states of the U.S. and political subdivisions of the states

 18,314

 ( 329

)

 18,101

 Total securities with a maturity of more than one year

 525,314

 ( 15,621

)

 509,823

 Total available-for-sale securities

 $

 1,748,836

 $

 $

 ( 27,639

)

 $

 1,721,391

 Equity securities:

 Publicly traded equity securities included in other current assets (2)

 $

 11,897

 $

 —

 $

 ( 1,358

)

 $

 10,539

 Privately held equity securities included in deposits and other assets (3)

 23,115

 17,257

 —

 40,372

 Total equity securities

 $

 35,012

 $

 17,257

 $

 ( 1,358

)

 $

 50,911

 Total available-for-sale and equity securities

 $

 1,783,848

 $

 17,451

 $

 ( 28,997

)

 $

 1,772,302

 ________________

 (1)

 Includes investments classified as cash equivalents in our consolidated
 balance sheets.

 (2)

 Our publicly traded equity securities are included in other current
 assets. We recognize publicly traded equity securities at fair value. In the year ended December 31, 2023, we recorded a $ 4.2 million net unrealized loss in our consolidated statements of
 operations related to changes in the fair value of our investments in publicly traded companies.

 (3)

 Our privately held equity securities are included in deposits and other assets. We recognize our privately held equity securities at cost minus impairments, plus or minus changes resulting from observable price changes in
 orderly transactions for the identical or similar investment of the same issuer, which are Level 3 inputs. In the year ended December 31, 2023, we recorded a $2.6 million net unrealized gain in our consolidated statements of operations related to changes in the fair value of our investments in privately held companies.

 The following is a summary of our investments we considered to be temporarily impaired at December 31, 2023 (in thousands, except for number of investments):

 Less than 12 Months of

 Temporary Impairment

 More than 12 Months of

 Temporary Impairment

 Total Temporary

 Impairment

 Number of

 Investments

 Unrealized

 Unrealized

 Unrealized

 Corporate debt securities

 $

 323,708

 $

 ( 553

)

 $

 178,183

 $

 ( 2,764

)

 $

 501,891

 $

 ( 3,317

)

 199,372

 ( 246

)

 14,777

 ( 386

)

 214,149

 ( 632

)

 Debt securities issued by the U.S. Treasury

 325,966

 ( 1,031

)

 131,000

 ( 1,338

)

 456,966

 ( 2,369

)

 Debt securities issued by states of the U.S. and political subdivisions of the states

 8,352

 ( 17

)

 7,888

 ( 100

)

 16,240

 ( 117

)

 Total temporarily impaired securities

 $

 857,398

 $

 ( 1,847

)

 $

 331,848

 $

 ( 4,588

)

 $

 1,189,246

 $

 ( 6,435

)

 We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest rates
 since purchase rather than underlying credit deterioration for any of the issuers. We believe it is more likely than not that we will be able to hold our debt securities with declines in value to maturity. Therefore, we intend to hold these securities
 to maturity and anticipate full recovery of our debt securities' amortized cost basis at maturity.

 6. Fair Value Measurements

 The following tables present the major security types we held at December 31, 2023 and 2022 that we regularly measure and carry at fair value. The following tables segregate each security type by the level within the fair value hierarchy of the valuation techniques we utilized to determine the respective securities' fair
 value (in thousands):

 At

 December 31, 2023

 Quoted Prices in

 Active Markets

 (Level 1)

 Significant Other

 Observable Inputs

 (Level 2)

 Cash equivalents (1)

 $

 185,424

 $

 185,424

 $

 —

 Corporate debt securities (2)

 801,228

 —

 801,228

 Debt securities issued by U.S. government agencies (3)

 334,828

 —

 334,828

 Debt securities issued by the U.S. Treasury (3)

 807,679

 807,679

 —

 Debt securities issued by states of the U.S. and political subdivisions of the states (3)

 21,155

 —

 21,155

 Publicly traded equity securities included in other current assets (5)

 6,301

 6,301

 —

 Total

 $

 2,156,615

 $

 999,404

 $

 1,157,211

 At

 December 31, 2022

 Quoted Prices in

 Active Markets

 (Level 1)

 Significant Other

 Observable Inputs

 (Level 2)

 Cash equivalents (1)

 $

 211,655

 $

 211,655

 $

 —

 Corporate debt securities (4)

 726,950

 —

 726,950

 Debt securities issued by U.S. government agencies (3)

 165,055

 —

 165,055

 Debt securities issued by the U.S. Treasury (3)

 748,475

 748,475

 —

 Debt securities issued by states of the U.S. and political subdivisions of the states (3)

 74,917

 —

 74,917

 Other municipal debt securities (3)

 5,994

 —

 5,994

 Publicly traded equity securities included in other current assets (5)

 10,539

 10,539

 —

 Total

 $

 1,943,585

 $

 970,669

 $

 972,916

 ________________

 (1)

 Included in cash and cash equivalents in our consolidated balance
 sheets.

 (2)

 $ 33.0 million was included in cash and cash equivalents, with the difference included in short-term investments in our consolidated balance sheets.

 (3)

 Included in short-term investments in our consolidated balance sheets.

 (4)

 $ 11.0 million was included in cash and cash equivalents, with the difference included in short-term investments in our consolidated balance sheets.

 (5)

 Included in other current assets in our consolidated balance sheets.

 Convertible Notes

 Our 1.75 % Notes, 0 % Notes and 0.125 % Notes had a fair value of $ 661.1 million, $ 667.8 million and $ 42.4 million at December 31, 2023,
 respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2 measurements because the notes do not trade regularly.

 7. Long-Term Obligations and Commitments

 The carrying value of our long-term obligations was as follows (in thousands):

 2023

 2022

 1.75 %
 convertible senior notes

 $

 562,285

 $

 —

 0 %
 convertible senior notes

 625,380

 622,242

 0.125 %
 convertible senior notes

 —

 544,504

 Liability related to sale of future royalties

 513,736

 —

 Lease liabilities

 178,969

 186,156

 Mortgage debt

 8,859

 8,998

 Other obligations

 33,714

 7,295

 Total

 $

 1,922,943

 $

 1,369,195

 Less: current portion

 ( 8,831

)

 ( 7,535

)

 Total Long-Term Obligations

 $

 1,914,112

 $

 1,361,660

 As of December 31, 2023, our 0.125 %
 Notes was classified as a current liability because it matures in December 2024.

 Convertible Debt and Call Spread

 1.75 %
 Convertible Senior Notes

 In 2023, we completed a $ 575.0
 million offering of convertible senior notes and used $ 488.2 million of the net proceeds from the issuance of the 1.75 % Notes to repurchase $ 504.4 million in
 principal of our 0.125 % Notes. We expect to use the remaining net proceeds to settle the 0.125 % Notes that remain outstanding.

 At December 31, 2023, we had the following 1.75 %
 Notes outstanding (in millions, except interest rate and price per share data):

 1.75 % Notes

 Outstanding principal balance

 $

 575.0

 Unamortized debt issuance costs

 $

 12.7

 Maturity date

 June 2028

 Interest rate

 1.75

 %

 Effective interest rate

 2.3

 %

 Conversion price per share

 $

 53.73

 Total shares of common stock subject to conversion

 10.7

 0 %
 Convertible Senior Notes and Call Spread

 In 2021, we completed a $ 632.5
 million offering of convertible senior notes. We used $ 319.0 million of the net proceeds from the issuance of the 0 % Notes to pay the remaining $ 309.9 million
 principal balance of our 1 % Notes in 2021.

 At December 31, 2023, we had the following 0 % Notes outstanding (in millions, except interest rate and price per share data):

 0 % Notes

 Outstanding principal balance

 $

 632.5

 Unamortized debt issuance costs

 $

 7.2

 Maturity date

 April 2026

 Interest rate

 %

 Effective interest rate

 0.5

 %

 Conversion price per share

 $

 57.84

 Effective conversion price per share with call spread

 $

 76.39

 Total shares of common stock subject to conversion

 10.9

 In conjunction with the 2021 offering, we entered into a call spread transaction, which was comprised of purchasing note hedges and
 selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0 % Notes by increasing the effective conversion
 price on our 0 % Notes. We increased our effective conversion price to $ 76.39 with the same number of underlying shares as our 0 % Notes. The call spread cost
 us $ 46.9 million, of which $ 136.7
 million was for the note hedge purchase, offset by $ 89.8 million we received for selling the warrants. Similar to our 0 % Notes, our note hedges are subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0 % Notes. The note hedges will expire upon maturity of the 0 %
 Notes, or April 2026. The note hedges and warrants are separate transactions and are not part of the terms of our 0 % Notes. The holders of the 0 % Notes do not
 have any rights with respect to the note hedges and warrants.

 We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in capital in our
 consolidated balance sheets. Refer to Note 1, Organization and Significant Accounting Policies, for our Call Spread accounting policy. We reassess our ability to continue to classify the note hedges and warrants in shareholders' equity at each reporting period.

 0.125 %
 Convertible Senior Notes and Call Spread

 In 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of
 our 1 % Notes to exchange $ 375.6
 million of our 1 % Notes for $ 439.3
 million of our 0.125 % Notes, and to issue $ 109.5
 million of our 0.125 % Notes.

 As discussed above, in 2023, we repurchased $ 504.4
 million of our 0.125 % Notes. We are holding the repurchased 0.125 % Notes in treasury until maturity. As a result, the remaining principal balance of our 0.125 %
 Notes was $ 44.5 million as of December 31, 2023.
 Additionally, during the year ended December 31, 2023, we recorded a $ 13.4 million gain on the early retirement of debt, which we recorded as other income in our consolidated statements of operations. The gain on the early retirement of our debt is the difference
 between the amounts paid to repurchase our 0.125 % Notes and the net carrying balance of the liability at the time that we completed the
 repurchases.

 At December 31, 2023, we had the following 0.125 % Notes outstanding with interest payable semi-annually (in millions, except interest rate and price per share data):

 0.125 % Notes

 Outstanding principal balance

 $

 44.5

 Unamortized debt issuance costs

 $

 0.2

 Maturity date

 December 2024

 Interest rate

 0.125

 %

 Effective interest rate

 0.5

 %

 Conversion price per share

 $

 83.28

 Effective conversion price per share with call spread

 $

 123.38

 Total shares of common stock subject to conversion, excluding shares related to 0.125 % Notes we have repurchased and are currently holding in treasury

 0.5

 In conjunction with the issuance of our 0.125 % Notes in 2019, we entered into a call spread transaction, which was
 comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0.125 %
 Notes by increasing the effective conversion price on our 0.125 % Notes. We increased our effective conversion price to $123.38 with the same number of underlying shares as our 0.125 % Notes. The call spread cost us $52.6 million, of
 which $108.7 million was for the note hedge purchase,
 offset by $56.1 million we received for selling the
 warrants. Similar to our 0.125 % Notes, our note hedges are
 subject to adjustment. Additionally, our note hedges are exercisable upon conversion of the 0.125 % Notes. The note hedges will expire upon maturity of the 0.125 % Notes, or December 2024. The note hedges and warrants are separate transactions and are not part of the terms of our 0.125 % Notes. The holders of the 0.125 % Notes do not have any rights with respect to the note hedges and warrants.

 We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in capital in our
 consolidated balance sheets. Refer to Note 1, Organization and Significant Accounting Policies, for our Call Spread accounting policy. We reassess our ability to continue to classify the note hedges and warrants in shareholders' equity at each reporting period.

 Other Terms of Convertible Senior Notes

 The 1.75 %, 0 % and 0.125 % Notes are convertible under
 certain conditions, at the option of the note holders. We can settle conversions of the notes, at our election, in cash, shares of our common stock or a combination of both. We may not redeem the notes prior to maturity, and we do not have to provide a
 sinking fund for them. Holders of the notes may require us to purchase some or all of their notes upon the occurrence of certain fundamental changes, as set forth in the indentures governing the notes, at a purchase price equal to 100 percent of the principal amount of the notes to be purchased, plus any accrued and unpaid interest.

 Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2023, 2022 and 2021 included $ 5.9 million, $ 5.3 million and $ 4.9 million, respectively, of
 non-cash interest expense related to the amortization of debt issuance costs for our convertible notes.

 Financing Arrangements

 Operating Facilities

 In 2017, we purchased the building that houses our primary R&D facility for $ 79.4 million and our manufacturing facility for $ 14.0 million. We financed the purchase
 of these two facilities with mortgage debt of $ 60.4
 million in total. Our primary R&D facility mortgage had an interest rate of 3.88 percent. Our manufacturing facility mortgage has an
 interest rate of 4.20 percent. During the first five years of both mortgages, we were only required to make interest payments. We began making principal payments in 2022. Our manufacturing facility mortgage matures in August 2027. We repaid
 our primary R&D facility mortgage in 2022 in conjunction with a sale and leaseback transaction.

 In 2022, we concurrently entered into two
 purchase and sale agreements with a real estate investor. In the same period, we closed the first transaction in which we sold the facilities at our headquarters in Carlsbad, California, which includes our primary R&D facility, for a purchase price
 of $ 263.4 million. As a result, we de-recognized the related land and improvements, building and building improvements, which resulted in a net
 gain of $ 150.1 million that we reported in other income in our consolidated statements of operations. We used a portion of the sale proceeds to
 extinguish our outstanding mortgage debt on our primary R&D facility of $ 51.3 million. In connection with this transaction, we leased back
 our headquarters facilities for an initial lease term of 15 years with options to extend the lease for two additional terms of five years each.

 In August 2023, we closed the second transaction and transferred legal ownership of two lots of undeveloped land adjacent to our headquarters to the real estate investor for a purchase price of $ 33 million. In connection with this transaction, we entered into a build-to-suit lease agreement with the same real estate investor to lease a new R&D facility. The lessor will develop and
 construct a new building composed of R&D and office space. We will design and construct tenant improvements to customize the facility's interior space. We will lease the facility for an initial term of 15 years with options to extend the lease for two additional terms of five years each. The lease will commence once the structure of this new facility is completed.

 Since the building is under construction and unavailable to lease, we are unable to complete the sale-leaseback evaluation under ASC 842,
 Leases. As a result, the land remains in our consolidated balance sheets and we accounted for the proceeds as a financial liability. We will reassess the transaction under the sale-leaseback accounting guidance when the facilities are available for
 lease commencement.

 Debt Maturity Schedules

 Annual convertible and mortgage debt maturities, including fixed and determinable interest, at December 31, 2023 are as follows (in thousands):

 2024

 $

 55,298

 2025

 10,657

 2026

 643,157

 2027

 10,509

 2028

 580,277

 Thereafter

 8,462

 Total debt and mortgage maturities

 $

 1,308,360

 Less: Current portion included in other current liabilities

 ( 157

)

 Less: Fixed and determinable interest

 ( 47,138

)

 Less: Debt issuance costs

 ( 20,061

)

 Total debt

 $

 1,241,004

 Operating Leases

 Carlsbad Leases

 We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our manufacturing
 facility. We lease this space under a non-cancelable operating lease. In 2020, we exercised our option to extend our lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional five-year period.

 We also lease an additional office space and warehouse space in Carlsbad. We lease these spaces under non-cancelable operating leases. In
 2022, we exercised our option to extend the office space lease, extending our term from January 2023 to May 2027. We have no remaining options
 to extend this lease. Our warehouse space lease in Carlsbad has an initial term ending in 2028 with no options to extend the lease.

 As discussed above in the section titled, Financing Arrangements, we lease our headquarters, which includes our primary R&D facility, as part of a sale and leaseback transaction that closed in 2022. The initial lease term for our headquarters facilities is 15 years with options to extend the lease for two
 additional terms of five years each. We determined at lease inception that it was not reasonably certain that we would exercise any of the
 options to extend the lease. We expect our lease payments over the initial term to total approximately $ 280 million. In connection with the
 transfer of legal ownership of the two lots of undeveloped land to the real estate investor, we entered into a build-to-suit lease agreement
 with the same real estate investor who will build a new R&D facility for us on those lots. The lease will commence once the structure of this new facility is completed.

 Oceanside Lease

 In 2022, we entered into a build-to-suit lease agreement to lease a development chemistry and manufacturing facility to be constructed by
 the lessor in Oceanside, California. We capitalized costs that we incurred related to the design and development of tenant improvements as construction-in-progress in our consolidated balance sheets. In August 2023, we reached a mutual agreement with
 the lessor to terminate the lease agreement. As a result, we recorded a charge of $ 20 million, primarily associated with the impairment of
 construction-in-progress assets, within SG&A expense in our consolidated statements of operations.

 Boston Leases

 We entered into an operating lease agreement for office space located in Boston, Massachusetts which commenced in August 2018. We are
 leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to extend the lease for an
 additional five-year term. Under the lease agreement, we received a three-month free rent period.

 In 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease commencement date was in
 January 2022 when the office space was ready for our tenant's occupancy. We are subleasing this space under a non-cancelable operating sublease with a sublease term ending 83 months following the sublease commencement date with no option to extend the
 sublease. Under the sublease agreement we provided a seven-month free rent period, which commenced in January 2022. We will receive lease
 payments over the sublease term totaling $ 9.6 million.

 We entered into an operating lease agreement for another office space located in Boston, Massachusetts which commenced in 2021. We are
 leasing this space under a non-cancelable operating lease with an initial term ending 91 months following the lease commencement date and an
 option to extend the lease for an additional five-year
 term. Under the lease agreement, we received a seven-month free rent period, which commenced in November 2021. Our lease payments over the
 initial term total $ 6.8 million.

 When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we did not include
 the extension options for these leases in the original lease term because it was not reasonably certain we would exercise those extension options.

 Amounts related to our operating leases were as follows (dollar amounts in millions):

 At December 31, 2023

 Right-of-use operating lease assets

 $

 171.9

 Operating lease liabilities

 $

 179.0

 Weighted average remaining lease term

 13.0 years

 Weighted average discount rate

 6.9

 %

 During the years ended December 31, 2023,
 2022, and 2021 we paid $ 20.1 million, $ 4.0 million and $ 3.3 million of lease payments, which were included in operating activities in our consolidated statements of cash flows.

 As of December 31, 2023,
 the future payments for our operating lease liabilities are as follows (in thousands):

 Operating Leases

 Year ending December 31,

 2024

 $

 20,398

 2025

 20,645

 2026

 20,781

 2027

 20,800

 2028

 20,774

 Thereafter

 176,138

 Total minimum lease payments

 279,536

 Less: Imputed interest

 ( 100,567

)

 Less: Current portion (included in other current liabilities)

 ( 8,094

)

 Total long-term lease liabilities

 $

 170,875

 Rent expense was $ 23.1 million,
 $ 8.3 million and $ 3.4 million for the
 years ended December 31, 2023, 2022
 and 2021, respectively.

 Royalty Revenue Monetization

 In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to monetize a portion of
 our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively. As a result, we received an upfront payment of $ 500 million and we are eligible to receive up to $ 625 million in additional milestone
 payments. Under the terms of the agreement, Royalty Pharma will receive 25 percent of our SPINRAZA royalty payments from 2023 through 2027,
 increasing to 45 percent of royalty payments in 2028, on up to $ 1.5 billion in annual sales. In addition, Royalty Pharma will receive 25 percent of
 any future royalty payments on pelacarsen. Royalty Pharma's royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $ 475 million or $ 550 million, depending on the timing and occurrence of FDA approval of
 pelacarsen.

 We recorded the upfront payment of $ 500
 million as a liability related to the sale of future royalties, net of transaction costs of $ 10.4 million, which we are amortizing over the
 estimated life of the arrangement using the effective interest rate method. We recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue. We record royalty payments made to Royalty
 Pharma as a reduction of the liability.

 We determine the effective interest rate used to record
 interest expense under this agreement based on an estimate of future royalty payments to Royalty Pharma. As of December 31, 2023, the estimated effective interest rate under the agreement was 13.5 percent.

 The following is a summary of our liability related to
 sale of future royalties for the year ended December 31, 2023 (in thousands):

 Proceeds from sale of future royalties

 $

 500,000

 Royalty payments to Royalty Pharma

 ( 44,628

)

 Interest expense related to sale of future royalties

 68,238

 Liability related to sale of future royalties as of December 31, 2023

 523,610

 Issuance costs related to sale of future royalties

 ( 10,434

)

 Amortization of issuance costs related to sale of future royalties as of December 31, 2023

 Net liability related to sale of future royalties as of December 31, 2023

 $

 513,736

 There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of royalty
 payments from Biogen and Novartis, and result in changes to our estimate of future royalty payments to Royalty Pharma. Such factors include, but are not limited to, the commercial sales of SPINRAZA, the regulatory approval and commercial sales of
 pelacarsen, competing products or other significant events.

 8. Stockholders ' Equity

 Preferred Stock

 We are authorized to issue up to 15
 million shares of "blank check" Preferred Stock. As of December 31, 2023, there were no shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or outstanding shares as of December 31, 2023.

 Common Stock

 At December 31, 2023 and 2022, we had 300 million shares of common
 stock authorized, of which 144.3 million and 142.1 million were issued and outstanding, respectively. As of December 31, 2023,
 total common shares reserved for future issuance were 49.7 million.

 During the years ended December 31, 2023,
 2022 and 2021, we issued 2.3 million, 1.2 million and 1.1 million shares of common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net
 proceeds from these transactions of $ 49.4 million, $ 6.4
 million and $ 11.6 million in 2023,
 2022 and 2021, respectively.

 Stock Plans

 1989 Stock Option Plan

 In 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, provides for
 the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock to our employees,
 directors, and consultants. The plan expires in January 2024. The 1989 Stock Option Plan, or 1989 Plan, does not allow us to grant stock bonuses or restricted stock awards and prohibits us from repricing any options outstanding under the plan unless
 our stockholders approve the repricing. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant
 and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. At December 31, 2023, no options were outstanding and 68,000 shares were available for future grant under the 1989 Plan.

 2011 Equity Incentive Plan

 In 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for the issuance of
 stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after receiving approval from our
 stockholders, we amended our 2011 Equity Incentive Plan, or 2011 Plan, to increase the total number of shares reserved for issuance. We increased the shares available
 under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. In June 2021, after receiving approval from our stockholders, we amended our 2011 Plan. The amendment increased the total number of shares of common stock authorized for issuance under the 2011 Plan from 23.0 million to 29.7 million and added a fungible share counting ratio whereby the share reserve will be reduced by 1.7 shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased by
 1.7 shares for each share of common stock returning from a
 full value award. In June 2023, after receiving approval from our stockholders, we amended our 2011 Plan to increase the total number of shares of common stock
 authorized for issuance under the 2011 Plan from 29.7
 million to 35.2 million.

 The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock
 appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our
 stockholders approve such action. Currently we anticipate awarding only stock options, RSU and PRSU awards to our employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years.
 We have granted restricted stock unit awards to our employees under the 2011 Plan which vest annually over a four-year period. At December 31, 2023, a total of 12.8 million
 options were outstanding, of which 8.7 million were exercisable, 3.3 million restricted stock unit awards were outstanding, and 8.0 million shares were
 available for future grant under the 2011 Plan.

 Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in
 control. In the absence of such provisions, no such acceleration will occur. In addition, we implemented a change of control and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our
 chief executive officer and chief financial officer, and vice presidents. If one of our executive officers or vice presidents is terminated or
 resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the company, the impacted employee's stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the termination date.

 2020 Equity Incentive Plan

 In connection with the Akcea Merger in 2020, we assumed the
 unallocated portion of the available share reserve under the Akcea 2015 Equity Incentive Plan. In 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or
 2020 Plan. The 2020 Plan provided for the issuance of up to 2.6 million shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. In the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The
 amendment decreased the total number of shares of common stock authorized for issuance under the 2020 Plan from approximately 2.6 million to 1.6 million. We assumed the 2020 Plan in connection with Ionis' reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part of the Akcea Merger.

 The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock options or stock
 appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our
 stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 31, 2021 have a term of ten years.
 We have granted restricted stock unit awards to our employees under the 2020 Plan which vest annually over a four-year period. At December 31, 2023, a total of 0.4 million
 options were outstanding, of which 0.1 million were exercisable, 0.2 million restricted stock unit awards were outstanding, and 1.0 million shares were
 available for future grant under the 2020 Plan.

 Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a change in
 control. In the absence of such provisions, no such acceleration will occur.

 Corporate Transactions and Change in Control under 2011 and 2020 Plans

 In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the following
 actions with respect to outstanding stock awards under the 2011 and 2020 Plans:

 arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent company);

 arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award to the surviving or
 acquiring corporation (or its parent company);

 accelerate the vesting and exercisability of a stock award followed by the termination of the stock award;

 arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued pursuant to a stock award;

 cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date of the corporate transaction, in exchange
 for cash consideration, if any, as the Board, in its sole discretion, may consider appropriate; and

 arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property the holder of the stock award would have
 received upon the exercise of the stock award, over (b) any exercise price payable by such holder in connection with such exercise.

 2002 Non-Employee Directors' Stock Option Plan

 In 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and restatement of the 1992 Non-Employee
 Directors' Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee Directors' Stock Option Plan, or the 2002
 Plan. In 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares reserved for issuance from 1.2
 million to 2.0 million. In 2020, after receiving approval from our stockholders, we further amended our 2002 Plan. The amendments included:

 An increase to the total number of shares reserved for issuance under the plan from 2.0 million to 2.8 million shares;

 A reduction to the amount of the automatic awards under the plan;

 A revision to the vesting schedule of new awards granted; and

 An extension of the term of the plan.

 Options under this plan expire 10 years
 from the date of grant. At December 31, 2023, a total of 0.9 million options were outstanding, of which 0.9 million were exercisable, 40,000 restricted stock unit awards were outstanding, and 0.5
 million shares were available for future grant under the 2002 Plan.

 Employee Stock Purchase Plan

 In 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of the ESPP and we
 reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 2019, we reserved an
 additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized under the plan as of December 31, 2023. The ESPP
 permits full-time employees to purchase common stock through payroll deductions (which cannot exceed 10 percent of each employee's compensation)
 at the lower of 85 percent of fair market value at the beginning of the purchase period or the end of each purchase period. Under the amended
 and restated ESPP, employees must hold the stock they purchase for a minimum of six months from the date of purchase. During 2023, employees purchased and we issued to employees 0.1
 million shares under the ESPP at a weighted average price of $ 30.53 per share. At December 31, 2023, there were 0.4 million shares available for purchase under the
 ESPP.

 Stock Option Activity

 The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2023 (in thousands, except per share and contractual life data):

 Number

 of Shares

 Weighted

 Average Exercise

 Price Per Share

 Average

 Remaining

 Contractual Term

 (Years)

 Aggregate

 Intrinsic

 Value

 Outstanding at December 31, 2022

 14,970

 $

 50.57

 Granted

 2,407

 $

 38.80

 Exercised

 ( 1,444

)

 $

 45.06

 Cancelled/forfeited/expired

 ( 1,842

)

 $

 55.90

 Outstanding at December 31, 2023

 14,091

 $

 48.43

 4.74

 $

 78,542

 Exercisable at December 31, 2023

 9,703

 $

 52.24

 3.20

 $

 28,349

 The weighted-average estimated fair values of options granted were $ 19.72, $ 18.66 and $ 24.35 for the years ended December 31, 2023, 2022 and 2021, respectively. The total intrinsic value of options
 exercised during the years ended December 31, 2023, 2022 and 2021 were $ 6.0 million, $ 1.4 million and $ 2.5 million, respectively, which we determined as of the date of exercise. The amount of cash received from the exercise of stock options was $ 65.1 million, $ 3.6 million and $ 8.5 million for the years ended December 31, 2023, 2022 and 2021, respectively. For the year
 ended December 31, 2023, the weighted-average fair value of options exercised was $ 49.23. As of December 31, 2023, total unrecognized compensation cost related to
 non-vested stock options was $ 36.6 million. We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

 Restricted Stock Unit Activity

 The following table summarizes the RSU activity for the year ended December 31, 2023 (in thousands, except per share data):

 Number

 of Shares

 Weighted Average

 Grant Date Fair

 Value Per Share

 Non-vested at December 31, 2022

 2,766

 $

 48.30

 Granted

 1,707

 $

 40.51

 Vested

 ( 1,055

)

 $

 51.64

 Cancelled/forfeited

 ( 179

)

 $

 42.90

 Non-vested at December 31, 2023

 3,239

 $

 43.40

 For the years ended December 31, 2023,
 2022 and 2021, the
 weighted-average grant date fair value of RSUs granted was $ 40.51, $ 36.14 and $ 57.02 per RSU, respectively. As of December 31, 2023, total unrecognized compensation cost related to RSUs was $ 53.7 million. We expect to recognize this cost over a weighted average period of 1.3
 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

 Performance Restricted Stock Unit Activity

 The following table summarizes the PRSU activity for the year ended December 31, 2023 (in thousands, except per share data):

 Number

 of Shares

 Weighted Average

 Grant Date Fair

 Value Per Share

 Non-vested at December 31, 2022

 $

 52.59

 Granted

 $

 57.43

 Vested

 ( 75

)

 $

 52.43

 Non-vested at December 31, 2023

 $

 56.04

 For the years ended December 31, 2023,
 2022 and 2021, the
 weighted-average grant date fair value of PRSUs granted was $ 57.43, $ 42.28 and $ 77.17 per PRSU, respectively. As of December 31, 2023, total unrecognized compensation cost related to PRSUs was $ 4.4 million. We expect to recognize this cost over a weighted average period of 1.4
 years. We will adjust the total unrecognized compensation cost for future changes in estimated forfeitures.

 Stock-based Compensation Expense and Valuation Information

 The following table summarizes stock-based compensation expense for the years ended December 31, 2023, 2022 and 2021 (in thousands):

 2023

 2022

 2021

 Cost of sales

 $

 $

 $

 Research, development and patent

 77,826

 73,704

 87,522

 Selling, general and administrative

 27,484

 26,027

 32,700

 Total

 $

 105,809

 $

 100,264

 $

 120,678

 Refer to Note 1, Organization and
 Significant Accounting Policies, for further details on how we determine the fair value of stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP.

 For the years ended December 31, 2023,
 2022 and 2021, we used the
 following weighted-average assumptions in our Black-Scholes calculations:

 Employee Stock Options:

 2023

 2022

 2021

 Risk-free interest rate

 3.8

 %

 2.1

 %

 0.6

 %

 Dividend yield

 0.0

 %

 0.0

 %

 0.0

 %

 Volatility

 46.8

 %

 54.5

 %

 54.0

 %

 Expected life

 6.3 years

 6.3 years

 4.9 years

 Board of Director Stock Options:

 2023

 2022

 2021

 Risk-free interest rate

 3.8

 %

 2.9

 %

 1.2

 %

 Dividend yield

 0.0

 %

 0.0

 %

 0.0

 %

 Volatility

 52.7

 %

 56.2

 %

 55.9

 %

 Expected life

 7.7 years

 7.4 years

 7.3 years

 ESPP:

 2023

 2022

 2021

 Risk-free interest rate

 5.3

 %

 1.2

 %

 0.1

 %

 Dividend yield

 0.0

 %

 0.0

 %

 0.0

 %

 Volatility

 36.0

 %

 50.1

 %

 42.4

 %

 Expected life

 6 months

 6 months

 6 months

 Risk-Free Interest Rate. We base
 the risk-free interest rate assumption on observed interest rates appropriate for the term of our stock option plans or ESPP.

 Dividend Yield. We base the
 dividend yield assumption on our history and expectation of dividend payouts. We have not paid dividends in the past and do not expect to in the future.

 Volatility. We use an average of
 the historical stock price volatility of our stock for the Black-Scholes model. We computed the historical stock volatility based on the expected term of the awards.

 Expected Life. The expected term
 of stock options we have granted represents the period of time that we expect them to be outstanding. Historically, we estimated the expected term of options we have granted based on actual and projected exercise patterns. In 2021, our Compensation
 Committee approved an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the 2020 Equity Incentive Plan, or 2020 Plan, that increased the contractual term of stock options granted under these plans from seven to ten years for stock options granted on January 1, 2022
 and thereafter. We determined that we are unable to rely on our historical exercise data as a basis for estimating the expected life of stock options granted to employees following this change because the contractual term changed and we have no other
 means to reasonably estimate future exercise behavior. We therefore used the simplified method for determining the expected life of stock options granted to employees in the years ended December 31, 2023 and 2022. Under the simplified method, we
 calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we gain additional historical information, we will transition to calculating our expected term based on our historical exercise patterns.

 Forfeitures. We reduce stock-based
 compensation expense for estimated forfeitures. We estimate forfeitures at the time of grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on historical experience.

 9. Income Taxes

 Loss before income taxes is comprised of (in thousands):

 2023

 2022

 2021

 $

 ( 334,707

)

 $

 ( 258,493

)

 $

 ( 29,966

)

 Foreign

 Loss before income taxes

 $

 ( 333,965

)

 $

 ( 257,985

)

 $

 ( 29,148

)

 Our income tax expense (benefit) was as follows (in thousands):

 2023

 2022

 2021

 Current:

 Federal

 $

 35,861

 $

 10,522

 $

 ( 200

)

 State

 ( 3,687

)

 1,129

 ( 690

)

 Foreign

 Total current income tax expense (benefit)

 32,321

 11,737

 ( 551

)

 Deferred:

 Federal

 —

 —

 —

 State

 —

 —

 —

 Total deferred income tax benefit

 —

 —

 —

 Total income tax expense (benefit)

 $

 32,321

 $

 11,737

 $

 ( 551

)

 Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal statutory rate to loss before income taxes. The sources
 and tax effects of the differences are as follows (in thousands):

 2023

 2022

 2021

 Pre-tax loss

 $

 ( 333,965

)

 $

 ( 257,985

)

 $

 ( 29,148

)

 Statutory rate

 ( 70,133

)

 21.0

 %

 ( 54,177

)

 21.0

 %

 ( 6,121

)

 21.0

 %

 State income tax net of federal benefit

 ( 22,597

)

 6.8

 %

 ( 13,622

)

 5.3

 %

 4,278

 ( 14.7

)%

 Foreign

 ( 22

)

 0.0

 %

 ( 49

)

 0.0

 %

 ( 0.5

)%

 Net change in valuation allowance

 175,388

 ( 52.5

)%

 104,951

 ( 40.7

)%

 2,885

 ( 9.9

)%

 Loss on debt transactions

 —

 —

 —

 —

 ( 0.9

)%

 Tax credits

 ( 67,131

)

 20.1

 %

 ( 39,729

)

 15.4

 %

 ( 23,198

)

 79.6

 %

 Deferred tax true-up

 0.0

 %

 ( 20

)

 0.0

 %

 ( 24

)

 0.1

 %

 Tax rate change

 1,023

 ( 0.3

)%

 ( 3,091

)

 1.2

 %

 12,838

 ( 44.0

)%

 Non-deductible compensation

 3,814

 ( 1.1

)%

 3,023

 ( 1.2

)%

 5,085

 ( 17.4

)%

 Other non-deductible items

 ( 0.1

)%

 0.0

 %

 ( 0.3

)%

 Foreign-derived intangible income benefit

 ( 7,493

)

 2.2

 %

 —

 —

 —

 —

 Stock-based compensation

 19,546

 ( 5.9

)%

 14,030

 ( 5.4

)%

 4,720

 ( 16.2

)%

 Other

 ( 405

)

 0.1

 %

 ( 0.1

)%

 ( 1,503

)

 5.1

 %

 Effective rate

 $

 32,321

 ( 9.7

)%

 $

 11,737

 ( 4.5

)%

 $

 ( 551

)

 1.9

 %

 Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and liabilities for
 financial reporting purposes and the amounts used for income tax purposes.

 Significant components of our deferred tax assets and liabilities as of December 31, 2023 and 2022 are as follows (in thousands):

 2023

 2022

 Deferred Tax Assets:

 Net operating loss carryovers

 $

 77,964

 $

 87,802

 Tax credits

 239,962

 277,436

 Deferred revenue

 71,683

 85,700

 Stock-based compensation

 77,468

 86,983

 Intangible and capital assets

 104,380

 104,649

 Convertible debt

 16,849

 34,384

 Capitalized research and development expenses

 238,738

 119,635

 Long-term lease liabilities

 43,718

 45,612

 Sale of future royalties

 144,608

 —

 Other

 10,343

 15,813

 Total deferred tax assets

 $

 1,025,713

 $

 858,014

 Deferred Tax Liabilities:

 Fixed assets

 ( 4,166

)

 ( 4,475

)

 Right-of-use assets

 ( 42,007

)

 ( 44,504

)

 Other

 ( 1,910

)

 ( 313

)

 Net deferred tax asset

 $

 977,630

 $

 808,722

 Valuation allowance

 ( 977,630

)

 ( 808,722

)

 Total net deferred tax assets and liabilities

 $

 —

 $

 —

 We evaluate our deferred tax assets regularly to determine whether adjustments to the valuation allowance are appropriate due to changes in facts or circumstances, such as
 changes in expected future pre-tax earnings, tax law, interactions with taxing authorities and developments in case law. In making this evaluation, we rely on our recent history of pre-tax earnings. Our material assumptions are our forecasts of future
 pre-tax earnings and the nature and timing of future deductions and income represented by the deferred tax assets and liabilities, all of which involve the exercise of significant judgment. Although we believe our estimates are reasonable, we are
 required to use significant judgment in determining the appropriate amount of valuation allowance recorded against our deferred tax assets.

 Our valuation allowance increased by $ 169
 million from December 31, 2022 to December 31, 2023.
 The increase was primarily related to increases in our deferred tax assets for capitalized research and development expenses and sale of future royalties.

 At December 31, 2023, we had
 federal and state, primarily California, tax net operating loss carryforwards of $ 242.8 million and $ 398.8 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards will begin to expire in 2032. At December 31, 2023, we also had federal and California research and development tax credit carryforwards of $ 169.7 million and $ 124.4 million, respectively. Our federal research and development
 tax credit carryforwards will begin to expire in 2038. Our California research and development tax credit carryforwards are available indefinitely. Our 2023 current tax expense includes a benefit of approximately $ 3.2 million related to utilization of state tax loss carryforwards, primarily California.

 Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership change
 limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation may result in the expiration of net operating losses and credits before utilization.

 We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open tax years
 in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is
 more-likely-than not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the applicable tax authority sustaining our position.

 The following table summarizes our gross unrecognized tax benefits (in thousands):

 2023

 2022

 2021

 Beginning balance of unrecognized tax benefits

 $

 56,567

 $

 55,085

 $

 54,163

 Decrease for lapse of statute of limitations

 ( 14,993

)

 —

 —

 Decrease for prior period tax positions

 ( 737

)

 ( 267

)

 ( 695

)

 Increase for prior period tax positions

 Increase for current period tax positions

 2,032

 1,490

 1,354

 Ending balance of unrecognized tax benefits

 $

 43,298

 $

 56,567

 $

 55,085

 Included in the balance of unrecognized tax benefits at December 31, 2023, 2022 and 2021 was $ 0.3 million, $ 6.2 million and $ 6.2 million respectively, that if we recognized, could impact our
 effective tax rate, subject to our remaining valuation allowance.

 We estimate that it is reasonably possible that the balance of our gross unrecognized tax benefits may decrease by approximately $ 7.6 million within the next 12 months due to the lapse of statute of limitations on underlying tax positions primarily related to amortization of certain
 capitalized state research and development expenditures.

 We recognize interest and/or penalties related to income tax matters in income tax expense. During the years ended December 31, 2023, 2022 and 2021, we recognized $ 0.1 million, $ 0.8 million and $ 0.5 million, respectively, of
 accrued interest and penalties related to gross unrecognized tax benefits.

 We are subject to taxation in the U.S. and various state and
 foreign jurisdictions. U.S. tax years 2020 through 2022 remain open to examination and tax years 2019 through 2022 remain open to examination by major state taxing jurisdictions, primarily California, although net operating loss and credit
 carryforwards generated prior to these periods may still be adjusted upon examination by the Internal Revenue Service or state tax authorities if they have been used in an open period or are used in a future period.

 10. Employment Benefits

 We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding a percentage of
 their salary up to the IRS annual limits of $ 22,500 and $ 30,000 in 2023 for employees under 50 years old and employees 50 years old or over,
 respectively. We made approximately $ 7.1 million, $ 5.6
 million and $ 5.5 million in matching contributions for the years ended December 31, 2023, 2022 and 2021, respectively.

 11. Legal Proceedings

 From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we evaluate the
 status of each legal matter and assess our potential financial exposure. If we consider the potential loss from any legal proceeding to be probable and we can reasonably estimate the amount, we accrue a liability for the estimated loss. The outcome of
 any proceeding is not determinable in advance. Therefore, we are required to use significant judgment to determine the probability of a loss and whether the amount of the loss is reasonably estimable. Our assessment of a potential liability and the
 amount of accruals we recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the potential liability related to the legal proceeding and may revise our estimates.

 There are no pending material legal proceedings to which we are a party or of which our property is the subject.

 12. Fourth Quarter Financial Data (Unaudited)

 The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, necessary
 for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2023 and 2022 are as follows (in thousands, except per share data).

 Three Months Ended December 31,

 2023

 2022

 Revenue (1)

 $

 324,505

 $

 151,890

 Operating expenses (2)

 $

 330,627

 $

 359,909

 Loss from operations

 $

 ( 6,122

)

 $

 ( 208,019

)

 Net loss (3)

 $

 ( 9,263

)

 $

 ( 52,430

)

 Basic net loss per share (4) (5)

 $

 ( 0.06

)

 $

 ( 0.37

)

 Diluted net loss per share (4) (6)

 $

 ( 0.06

)

 $

 ( 0.37

)

 ________________

 (1)

 Revenue was higher in the three months ended December 31, 2023
 compared to the same period in 2022 primarily due to the $ 50 million milestone payment we earned from AstraZeneca when the FDA approved
 WAINUA for ATTRv-PN in the U.S., $ 36 million payment we earned when AstraZeneca licensed ION826 and revenue we recognized in the fourth
 quarter of 2023 from the upfront payments we received from our new collaborations with Otsuka, Roche and Novartis.

 (2)

 Operating expenses were lower in the three months ended December 31,
 2023 compared to the same period in 2022 primarily due to the $ 80 million upfront payment we made for our collaboration with Metagenomi
 in the fourth quarter of 2022.

 (3)

 Our net loss for the three months ended December 31, 2022 includes
 the $ 150.1 million gain we recognized from the sale and leaseback transaction for our headquarters in Carlsbad, California.

 (4)

 We compute net loss per share independently for each quarter during the year.

 (5)

 As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net loss per share by dividing the total net loss by our weighted-average number of common shares outstanding
 during the period.

 (6)

 We incurred a net loss for the fourth quarter of 2023 and 2022. As a
 result, we did not include dilutive common equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive.