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What changed in IONIS PHARMACEUTICALS INC's 10-K — 2024 vs 2025

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Paragraph-level year-over-year comparison of IONIS PHARMACEUTICALS INC's 2024 and 2025 10-K annual filings, covering the Business, Risk Factors, Legal Proceedings, Cybersecurity, MD&A and Market Risk sections. Every new, removed and edited paragraph is highlighted side-by-side so you can see exactly what management changed in the 2025 report.

+460 added−466 removedSource: 10-K (2026-02-26) vs 10-K (2025-02-19)

Top changes in IONIS PHARMACEUTICALS INC's 2025 10-K

460 paragraphs added · 466 removed · 356 edited across 7 sections

Item 1. Business

Business — how the company describes what it does

196 edited+52 added−72 removed111 unchanged
Biggest changeMarketed Medicines TRYNGOLZA/Olezarsen and WAYLIVRA We believe that the following medicines could compete with TRYNGOLZA/olezarsen and WAYLIVRA in FCS and sHTG: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) ARO-APOC3 (Plozasiran) Arrowhead Targets APOCIII by utilizing Targeted RNAi Molecule Platform Submitted in US for FCS, Phase 3 sHTG Subcutaneous Injection Pegozafermin 89bio FGF21 analog Phase 3 sHTG Subcutaneous Injection NST-1024 NorthSea Therapeutics CETP Inhibitor Phase 2a Oral (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations. 31 Table of Contents WAINUA/Eplontersen and TEGSEDI We consider the following medicines as competitors and potential future competitors to WAINUA/eplontersen and TEGSEDI for ATTRv-PN and/or ATTR-CM: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Onpattro (Patisiran) Alnylam An RNAi medicine formulated with lipid nanoparticles to inhibit TTR mRNA 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 (not approved in the US); ATTR-CM approved in the US, EU and other geographies Oral Amvuttra (Vutrisiran) Alnylam An RNAi medicine conjugated with GalNAc to inhibit TTR mRNA Approved for ATTRv-PN in the US, EU and Japan; Submitted in US, EU for ATTR-CM Subcutaneous Injection Attruby (Acoramidis) BridgeBio Small molecule that binds and stabilizes TTR in the blood Approved in US; Submitted in EU and Japan Oral NTLA-2001 (Nexiguran Ziclumeran (nex-z)) Intellia/ Regeneron CRISPR therapeutic candidate designed to reduce circulating TTR protein levels Phase 3 ATTR-CM, Phase 3 ATTRv-PN Intravenous Infusion ALXN2220 AstraZeneca A monoclonal IgG1 which acts by depleting TTR protein Phase 3 ATTR-CM Intravenous Infusion NNC6019-0001 Novo Nordisk A monoclonal antibody to deplete amyloid Phase 2 ATTR-CM Intravenous Infusion (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
Biggest changeDAWNZERA We believe that the following medicines could compete with DAWNZERA as a prophylactic treatment for patients with HAE: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Takhzyro (lanadelumab-flyo) Takeda A monoclonal antibody that inhibits plasma kallikrein activity Approved for HAE patients two years and older Subcutaneous Injection Cinryze (C1 esterase inhibitor) Takeda A human plasma protein that mediates inflammation and coagulation Approved for HAE patients six years and older Intravenous Infusion Orladeyo (berotralstat) BioCryst Oral plasma kallikrein inhibitor Approved for HAE patients 12 years and older Oral Andembry (Garadacimab) CSL Behring An anti-factor XIIa monoclonal antibody Approved for HAE patients 12 years and older Subcutaneous Injection Haegarda (C1 esterase inhibitor) CSL Behring C1 esterase inhibitor Approved for HAE patients 6 years and older Subcutaneous Injection Deucrictibant Pharvaris An oral B2-receptor antagonist Phase 3 Oral Lonvoguranziclumeran (lonvo-z) (NTLA-2002) Intellia CRISPR therapeutic candidate designed to inactivate the kallikrein B1 gene Phase 3 Intravenous Infusion STAR-0215 (Navenibart) Astria/BioCryst A monoclonal antibody inhibitor of plasma kallikrein Phase3 Subcutaneous Injection ADX-324 ADARx An siRNA designed to reduce the product of PKK Phase 3 Subcutaneous Injection BW-20805 Argo An siRNA designed to reduce the product of PKK Phase 2 Subcutaneous Injection (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations. 33 WAINUA/Eplontersen and TEGSEDI We consider the following medicines as competitors and potential future competitors to WAINUA/eplontersen and TEGSEDI for ATTRv-PN and/or ATTR-CM: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Onpattro (Patisiran) Alnylam An RNAi medicine formulated with lipid nanoparticles to inhibit TTR mRNA Approved in U.S., 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 (not approved in the U.S.); ATTR-CM approved in the U.S., EU and other geographies Oral Amvuttra (Vutrisiran) Alnylam An RNAi medicine conjugated with GalNAc to inhibit TTR mRNA Approved for ATTRv-PN and ATTR-CM in the U.S., EU and Japan Subcutaneous Injection Attruby (Acoramidis) BridgeBio Small molecule that binds and stabilizes TTR in the blood Approved in U.S., EU and Japan for ATTR-CM Oral NTLA-2001 (Nexiguran Ziclumeran (nex-z)) Intellia/ Regeneron CRISPR therapeutic candidate designed to reduce circulating TTR protein levels Phase 3 ATTR-CM, Phase 3 ATTRv-PN Intravenous Infusion Cliramitug (ALXN2220) AstraZeneca A monoclonal IgG1 which acts by depleting TTR protein Phase 3 ATTR-CM Intravenous Infusion Coramitug (NNC6019-0001) Novo Nordisk A monoclonal antibody to deplete amyloid Phase 3 ATTR-CM Intravenous Infusion Nucresiran Alnylam Third generation RNAi TTR therapy Phase 3 ATTR-CM Subcutaneous Injection (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
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.
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 federal false claims statutes.
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 the FCPA or local 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.
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 the FCPA or local anti-bribery laws. Importantly, we do not control the actions of contract manufacturers and other third-party agents, although we may be liable for their actions.
Additionally, Biogen conducted 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 which showed that early and sustained treatment with SPINRAZA helped participants to maintain and/or make progressive gains in motor function with most children achieving motor milestones within age-appropriate timelines and no major motor milestones were lost.
Additionally, Biogen conducted 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 that showed that early and sustained treatment with SPINRAZA helped participants to maintain and/or make progressive gains in motor function with most children achieving motor milestones within age-appropriate timelines and no major motor milestones were lost.
We currently have multiple new programs using our MsPA backbone 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.
We currently have multiple new programs using our MsPA backbone in preclinical development. 12 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.
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.
Violations of fraud and abuse laws may be punishable by criminal, civil and administrative 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.
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 (and in some areas, heightened) restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries.
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. 31 Similar rigid (and in some areas, heightened) restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries.
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.
In foreign jurisdictions, the drug approval process is similarly demanding. 28 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.
WAINUA is also approved in other markets, including the UK and Canada, with additional regulatory reviews underway. We and AstraZeneca are co-commercializing WAINUA in the U.S. and AstraZeneca has exclusive rest of world commercialization rights.
WAINUA is also approved in other markets, including the UK, Canada and China, with additional regulatory reviews underway. We and AstraZeneca are co-commercializing WAINUA in the U.S. and AstraZeneca has exclusive rest of world commercialization rights.
Positive results from a February 2024 data cut from the ongoing OLE cohort showed that HAE attack rates continued to improve over time and extended treatment resulted in further improved quality of life measures and high levels of disease control. In the OASISplus switch cohort, patients followed a pre-defined specific protocol to transition from their prior therapy to donidalorsen.
Positive results from a February 2024 data cut from the ongoing OLE cohort showed that HAE attack rates continued to improve over time and extended treatment resulted in further improved quality of life measures and high levels of disease control. In the OASISplus switch cohort, patients followed a pre-defined specific protocol to transition from their prior therapy to DAWNZERA.
Title Expiration Description of Claims United States 7,399,845 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs United States 7,741,457 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs United States 8,022,193 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides containing cEt nucleoside analogs Europe 1984381 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs Europe 2314594 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides containing cEt nucleoside analogs and methods of use United States 7,569,686 COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS 2027 Methods of synthesizing cEt nucleosides Europe 2092065 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having 2’-modifed and LNA nucleosides Europe 2410053 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides Europe 2410054 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing United States 9,550,988 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides United States 10,493,092 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides Europe 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 United States 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 26 Table of Contents 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.
Title Expiration Description of Claims United States 7,399,845 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs United States 7,741,457 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs United States 8,022,193 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides containing cEt nucleoside analogs Europe 1984381 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 cEt nucleosides and oligonucleotides containing these nucleoside analogs Europe 2314594 6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS 2027 Oligonucleotides containing cEt nucleoside analogs and methods of use United States 7,569,686 COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS 2027 Methods of synthesizing cEt nucleosides Europe 2092065 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having 2’-modifed and LNA nucleosides Europe 2410053 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides Europe 2410054 ANTISENSE COMPOUNDS 2027 Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing United States 9,550,988 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides United States 10,493,092 ANTISENSE COMPOUNDS 2028 Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides Europe 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 United States 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 27 LIgand-Conjugated Antisense (LICA) Technology We also have patent claims to chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve a drug’s properties.
Vect-Horus In December 2023, we entered into a license agreement with Vect-Horus to provide us with a worldwide, exclusive license for a specified number of targets using Vect-Horus’ platform technology “VECTrans” for systemic delivery of RNA-targeted therapeutics that may cross the blood-brain barrier and address targets in the central nervous system.
Vect-Horus In December 2023, we entered into a license agreement with Vect-Horus to provide us with a worldwide, exclusive license for a specified number of targets using Vect-Horus' technology for systemic delivery of RNA-targeted therapeutics that may cross the blood-brain barrier and address targets in the central nervous system.
Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those tested and that 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.
Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those tested and that 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’ pre-approval communications and communications regarding off-label uses.
WAINUA/WAINZUA/Eplontersen and Transthyretin Patents We believe WAINUA/WAINZUA (eplontersen) is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent applications to protect WAINUA/WAINZUA in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting WAINUA/WAINZUA in the U.S. and Europe: Jurisdiction Patent No.
WAINUA/WAINZUA/Eplontersen and Transthyretin Patents We believe WAINUA/WAINZUA (eplontersen) is protected from generic competition in the U.S. and Europe until at least 2034. Patent applications to protect WAINUA/WAINZUA in other jurisdictions are being pursued. The table below lists some key issued patents protecting WAINUA/WAINZUA in the U.S. and Europe: Jurisdiction Patent No.
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.
When 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.
TRYNGOLZA/Olezarsen For TRYNGOLZA’s commercial drug supply, we are using CMOs to produce API and finished goods. For the ongoing olezarsen clinical studies, we and/or our CMOs have supplied the API and the finished drug product. We intend to leverage our relationships with CMOs to meet and maintain long-term commercial supply at competitive prices in the future.
TRYNGOLZA/Olezarsen For TRYNGOLZA’s commercial drug supply, we are using CMOs to produce API and finished goods for ourselves and Sobi. For the ongoing olezarsen clinical studies, we and/or our CMOs have supplied the API and the finished drug product. We intend to leverage our relationships with CMOs to meet and maintain long-term commercial supply at competitive prices in the future.
We and AstraZeneca are co-developing WAINUA globally and co-commercializing WAINUA in the U.S. AstraZeneca has exclusive rights to commercialize WAINUA outside of the U.S. • SPINRAZA is a global market leader for the treatment of pediatric and adult patients with spinal muscular atrophy, or SMA.
We and AstraZeneca are co-developing WAINUA globally and co-commercializing WAINUA in the U.S. AstraZeneca has exclusive rights to commercialize WAINUA outside of the U.S. ● SPINRAZA is a global market leader for the treatment of patients with spinal muscular atrophy, or SMA.
Pursuant to our collaboration with AstraZeneca, we will supply WAINUA using CMOs for the ongoing clinical trials. SPINRAZA Biogen is responsible for SPINRAZA drug supply. QALSODY Biogen is responsible for QALSODY drug supply. TEGSEDI and WAYLIVRA For TEGSEDI’s commercial drug supply, we are using CMOs to produce API and finished goods for ourselves, Sobi and PTC.
Pursuant to our collaboration with AstraZeneca, we will supply WAINUA using CMOs for the ongoing clinical trials. 18 SPINRAZA Biogen is responsible for SPINRAZA drug supply. QALSODY Biogen is responsible for QALSODY drug supply. TEGSEDI and WAYLIVRA For TEGSEDI’s commercial drug supply, we are using CMOs to produce API and finished goods for Sobi and PTC.
Title Expiration Description of Claims United States 11,261,446 COMPOUNDS AND METHODS FOR MODULATING UBE3A-ATS 2040 Composition of ION582 United States 9,617,539 MODULATION OF UBE3A-ATS EXPRESSION 2033 Methods of treating Angelman syndrome with an antisense compound targeting a region of UBE3A-ATS Europe 3770258 MODULATION OF UBE3A-ATS EXPRESSION 2033 Oligonucleotides complementary to a region of UBE3A-ATS for use in treating Angelman syndrome Late-Stage Partnered Programs Bepirovirsen and Hepatitis B Virus We believe bepirovirsen is protected from generic competition in the U.S. and Europe until at least 2032.
Title Expiration Description of Claims United States 11,261,446 COMPOUNDS AND METHODS FOR MODULATING UBE3A-ATS 2040 Composition of obudanersen Europe 3947684 COMPOUNDS AND METHODS FOR MODULATING UBE3A-ATS 2040 Composition of obudanersen United States 9,617,539 MODULATION OF UBE3A-ATS EXPRESSION 2033 Methods of treating Angelman syndrome with an antisense compound targeting a region of UBE3A-ATS Europe 3770258 MODULATION OF UBE3A-ATS EXPRESSION 2033 Oligonucleotides complementary to a region of UBE3A-ATS for use in treating Angelman syndrome 24 Late-Stage Partnered Programs Bepirovirsen and Hepatitis B Virus We believe bepirovirsen is protected from generic competition in the U.S. and Europe until at least 2032.
Our key recent achievements, combined with our independent and partnered product launches anticipated over the next three years, position us well to help millions of patients with serious diseases and deliver increasing product and royalty revenue.
Our key recent achievements, combined with our independent and partnered product launches anticipated over the next two years, position us well to help millions of patients with serious diseases and deliver increasing product and royalty revenue.
In 2024, we presented positive results from the completed multiple ascending dose, or MAD, portion of the study in people with AS demonstrating consistent and encouraging clinical improvement on measures assessing all functional domains including communication, cognition and motor function. ION582 showed favorable safety and tolerability at all dose levels in the study.
In 2024, we presented positive results from the completed multiple ascending dose, or MAD, portion of the HALOS study in people with AS demonstrating consistent and encouraging clinical improvement on measures assessing all functional domains including communication, cognition and motor function. Obudanersen showed favorable safety and tolerability at all dose levels in the study.
In April 2021, we initiated a Phase 3 study of ulefnersen in patients with FUS-ALS designed to assess the efficacy, safety and tolerability of ulefnersen. The FDA and EMA granted Orphan Drug designation to ulefnersen.
In April 2021, we initiated the Phase 3 FUSION study of ulefnersen in patients with FUS-ALS designed to assess the efficacy, safety and tolerability of ulefnersen. The FDA and EMA granted Orphan Drug designation to ulefnersen.
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. 12 Table of Contents Gene editing is highly complementary and synergistic with RNA-targeted therapeutics.
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.
Title Expiration Description of Claims United States 8,642,752 MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION 2032 Composition of bepirovirsen Europe 3505528 MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION 2032 Composition of bepirovirsen 24 Table of Contents Pelacarsen and Apo(a) We believe pelacarsen is protected from generic competition in the U.S. and Europe until at least 2034.
Title Expiration Description of Claims United States 8,642,752 MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION 2032 Composition of bepirovirsen Europe 3505528 MODULATION OF HEPATITIS B VIRUS (HBV) EXPRESSION 2032 Composition of bepirovirsen Pelacarsen and Apo(a) We believe pelacarsen is protected from generic competition in the U.S. and Europe until at least 2034.
ION582 (UBE3A) (BIIB121) – ION582 is an investigational RNA-targeted medicine we designed to inhibit the expression of the UBE3A antisense transcript, or UBE3A-ATS, and increase production of UBE3A protein, for the potential treatment of AS. AS is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene.
Obudanersen (UBE3A) – Obudanersen (formerly ION582) is an investigational RNA-targeted medicine we designed to inhibit the expression of the UBE3A antisense transcript, or UBE3A-ATS, and increase production of UBE3A protein, for the potential treatment of AS. AS is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene.
We will share progress on our CR goals and more details on our initiatives in our 2024 CR Report, which we expect to publish in April 2025 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.
We continue to share progress on our CR goals and more details on our initiatives in our 2025 CR Report, which we expect to publish in April 2026 and will be 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.
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.
Other Healthcare Laws 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 FDA also granted Fast Track designation to eplontersen for ATTR-CM. 9 Table of Contents Pelacarsen (Apo(a)) (TQJ230) – Pelacarsen is an investigational RNA-targeted medicine we designed to inhibit the production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD.
The FDA also granted Fast Track designation to eplontersen for ATTR-CM. 10 Pelacarsen (Apo(a)) (TQJ230) – Pelacarsen is an investigational RNA-targeted medicine we designed to inhibit the production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD.
SPINRAZA We consider the following medicines as competitors to SPINRAZA for the indication of SMA: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Zolgensma (Onasemnogene abeparvovec) Novartis 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) Novartis 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. 32 Table of Contents QALSODY We believe that the following medicine could compete with QALSODY in SOD1-ALS: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) NI-005 / AP-101 Neurimmune (AL-S Pharma) / Lilly A human derived antibody targeting misfolded SOD1 Phase 2 Intravenous Infusion (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
SPINRAZA We consider the following medicines as competitors to SPINRAZA for the indication of SMA: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Zolgensma (Onasemnogene abeparvovec) Novartis 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 Itvisma (Onasemnogene abeparvovec) Novartis Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene Approved for SMA in pediatric and adult patients Intrathecal Injection (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations. 34 QALSODY We believe that the following medicine could compete with QALSODY in SOD1-ALS: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) AP-101 Neurimmune (AL-S Pharma) / Lilly A human derived antibody targeting misfolded SOD1 Phase 2 Intravenous Infusion (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
Title Expiration Description of Claims United States 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 United States 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 United States 9,884,072 METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION 2033 Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen Europe 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 United States 9,181,550 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION 2034 Composition of p elacarsen Europe 2992009 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION 2034 Composition of pelacarsen Sefaxersen and Factor B We believe sefaxersen is protected from generic competition in the U.S. and Europe until at least 2035.
Title Expiration Description of Claims United States 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 pelacarsen United States 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 pelacarsen United States 9,884,072 METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION 2033 Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen Europe 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 United States 9,181,550 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION 2034 Composition of pelacarsen United States 12,291,709 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION 2034 Methods of administering pelacarsen Europe 2992009 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION 2034 Composition of pelacarsen 25 Sefaxersen and Factor B We believe sefaxersen is protected from generic competition in the U.S. and Europe until at least 2035.
Title Expiration Description of Claims United States 9,163,239 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of olezarsen United States 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 United States 9,157,082 MODULATION OF APOLIPOPROTEIN CIII (APOCIII) EXPRESSION 2032 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL Europe 2991656 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of olezarsen Europe 2956176 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 Europe 3357497 MODULATION OF APOLIPOPROTEIN CIII (APOCIII) EXPRESSION 2032 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL Europe 4119569 CONJUGATED ANTISENSE COMPOUNDS FOR USE IN THERAPY 2036 Methods of administering olezarsen at identified doses Trademark The name “TRYNGOLZA” is protected by trademarks throughout the world.
Title Expiration Description of Claims United States 9,163,239 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of TRYNGOLZA United States 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 United States 9,157,082 MODULATION OF APOLIPOPROTEIN CIII (APOCIII) EXPRESSION 2032 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL United States 12,509,684 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Methods of treating FCS or hypertriglyceridemia by administering TRYNGOLZA Europe 2991656 COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION 2034 Composition of TRYNGOLZA Europe 2956176 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 Europe 3357497 MODULATION OF APOLIPOPROTEIN CIII (APOCIII) EXPRESSION 2032 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL Europe 4119569 CONJUGATED ANTISENSE COMPOUNDS FOR USE IN THERAPY 2036 Methods of administering TRYNGOLZA at identified doses 20 Trademark The name “TRYNGOLZA” is protected by trademarks throughout the world.
The table below lists some key issued patents protecting olezarsen in the U.S. and Europe. Jurisdiction Patent No.
The table below lists some key issued patents protecting TRYNGOLZA in the U.S. and Europe. Jurisdiction Patent No.
Nothing on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K. 36 Table of Contents Benefits We reward our employees individually on the basis of their responsibilities and accomplishments. We offer competitive compensation and benefits to our employees.
Nothing on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K. 38 Benefits We reward our employees individually on the basis of their responsibilities and accomplishments. We offer competitive compensation and benefits to our employees.
TRYNGOLZA was approved by the FDA in December 2024 and is the first-ever FDA-approved treatment that significantly and substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in AP events when used with an appropriate diet (≤20 grams of fat per day). TRYNGOLZA is currently under regulatory review in the EU.
TRYNGOLZA was approved by the FDA in December 2024 and is the first-ever FDA-approved treatment that significantly and substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in AP events when used with an appropriate diet (≤20 grams of fat per day).
From inception through December 31, 2024, we have generated more than $65 million in payments under this collaboration. Roche Sefaxersen for Complement-Mediated Diseases In 2018, we entered into an agreement with Roche to develop sefaxersen for the treatment of complement-mediated diseases, including IgAN, and geographic atrophy, or GA.
From inception through December 31, 2025, we have generated more than $285 million in payments under this collaboration. 15 Roche Sefaxersen for Complement-Mediated Diseases In 2018, we entered into an agreement with Roche to develop sefaxersen for the treatment of complement-mediated diseases, including IgAN, and geographic atrophy, or GA.
Over the term of the collaboration, we are eligible to receive a license fee, development milestone payments, regulatory milestone payments and sales milestone payments. We are also eligible to receive tiered royalties from the high teens to 20 percent on net sales. From inception through December 31, 2024, we have generated more than $140 million in payments under this collaboration.
Over the term of the collaboration, we are eligible to receive a license fee, development milestone payments, regulatory milestone payments and sales milestone payments. We are also eligible to receive tiered royalties from the high teens to 20 percent on net sales. From inception through December 31, 2025, we have generated approximately $140 million in payments under this collaboration.
In 2024, we reported progress on our CR goals aligned to the three strategic CR pillars that we believe are most important to our business: 35 Table of Contents 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.
In 2025, we reported progress on our CR goals aligned to the three strategic CR pillars that we believe are most important to our business: 37 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.
Our average employee turnover rate in 2023 was 6 percent, while the turnover for life sciences and medical device companies over this period was 21 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.
Our average employee turnover rate in 2025 was 7 percent, while the turnover for life sciences and medical device companies over this period was 20 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.
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 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.
QALSODY received accelerated approval from the FDA and marketing authorization under exceptional circumstances from the European Medicines Agency, or EMA. QALSODY was the first treatment approved to target a genetic cause of ALS. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. • TEGSEDI is approved in the EU, Canada and Brazil for the treatment of ATTRv-PN in adults.
Food and Drug Administration, or FDA, and marketing authorization under exceptional circumstances from the European Medicines Agency, or EMA. QALSODY was the first treatment approved to target a genetic cause of ALS. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. ● TEGSEDI is approved in the EU, Canada and Brazil for the treatment of ATTRv-PN in adults.
The QALSODY regulatory submissions 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 open-label extension, or OLE, study.
The QALSODY regulatory submissions 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 OASISplus study includes an OLE cohort and a prospective cohort to assess patients switching from currently available long-term prophylactic treatments to donidalorsen.
The OASISplus study includes an OLE cohort and a prospective switch cohort to assess patients switching from currently available long-term prophylactic treatments to DAWNZERA.
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 endpoints of serum TTR concentration and Neuropathy Impairment Score +7, or mNIS+7.
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 endpoints of serum TTR concentration and Neuropathy Impairment Score +7, or mNIS+7. Additionally, WAINUA demonstrated a favorable safety and tolerability profile in the NEURO-TTRansform study.
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. In addition, we will pay Bicycle milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events.
Our payment to Bicycle for licensing its technology included an equity investment in Bicycle. In addition, we will pay Bicycle milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events.
In addition, we established our TRYNGOLZA field sales team during 2024 and plan to build additional field teams as we approach each of our launches. 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.
In addition, we established our TRYNGOLZA, DAWNZERA and olezarsen (sHTG) field sales team and plan to build additional field teams as we approach each of our launches. 19 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 partner, Biogen, is responsible for commercializing SPINRAZA worldwide. • QALSODY is approved in the U.S., European Union, or EU, China and Japan for the treatment of Amyotrophic Lateral Sclerosis, or ALS, in adults who have a mutation in the superoxide dismutase 1, or SOD1, gene, or SOD1-ALS.
Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide. ● QALSODY is approved in the U.S., EU, China and Japan for the treatment of amyotrophic lateral sclerosis, or ALS, in adults who have a mutation in the superoxide dismutase 1 , or SOD1 , gene, or SOD1-ALS. QALSODY received accelerated approval from the U.S.
Our Innovative Mid-Stage Pipeline of Investigational Medicines We also have a rich mid-stage pipeline with numerous potentially transformational investigational medicines, including both Ionis-owned and partnered therapies. The table below lists our medicines in mid-stage development. For further information on our collaboration agreements, refer to the section titled, Collaborative Arrangements .
The FDA also granted Fast Track designation to ulefnersen. 11 Our Innovative Mid-Stage Pipeline of Investigational Medicines We also have a rich mid-stage pipeline with numerous potentially transformational investigational medicines, including both Ionis-owned and partnered therapies. The table below lists our medicines in mid-stage development. For further information on our collaboration agreements, refer to the section titled, Collaborative Arrangements .
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.
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 yields and process efficiencies, while at the same time increasing our capacity to make our medicines.
Employees and Human Capital As of February 13, 2025, we employed 1,069 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.
Employees and Human Capital As of February 19, 2026, we employed 1,402 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.
Title Expiration Description of Claims United States 8,101,743 MODULATION OF TRANSTHYRETIN EXPRESSION 2025 Antisense sequence and chemistry of TEGSEDI United States 8,697,860 DIAGNOSIS AND TREATMENT OF DISEASE 2031 Composition of TEGSEDI United States 9,061,044 MODULATION OF TRANSTHYRETIN EXPRESSION 2031 Sodium salt composition of TEGSEDI United States 9,399,774 MODULATION OF TRANSTHYRETIN EXPRESSION 2031 Methods of treating transthyretin amyloidosis by administering TEGSEDI Europe 2563920 MODULATION OF TRANSTHYRETIN EXPRESSION 2031 Composition of TEGSEDI Trademarks The name “TEGSEDI” is protected by trademark throughout the world. 22 Table of Contents WAYLIVRA and ApoC-III Patents We believe WAYLIVRA (volanesorsen) is protected from generic competition in Europe until at least 2034.
Title Expiration Description of Claims United States 8,697,860 DIAGNOSIS AND TREATMENT OF DISEASE 2031 Composition of TEGSEDI United States 9,061,044 MODULATION OF TRANSTHYRETIN EXPRESSION 2031 Sodium salt composition of TEGSEDI United States 9,399,774 MODULATION OF TRANSTHYRETIN EXPRESSION 2031 Methods of treating transthyretin amyloidosis by administering TEGSEDI Europe 2563920 MODULATION OF TRANSTHYRETIN EXPRESSION 2031 Composition of TEGSEDI Trademarks The name “TEGSEDI” is protected by trademark throughout the world. 23 WAYLIVRA and ApoC-III Patents We believe WAYLIVRA (volanesorsen) is protected from generic competition in Europe until at least 2034.
Sefaxersen (IONIS-FB-L Rx ) We supplied API for the sefaxersen Phase 1 and Phase 2 IgAN programs. Pursuant to our collaboration with Roche, Roche is responsible for any further drug supply for sefaxersen.
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. Sefaxersen (IONIS-FB-L Rx ) We supplied API for the sefaxersen Phase 1 and Phase 2 IgAN programs.
(Patent Application No.) Title Expiration Description of Claims United States 11,786,546 COMPOUNDS AND METHODS FOR MODULATING GFAP 2041 Composition of zilganersen Europe (20846055.0) COMPOUNDS AND METHODS FOR MODULATING GFAP 2041 Composition of zilganersen ION582 and UBE3A We believe ION582 is protected from generic competition in the U.S. until at least 2040.
Title Expiration Description of Claims United States 11,786,546 COMPOUNDS AND METHODS FOR MODULATING GFAP 2041 Composition of zilganersen Europe 3956450 COMPOUNDS AND METHODS FOR MODULATING GFAP 2040 Composition of zilganersen Obudanersen and UBE3A We believe obudanersen is protected from generic competition in the U.S. and Europe until at least 2040.
Additionally, QALSODY was recently approved in China and Japan. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. SOD1- ALS is a rare, fatal, neurodegenerative disorder caused by a mutation in the SOD1 gene leading to a progressive loss of motor neurons.
In May 2024, QALSODY was also approved in the EU under exceptional circumstances. Additionally, QALSODY was approved in China and Japan. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. SOD1- ALS is a rare, fatal, neurodegenerative disorder caused by a mutation in the SOD1 gene leading to a progressive loss of motor neurons.
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. We are also eligible to receive royalties and additional milestones under our partnerships.
Our partners include the following companies, among others: AstraZeneca, Biogen, GSK, Novartis, Ono, Otsuka and Roche. Through our partnerships, we have earned both commercial revenue in the form of royalties and sales milestones and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone payments.
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.
For example, the 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.
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.
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.
From inception through December 31, 2024, we recognized more than $110 million in total revenue under this collaboration, including approximately $4 million in revenue from QALSODY royalties and $108 million in R&D revenue.
From inception through December 31, 2025, we recognized more than $120 million in total revenue under this collaboration, including approximately $14 million in revenue from QALSODY royalties and $108 million in R&D revenue.
Commercial products are also protected by trademarks filed throughout the world. 19 Table of Contents Marketed Products TRYNGOLZA/Olezarsen and ApoC-III We believe TRYNGOLZA (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.
Commercial products are also protected by trademarks filed throughout the world. Marketed Products TRYNGOLZA/Olezarsen and ApoC-III We believe TRYNGOLZA (olezarsen) is protected from generic competition in the U.S. and Europe until at least 2034. Patent applications to protect TRYNGOLZA in other jurisdictions have been granted or are being pursued.
The FDA and EMA granted Orphan Drug designation to ION582. Additionally, the FDA granted Fast Track and Rare Pediatric designations to ION582. Our Innovative Late-Stage Pipeline of Partnered Investigational Medicines In addition to our Ionis-owned investigational medicines, we also have numerous potentially transformational partnered medicines in clinical development. The table below lists our partnered medicines in late-stage development.
Additionally, the FDA granted Breakthrough Therapy, Fast Track and Rare Pediatric designations to obudanersen. 9 Our Innovative Late-Stage Pipeline of Partnered Investigational Medicines In addition to our Ionis-owned investigational medicines, we also have numerous potentially transformational partnered medicines in clinical development. The table below lists our partnered medicines in late-stage development.
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.
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.
People living with FCS can also experience psychological and financial stress, which can significantly impact their quality of life. FCS is estimated to impact up to approximately 3,000 people in the U.S., the vast majority of whom remain undiagnosed. We are also developing olezarsen to treat severe hypertriglyceridemia, or sHTG.
People living with FCS can also experience psychological and financial stress, which can significantly impact their quality of life. FCS is estimated to impact up to approximately 3,000 people in the U.S., the vast majority of whom remain undiagnosed.
Title Expiration Description of Claims United States 17/613,183 COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION 2040 Composition of ulefnersen Europe 20815459.1 COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION 2040 Composition of ulefnersen 25 Table of Contents 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.
Title Expiration Description of Claims United States 17/613,183 COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION 2040 Composition of ulefnersen Europe 3976791 COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION 2040 Composition of ulefnersen Platform IP In addition to the IP that provides exclusivity for specific products, we also pursue IP that provides exclusivity for our core technology more generally.
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.
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. Moreover, healthcare reform legislation has strengthened certain of these laws.
A Culture of Inclusion At Ionis, 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 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.
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, 2024, we have generated more than $150 million in payments under this collaboration.
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, 2025, we have generated more than $150 million in payments under this collaboration.
Additional patent protection designed to protect sefaxersen in other foreign jurisdictions is being pursued. The table below lists some key issued patents protecting sefaxersen in the U.S. and Europe: Jurisdiction Patent No.
Patent applications to protect sefaxersen in other jurisdictions are being pursued. The table below lists some key issued patents protecting sefaxersen in the U.S. and Europe: Jurisdiction Patent No.
Pelacarsen We believe that the following medicines could compete with pelacarsen in CVD in patients with elevated LP(a): Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Olpasiran Amgen/ Arrowhead RNAi therapeutic designed to lower Lp(a) Phase 3 Subcutaneous Injection Lepodisiran Lilly RNAi therapeutic designed to lower Lp(a) Phase 3 Subcutaneous Injection Zerlasiran Silence RNAi therapeutic designed to lower Lp(a) Phase 2 Subcutaneous Injection Muvalaplin Lilly Small molecule therapy to lower Lp(a) Phase 2 Oral (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations. 34 Table of Contents Sefaxersen We believe that the following medicines could compete with sefaxersen in IgAN: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Tarpeyo (budesonide) Asahi Kasei (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 Fabhalta (Iptacopan) Novartis (Chinook) A factor B inhibitor of the alternative complement pathway Approved for IgAN Oral Atrasentan Novartis (Chinook) An endothelin A receptor antagonist Phase 3 (IgAN); Submitted in US for accelerated approval Oral Zigakibart Novartis (Chinook) An anti-APRIL monoclonal antibody Phase 3 (IgAN) Subcutaneous Injection Sibeprenlimab Otsuka (Visterra) A humanized IgG2 monoclonal antibody that inhibits APRIL Phase 3 (IgAN) Intravenous Infusion Atacicept Vera A recombinant fusion protein a dual inhibitor of BLyS and APRIL Phase 3 (IgAN) Subcutaneous Injection Ravulizumab Alexion (AstraZeneca) A humanized monoclonal antibody to complement factor 5 Phase 3 (IgAN) Subcutaneous Injection Povetacicept Alpine Immune Sciences A dual BAFF and APRIL inhibitor Phase 3 (IgAN) Intravenous Infusion / Subcutaneous Injection Telitacicept RemeGen A dual BAFF and APRIL inhibitor Phase 3 (IgAN) Subcutaneous Injection Vemircopan Alexion (AstraZeneca) A complement factor D inhibitor Phase 2 (IgAN) Oral Felzartamab Hi-Bio A monoclonal antibody directed against CD38 Phase 2 (IgAN) Intravenous Infusion (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
Pelacarsen We believe that the following medicines could compete with pelacarsen in CVD in patients with elevated Lp(a): Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Olpasiran Amgen/ Arrowhead RNAi therapeutic designed to lower Lp(a) Phase 3 Subcutaneous Injection Lepodisiran Eli Lilly RNAi therapeutic designed to lower Lp(a) Phase 3 Subcutaneous Injection Muvalaplin Eli Lilly Small molecule therapy to lower Lp(a) Phase 3 Oral DII235 Argo Biopharmaceutical RNAi therapeutic designed to lower Lp(a) Phase 3 ready Subcutaneous Injection Zerlasiran Silence RNAi therapeutic designed to lower Lp(a) Phase 2 Subcutaneous Injection Obicetrapib NewAmsterdam Pharma CETP inhibitor Phase 2 Oral (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations. 36 Sefaxersen We believe that the following medicines could compete with sefaxersen in IgAN: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Tarpeyo (budesonide) Asahi Kasei (Calliditas) A corticosteroid indicated to reduce proteinuria in adults with primary IgAN Approved to slow kidney-function decline in adults with IgAN Oral Filspari (Sparsentan) Travere An endothelin & angiotensin II receptor antagonist to reduce proteinuria in adults with primary IgAN Approved to slow kidney-function decline in adults with IgAN Oral Fabhalta (Iptacopan) Novartis (Chinook) A factor B inhibitor of the alternative complement pathway Approved to reduce proteinuria in adults with IgAN Oral Vanrafia (Atrasentan) Novartis (Chinook) An endothelin A receptor antagonist Approved to reduce proteinuria in adults with IgAN Oral Voyxact (Sibeprenlimab) Otsuka (Visterra) A humanized IgG2 monoclonal antibody that inhibits APRIL Approved to reduce proteinuria in adults with IgAN Subcutaneous Injection Zigakibart Novartis (Chinook) An anti-APRIL monoclonal antibody Phase 3 (IgAN) Subcutaneous Injection Atacicept Vera A recombinant fusion protein a dual inhibitor of BLyS and APRIL Phase 3 (IgAN) Subcutaneous Injection Ravulizumab Alexion (AstraZeneca) A humanized monoclonal antibody to complement factor 5 Phase 3 (IgAN) Subcutaneous Injection Povetacicept Vertex (Alpine) A dual BAFF and APRIL inhibitor Phase 3 (IgAN) Intravenous Infusion / Subcutaneous Injection Telitacicept RemeGen A dual BAFF and APRIL inhibitor Phase 3 (IgAN) Subcutaneous Injection Felzartamab Biogen (Hi-Bio) A monoclonal antibody directed against CD38 Phase 3 (IgAN) Intravenous Infusion Mezagitamab Takeda anti-CD38 IgG1 monoclonal antibody Phase 3 Subcutaneous Injection WAL0921 Walden Biosciences uPAR antagonist monoclonal antibody Phase 2 Intravenous Infusion (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
TRYNGOLZA is the first medicine we are commercializing independently in the U.S. • WAINUA is approved in numerous countries, including the U.S. and United Kingdom, or UK, for the treatment of the polyneuropathy of hereditary transthyretin-medicated amyloidosis, or ATTRv-PN, in adults. WAINUA is the only approved medicine for the treatment of ATTRv-PN that can be self-administered via an auto-injector.
We are also independently commercializing DAWNZERA in the U.S. ● WAINUA is approved in the U.S., EU, China and numerous other countries for the treatment of the polyneuropathy of hereditary transthyretin-medicated amyloidosis, or ATTRv-PN, in adults. WAINUA is the only approved medicine for the treatment of ATTRv-PN that can be self-administered via an auto-injector.
QALSODY was granted accelerated approval in April 2023 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). In May 2024, QALSODY was also approved in the EU under exceptional circumstances.
QALSODY inhibits the production of SOD1 protein. QALSODY was granted accelerated approval in April 2023 based on reduction in plasma neurofilament light chain protein, 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).
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 program that utilizes Bicycle technology into preclinical development in 2023.
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).
WAINUA causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. WAINUA was approved in the U.S. in December 2023 and was recommended for approval by the CHMP in the EU in October 2024.
WAINUA causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. WAINUA was approved in the U.S. in December 2023 and in the EU in March 2025.
Department of Health and Human Services, or HHS, to negotiate, through a negotiation program, the price of certain single-source drugs and biologics that have been on the market for at least seven years covered under Medicare, or the Medicare Drug Price Negotiation Program, and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
The IRA, among other things, (1) directed HHS to negotiate, through a negotiation program, the price of certain single-source drugs and biologics that have been on the market for at least seven years covered under Medicare, or the Medicare Drug Price Negotiation Program, and (2) imposed rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
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. The IRA, among other things, (1) directs the U.S.
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, or CMS.
Also known as Berger’s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage. Our partner, Roche, is responsible for ongoing development and commercialization of sefaxersen worldwide.
Also known as Berger’s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage. Our partner, Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd, collectively Roche , is responsible for ongoing development and commercializ ation of sefaxersen worldwide.
Additional patent protection designed to protect bepirovirsen in other foreign jurisdictions is 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: Jurisdiction Patent No.
Patent applications to protect bepirovirsen in other jurisdictions have been granted for 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: Jurisdiction Patent No.
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.
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. 39
Additionally, WAINUA demonstrated a favorable safety and tolerability profile in the NEURO-TTRansform study. 5 Table of Contents The FDA granted Orphan Drug designation to WAINUA for the treatment of ATTR. SPINRAZA (SMN) – 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.
The FDA granted Orphan Drug designation to WAINUA for the treatment of ATTR. SPINRAZA (SMN) – 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.
Results showed that patients were able to switch to donidalorsen from prior prophylactic treatment without an increase in breakthrough attacks. Donidalorsen treatment also led to a further improvement in mean monthly HAE attack rates and continued improvements in measures of quality of life. A majority of patients surveyed reported a preference for donidalorsen over their previous treatment.
Results showed that patients were able to switch to DAWNZERA from prior prophylactic treatment without an increase in breakthrough attacks. Switching to DAWNZERA also reduced mean HAE attack rate and led to continued improvement in quality-of-life measures compared to baseline with prior prophylactic treatment. The majority of patients surveyed reported a preference for DAWNZERA over their previous treatment.
Sefaxersen treatment also resulted in sustained reductions in proteinuria with patients maintaining kidney function, as measured by estimated glomerular filtration rate, or eGFR, during six months of treatment.
Sefaxersen treatment also resulted in sustained reductions in proteinuria with patients maintaining kidney function, as measured by estimated glomerular filtration rate, or eGFR, during six months of treatment. Sefaxersen demonstrated a favorable safety and tolerability profile in the study.
Through both our internal research and development programs and collaborations with outside vendors, we may achieve even greater efficiency and further cost reductions. 17 Table of Contents Our manufacturing facility is located in a 26,800 square foot building in Carlsbad, California. We purchased this building in 2017.
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.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeThe 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. 45 Table of Contents 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.
Biggest changeThe 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 satisfactorily demonstrate 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.
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 the results of such post-marketing studies are not satisfactory, the FDA, EC or other foreign regulatory authorities may withdraw the marketing authorization or may condition continued marketing on commitments from us or our partners that may be expensive and time consuming to fulfill.
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 building and maintaining new support functions and scaling up existing internal support functions and expanding our manufacturing capabilities. All of these activities will require significant cash.
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 building and maintaining new support functions, scaling up existing internal support functions and expanding our manufacturing capabilities. All of these activities will require significant cash.
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 disclosing clinical data, 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.
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 disclosing clinical data, when we anticipate completing a clinical study, when we anticipate filing an application for, or obtaining, marketing authorization, or when we or our partners plan to commercially launch a medicine.
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 or a substantially similar medicine in a safer or more effective form or that makes a major contribution to patient care.
Even if approval is obtained for 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 or a substantially similar medicine in a safer or more effective form or that makes a major contribution to patient care.
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 or our partners may not be able to manufacture our medicines at a cost or in quantities necessary to make commercially successful products. 44 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.
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. Risks related to compliance with laws Our operations are subject to extensive legal and regulatory requirements affecting the health care industry.
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. 55 Risks related to compliance with laws Our operations are subject to extensive legal and regulatory requirements affecting the health care industry.
The personal information we process subjects us to stringent and evolving U.S. and foreign laws, rules and regulations, contractual obligations, industry standards and other obligations related to data privacy and security. Our personal information obligations require us to implement and maintain certain practices, including those in relation to cross-border transfers of personal information.
The personal information we process subjects us to stringent and evolving U.S. and foreign laws, rules and regulations, contractual obligations, industry standards and other obligations related to data privacy and security. Our obligations (including in relation to personal information) require us to maintain certain practices, including those in relation to cross-border transfers of data.
We rely on third-party manufacturers to supply the drug substance and drug product for TRYNGOLZA and WAINUA and drug product for WAYLIVRA. The operations of our suppliers, many of which are located outside of the United States, are subject to additional risks that are beyond our control.
We rely on third-party manufacturers to supply the drug substance and drug product for TRYNGOLZA, DAWNZERA and WAINUA and drug product for WAYLIVRA. The operations of our suppliers, many of which are located outside of the United States, are subject to additional risks that are beyond our control.
A security breach or privacy violation (including perceived breaches or violations) could result in any of the following, any of which could disrupt our business and result in increased costs or loss of revenue: ● harm our reputation; ● delay progress on the development of our medicines; ● compel us to comply with applicable security or data breach notification obligations (including laws); ● result in the diversion of monetary funds and other company resources; ● subject us to financial or other penalties, regulatory investigations or actions, including mandatory and costly corrective actions; and ● require us to verify the correctness of database contents and otherwise subject us to litigation or other liabilities.
A security breach or a violation of obligations related to privacy or cybersecurity (including perceived breaches or violations) could result in any of the following, any of which could disrupt our business and result in increased costs or loss of revenue: ● harm our reputation; ● delay progress on the development of our medicines; ● compel us to comply with applicable security or data breach notification obligations (including laws); ● result in the diversion of monetary funds and other company resources; ● subject us to financial or other penalties, regulatory investigations or actions, including mandatory and costly corrective actions, and otherwise subject us to litigation or other liabilities; and ● require us to verify the correctness of database contents.
In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% 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.
In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes due 2026, 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.
We manufacture the finished drug product for TRYNGOLZA, WAYLIVRA and eplontersen for ongoing clinical trials at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA and QALSODY and AstraZeneca is responsible for WAINUA’s commercial drug supply.
We manufacture the finished drug product for TRYNGOLZA, DAWNZERA, WAYLIVRA and eplontersen for ongoing clinical trials at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA and QALSODY and AstraZeneca is responsible for WAINUA’s commercial drug supply.
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. 49 Table of Contents 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.
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. 49 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.
However, it is possible the authority for FDA to award rare pediatric disease PRV will be further extended by Congress. 48 Table of Contents 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.
However, it is possible the authority for the FDA to award rare pediatric disease PRV will be further extended by Congress. 48 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.
Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material. 50 Table of Contents 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.
Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material. 50 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.
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.
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 such medicine or will require additional studies, which could be time consuming and expensive and delay or harm commercialization of the medicine.
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. The addition of any of these shares into the public market may have an adverse effect on the price of our securities.
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 due 2026. The addition of any of these shares into the public market may have an adverse effect on the price of our securities.
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 offset any cash payments we are required to make in excess of the principal amount of the converted 0% Notes, as the case may be.
The call spread transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes due 2026 or offset any cash payments we are required to make in excess of the principal amount of the converted 0% Notes due 2026, as the case may be.
Data privacy or security incidents or breaches 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. Cyber-attacks are increasing in their frequency, sophistication and intensity, particularly as companies (including us) continue to move to more remote work structures.
Data privacy or security incidents or breaches 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. Cyber-attacks are increasing in their frequency, sophistication and intensity, particularly as companies (including us) continue to leverage remote work structures.
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, acts of terrorism, political instability or public health issues or health epidemics, 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; ● the potential for a local seller, faced with higher local prices, importing medicines from an international market with lower prices rather than buying such medicines locally, which is referred to as parallel importation; ● 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.
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; ● U.S. restrictions on the use of certain foreign biotech equipment and service providers, such as those set forth in the BIOSECURE Act; ● 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, acts of terrorism, political instability or public health issues or health epidemics, 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; ● the potential for a local seller, faced with higher local prices, importing medicines from an international market with lower prices rather than buying such medicines locally, which is referred to as parallel importation; ● 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.
Since corporate partnering is 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.
Since corporate partnering is part of our strategy to fund the advancement and commercialization of some 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 those drug development programs.
As of December 31, 2024, we had an accumulated deficit of approximately $2.2 billion and stockholders’ equity of approximately $0.6 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.
As of December 31, 2025, we had an accumulated deficit of approximately $2.6 billion and stockholders’ equity of approximately $0.5 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.
The FDA has granted Orphan Drug designation to TRYNGOLZA for the treatment of patients with FCS, to WAINUA for the treatment of patients with ATTR, to ulefnersen for the treatment of patients with FUS-ALS, to ION582 for the treatment of patients with Angelman syndrome, and to some of our earlier stage medicines.
The FDA has granted Orphan Drug designation to TRYNGOLZA for the treatment of patients with FCS, to WAINUA for the treatment of patients with ATTR, to ulefnersen for the treatment of patients with FUS-ALS, to obudanersen for the treatment of patients with Angelman syndrome, and to some of our earlier stage medicines.
In addition, violations may also result in reputational harm, diminished profits and future earnings. 55 Table of Contents 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.
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.
In 2021, we completed a $632.5 million offering of 0% Notes and used $319.0 million of the net proceeds from the issuance of the 0% Notes to repurchase the remaining $309.9 million of our 1% Notes.
In 2021, we completed a $632.5 million offering of 0% Notes due 2026 and used $319.0 million of the net proceeds from the issuance of the 0% Notes due 2026 to repurchase the remaining $309.9 million of our 1% Notes due 2021.
Broad market factors may materially harm the market price of our common stock irrespective of our operating performance. For example, events such as the ongoing conflicts in Eastern Europe and the Middle East have caused disruptions of global financial markets and resulted in increased volatility in the trading price of our common stock.
Broad market factors may materially harm the market price of our common stock irrespective of our operating performance. For example, events such as recent tariffs announcements and the ongoing conflicts in Eastern Europe and the Middle East have caused disruptions of global financial markets and resulted in increased volatility in the trading price of our common stock.
The FDA and EMA have granted Orphan Drug designation to donidalorsen for the treatment of patients with HAE, to WAYLIVRA for the treatment of patients with FCS, to tominersen for the treatment of patients with HD, and to some of our earlier stage medicines.
The FDA and EMA have granted Orphan Drug designation to DAWNZERA for the treatment of patients with HAE, to WAYLIVRA for the treatment of patients with FCS, to tominersen for the treatment of patients with HD, and to some of our earlier stage medicines.
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.
Our operations are subject to extensive legal and regulatory requirements affecting the health care industry, including federal, state, and foreign fraud and abuse (including anti-kickback laws and 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.
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.
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, DAWNZERA, obudanersen, olezarsen, ulefnersen and zilganersen.
The IRA, among other things, (1) directs HHS to negotiate the price of certain single-source drugs and biologics that have been on the market for at least seven years covered under Medicare, or the Medicare Drug Price Negotiation Program, and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
The IRA, among other things, (1) directed HHS to negotiate the price of certain single-source drugs and biologics that have been on the market for at least seven years covered under Medicare, or the Medicare Drug Price Negotiation Program, and (2) imposed rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
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. 46 Table of Contents Moreover, our commercial medicines are chemically similar to each other.
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.
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 sefaxersen.
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; ● Roche for development and funding of sefaxersen; and ● Otsuka for development and funding of ulefnersen.
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, sefaxersen and pelacarsen.
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 DAWNZERA, QALSODY, SPINRAZA, WAINUA, bepirovirsen, sefaxersen, pelacarsen and ulefnersen.
As of December 31, 2024, 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.
As of December 31, 2025, we had cash, cash equivalents and short-term investments equal to $2.7 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.
The OECD is leading work on an iteration of the BEPS project based on two “pillars” (subject to certain revenue thresholds), involving the reallocation of taxing rights in respect of certain multinational enterprises above a fixed profit margin to the jurisdictions in which they carry on business) (referred to as “Pillar One”) and imposing a minimum effective corporate tax rate on certain multinational enterprises (referred to as “Pillar Two”).
The OECD is leading work on an iteration of the BEPS project based on two “pillars” (subject to certain revenue thresholds), involving, among other measures, the reallocation of taxing rights in respect of certain multinational enterprises above a fixed profit margin to the jurisdictions in which they carry on business (referred to as “Pillar One”) and imposition of a minimum effective corporate tax rate on certain multinational enterprises (referred to as “Pillar Two”).
PTO. 51 Table of Contents Risks related to personal information, cybersecurity, social media and artificial intelligence We are dependent on data as well as information technology systems and infrastructure, which exposes us to data protection risks. We are dependent upon our own and third-party data as well as information technology systems and infrastructure, including mobile technologies, to operate our business.
Risks related to personal information, cybersecurity, social media and artificial intelligence 51 We are dependent on data as well as information technology systems and infrastructure, which exposes us to data protection risks. We are dependent upon our own and third-party data as well as information technology systems and infrastructure, including mobile technologies, to operate our business.
We must also continue to scale-up existing internal support functions to aid our commercialization efforts. Further, these existing support functions will need to work effectively in coordination with new commercial functional areas.
We must also continue to scale-up existing internal support functions to aid our commercialization efforts, which will need to work effectively in coordination with new commercial functional areas.
In addition, our development and commercialization activities could be harmed or delayed by a shutdown or significant disruption of the U.S. government, including the FDA or the U.S.
In addition, our development and commercialization activities could be harmed or delayed by staffing shortages or a shutdown or other significant disruption of the U.S. government, including the FDA or the U.S. PTO.
The multitude and complexity of our information technology systems and infrastructure make them vulnerable to a variety of evolving threats that may result in systems or data interruption, corruption, destruction, disruption of data integrity, malicious intrusion, or random attacks or other compromise (such as due to malfunctions, software vulnerabilities, natural disasters, telecommunications failures, malicious actors and personnel error).
The multitude and complexity of our information technology systems and infrastructure (including those of third parties with whom we work) make them vulnerable to a variety of evolving threats that may result in systems or data interruption, corruption, destruction, disruption of data integrity, malicious intrusion, or random attacks or other compromise (such as due to malfunctions, software vulnerabilities, natural disasters, telecommunications failures, malicious actors and personnel error).
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.
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.
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.
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. 43 We depend on our collaborations with Biogen for the development and commercialization of SPINRAZA and QALSODY.
TRYNGOLZA is our first independently launched medicine and we expect to independently launch additional medicines in the future. Any failure to effectively commercialize our medicines, including our failure to allocate resources to our commercial launches efficiently or timely, could adversely impact the revenue we generate from our medicines.
We currently have two independently launched medicines, TRYNGOLZA and DAWNZERA, and we expect to independently launch additional medicines in the near future. Any failure to effectively commercialize our medicines, including our failure to allocate resources to our commercial launches efficiently or timely, could adversely impact the revenue we generate from our medicines.
Non-compliance with relevant data protection obligations or a failure to secure our data, information technology systems or infrastructure 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.
Non-compliance with relevant data protection obligations or a failure to secure our data, information technology systems or infrastructure 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 presents new risks and challenges.
Risks related to health epidemics, climate change and other events Our business may be adversely affected by health epidemics, climate change, extreme weather events, fires, earthquakes, war, civil or political unrest, terrorism or other catastrophic events.
Risks related to health epidemics, climate change and other events Our business may be adversely affected by health epidemics, climate change, extreme weather events, fires, earthquakes, war, civil or political unrest, terrorism or disruptions of the U.S. government.
Cybersecurity related events could include the deployment or use of harmful malware or malicious code, denial-of-service attacks, credential stuffing attacks, credential harvesting attacks, social engineering attacks (including deep fakes), ransomware and other means to affect the confidentiality, integrity or availability of our data as well as information systems and infrastructure.
Cybersecurity related events could include the deployment or use of harmful malware or malicious code, denial-of-service attacks, credential stuffing attacks, credential harvesting attacks, social engineering attacks (including deep fakes and phishing attacks), ransomware and other means to affect, as applicable, the confidentiality, privacy, security, integrity or availability of our data as well as information systems and infrastructure (including that of third parties with whom we work).
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.
For example, the Affordable Care Act substantially changed the way healthcare is financed by both governmental and private insurers and continues to significantly impact the U.S. pharmaceutical industry.
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.
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. 53 Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, financial condition or stock price.
If we are unable to effectively establish and maintain 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 successfully commercialize our medicines. We have historically relied on third parties to commercialize our marketed medicines and have limited experience as a company in commercializing medicines.
If we are unable to effectively establish or maintain an effective commercialization infrastructure, or enter into agreements with third parties to commercialize our medicines, we may not be able to successfully commercialize our medicines. We have historically relied on third parties to commercialize our marketed medicines and have limited experience as a company in commercializing medicines.
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.
Under the terms of the collaboration agreement, we and AstraZeneca are co-developing and co-commercializing WAINUA in the U.S. and AstraZeneca has the sole right to commercialize WAINUA in all other countries. As a company we do not have experience with co-commercialization arrangements.
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 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.
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.
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, 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.
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.
Any failure or delay in our clinical studies could reduce the commercial potential or viability of our medicines. 46 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.
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.
The biotechnology and pharmaceutical industries are highly competitive and subject to significant and rapid technological change. 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.
For example, in June 2024, California enacted Senate Bill 167, or SB 167, which, with certain exceptions, suspends the ability to use California net operating losses to offset California income and limits the ability to use California business tax credits to offset California taxes, for taxable years beginning after 2023 and before 2027. 56 Table of Contents Our future taxable income could be impacted by changes in tax laws, regulations and treaties.
For example, in June 2024, California enacted Senate Bill 167, or SB 167, which, with certain exceptions, suspends the ability to use California net operating losses to offset California income and limits the ability to use California business tax credits to offset California taxes, for taxable years beginning after 2023 and before 2027.
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.
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. 56 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.
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.
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.
For example, we may issue approximately 21.6 million shares of our common stock upon conversion of our 1.75% Notes and 0% Notes. In connection with the issuance of the 0% Notes, we entered into certain call spread transactions covering 10.9 million shares that we expect will offset the dilution to holders of common stock upon any conversion of those notes.
In connection with the issuance of the 0% Notes due 2026, we entered into certain call spread transactions covering 10.9 million shares that we expect will offset the dilution to holders of common stock upon any conversion of those notes.
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.
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; ● QALSODY could face competition from a commercial competitor in the future; and ● Obudanersen, if approved, could face competition from commercial competitors in the future, including oral products.
Our current, past and prospective business partners face similar risks and any security breaches of their systems could adversely affect our security posture.
Our current, past and prospective business partners face similar risks and any security breaches of their systems (or those of third parties upon which they rely) could adversely affect our security posture.
During the 12 months preceding December 31, 2024 , the closing market price of our common stock ranged from $ 53.55 to $ 33.73 per share.
During the 12 months preceding December 31, 2025, the closing market price of our common stock ranged from $82.73 to $25.51 per share.
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.
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.
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.
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. 47 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 ● devote fewer resources to our medicines than it does to its own medicines.
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.
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.
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.
We also must ensure that we have the manufacturing capabilities in place to support advances in our drug development activities, such as new chemistries. 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.
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, public perception regarding 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.
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. 40 The degree of market acceptance for our medicines, including our commercial medicines and our medicines in development, depends upon several 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, public perception regarding 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.
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.
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.
Terminating or unwinding the call spread transactions for our 0% Notes 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.
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.
Similarly, topline, preliminary or interim data we release for any of our clinical studies may not be indicative of full or final results from such study. 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.
Even if our medicines are successful in preclinical and human clinical studies, the medicines may not be successful in late-stage clinical studies. Similarly, topline, preliminary or interim data we release for any of our clinical studies may not be indicative of full or final results from such study.
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.
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 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. 53 Table of Contents A variety of risks associated with operating our business and marketing our medicines internationally could adversely affect our business.
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.
These competitive developments could make our medicines, including our commercial medicines and our medicines in development, obsolete or non-competitive. 42 Table of Contents 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.
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 that our own programs target.
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. 54 Table of Contents 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.
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.
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.
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, 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.
In addition, 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. The proximity of our current and planned independent launches could increase the likelihood that the risks set forth above will occur.
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.
Since its enactment, there have been amendments and judicial, Congressional and executive branch challenges to certain aspects of the Affordable Care Act, as well as efforts to repeal or replace certain aspects of the Affordable Care Act.
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.
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. 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 addition to our U.S. operations, we are commercializing 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.
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.
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.
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. 42 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 or of medicines we are commercializing.
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.
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.
If the commercialization of TRYNGOLZA and future sales are less successful than anticipated by us or our investors or securities analysts, our stock price could decline and our business may be harmed. We will have to continue to invest significant financial and management resources to build and maintain the infrastructure required to successfully commercialize our medicines.
If the commercialization of our independently launched medicines and future sales of such are less successful than anticipated by us or our investors or securities analysts, our stock price could decline and our business may be harmed.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeOur 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 designed to identify vulnerabilities. 57 Table of Contents Depending on the environment, system and data, 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 and data, 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.
Biggest changeDepending on the environment, system and data, 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 and data, 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.
For an additional description of the risks from cybersecurity threats that may materially affect us and how they may do so, see our risk factors under Item 1A, Risk Factors , in this Annual Report on Form 10-K, including the risk factor titled “ We are dependent on data as well as information technology systems and infrastructure, which exposes us to data protection risks .” Governance Our Board of Directors addresses our cybersecurity risk management as part of its general oversight function.
For an additional description of the risks from cybersecurity threats that may materially affect us and how they may do so, see our risk factors under Item 1A, Risk Factors , in this Annual Report on Form 10-K, including the risk factor titled “ We are dependent on data as well as information technology systems and infrastructure, which exposes us to data protection risks .” 58 Governance Our Board of Directors addresses our cybersecurity risk management as part of its general oversight function.
The Audit Committee of the Board of Directors receives reports from our Senior Vice President, Information Technology concerning our significant cybersecurity threats and risks (including certain cybersecurity threats) and the processes we have implemented that are designed to address them. 58 Table of Contents
The Audit Committee of the Board of Directors receives reports from our Senior Vice President, Information Technology concerning our significant cybersecurity threats and risks (including certain cybersecurity threats) and the processes we have implemented that are designed to address them.
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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 designed to identify vulnerabilities.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeProperties As of February 13, 2025, 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 Carlsbad, CA 176,300 Leased 2037 Two, five-year options to extend Office and meeting space facility Carlsbad, CA 74,000 Leased 2037 Two, five-year options to extend Manufacturing facility Carlsbad, CA 26,800 Owned Manufacturing support facility Carlsbad, CA 25,800 Leased 2026 One, five-year option to extend Office space facility Boston, MA 14,300 Leased 2029 One, five-year option to extend Office space facility Carlsbad, CA 5,800 Leased 2027 None Warehouse facility Carlsbad, CA 4,200 Leased 2028 None Office space facility Dublin, Ireland 3,900 Leased 2025 None 331,100 We believe that our current and future facilities will be adequate for the foreseeable future.
Biggest changeProperties As of February 19, 2026, the following are the primary facilities in which we operate: Owned Initial Lease Lease Property Description Location Square Footage or Leased Term End Date Extension Options Laboratory and office space facility Carlsbad, CA 176,300 Leased 2037 Two, five-year options to extend Laboratory and office space facility Carlsbad, CA 164,800 Leased 2040 Two, five-year options to extend Office and meeting space facility Carlsbad, CA 74,000 Leased 2037 Two, five-year options to extend Manufacturing facility Carlsbad, CA 26,800 Owned Manufacturing support facility Carlsbad, CA 25,800 Leased 2031 None Office space facility Boston, MA 14,300 Leased 2038 None Office space facility Carlsbad, CA 5,800 Leased 2027 None Warehouse facility Carlsbad, CA 4,200 Leased 2028 None Office space facility Dublin, Ireland 3,900 Leased 2030 None 495,900 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.
Refer to Part IV, Section 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for details on our facilities.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeWe have never paid dividends and do not anticipate paying any dividends in the foreseeable future. 59 Table of Contents 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, 2019 in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index.
Biggest changeSecurities Authorized for Issuance Under Equity Compensation Plans Refer to Part III, Item 12, Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters , for information about our equity compensation plans, which is incorporated by reference herein. 60 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, 2020 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, 2019 in stock or index, including reinvestment of dividends. Fiscal year ending December 31.
The total return assumes reinvestment of dividends. * $100 invested on December 31, 2020 in stock or index, including reinvestment of dividends. Fiscal year ending December 31.
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 13, 2025, there were approximately 447 stockholders of record of our common stock.
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 19, 2026, there were approximately 412 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.
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.
COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Dec-19 Dec-20 Dec-21 Dec-22 Dec-23 Dec-24 Ionis Pharmaceuticals, Inc. $ 100.00 $ 93.59 $ 50.37 $ 62.52 $ 83.74 $ 57.87 Nasdaq Composite Index $ 100.00 $ 144.92 $ 177.06 $ 119.45 $ 172.77 $ 223.87 Nasdaq Biotechnology Index $ 100.00 $ 126.42 $ 126.45 $ 113.65 $ 118.87 $ 118.20 ___________ (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. 60 Table of Contents Item 6 .
COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Dec-20 Dec-21 Dec-22 Dec-23 Dec-24 Dec-25 Ionis Pharmaceuticals, Inc. $ 100.00 $ 53.82 $ 66.80 $ 89.48 $ 61.83 $ 139.92 Nasdaq Composite Index $ 100.00 $ 122.18 $ 82.43 $ 119.22 $ 154.48 $ 187.14 Nasdaq Biotechnology Index $ 100.00 $ 100.02 $ 89.90 $ 94.03 $ 93.49 $ 124.75 ___________ (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. 61 Item 6.

Item 7. Management's Discussion & Analysis

Management's Discussion & Analysis (MD&A) — revenue / margin commentary

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Biggest changeThe following table provides selected summary information from our consolidated statements of operations for 2024 and 2023 (in millions): Year Ended December 31, 2024 2023 Total revenue $ 705.1 $ 787.6 Total operating expenses $ 1,180.2 $ 1,141.4 Loss from operations $ (475.1 ) $ (353.7 ) Net loss $ (453.9 ) $ (366.3 ) Cash, cash equivalents and short-term investments $ 2,297.7 $ 2,331.2 61 Table of Contents Revenue Total revenue for 2024 was $705.1 million compared to $787.6 million in 2023 and was comprised of the following (in millions): Year Ended December 31, 2024 2023 Revenue: Commercial revenue: SPINRAZA royalties $ 216.1 $ 240.4 WAINUA royalties 20.2 — Other commercial revenue: TEGSEDI and WAYLIVRA revenue, net 34.2 34.9 Other revenue 22.6 33.3 Total other commercial revenue 56.8 68.2 Total commercial revenue 293.1 308.6 R&D revenue: Amortization from upfront payments 131.4 125.3 Milestone payments 106.4 100.5 License fees 71.3 116.8 Other services 23.5 10.0 Collaborative agreement revenue 332.6 352.6 WAINUA joint development revenue 79.4 126.4 Total R&D revenue 412.0 479.0 Total revenue $ 705.1 $ 787.6 Commercial revenue in 2024 included new sources of commercial revenue with the launch of WAINUA in the U.S. in late January 2024 and the launch of TRYNGOLZA in the U.S. in late December 2024.
Biggest changeResults of Operations The following table provides selected summary information from our consolidated statements of operations for 2025 and 2024 (in millions): Year Ended December 31, 2025 2024 Total revenue $ 943.7 $ 705.1 Total operating expenses $ 1,325.4 $ 1,180.2 Loss from operations $ (381.7 ) $ (475.1 ) Net loss $ (381.4 ) $ (453.9 ) Cash, cash equivalents and short-term investments $ 2,677.4 $ 2,297.7 62 Revenue Total revenue for 2025 was $943.7 million compared to $705.1 million in 2024 and was comprised of the following (in millions): Year Ended December 31, 2025 2024 Revenue: Commercial revenue: Product sales, net: TRYNGOLZA sales, net $ 107.5 $ - DAWNZERA sales, net 7.8 - Total product sales, net 115.3 - Royalty revenue: SPINRAZA royalties 212.3 216.1 WAINUA royalties 49.1 20.2 Other royalties 24.1 21.0 Total royalty revenue 285.5 257.3 Other commercial revenue 35.0 35.8 Total commercial revenue 435.8 293.1 Research and development revenue: Collaborative agreement revenue 465.8 332.6 WAINUA joint development revenue 42.1 79.4 Total research and development revenue 507.9 412.0 Total revenue $ 943.7 $ 705.1 Commercial revenue in 2025 increased 49 percent compared to 2024.
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.
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.
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.
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. 70 The following is a summary of the critical accounting estimates we make with respect to our revenue.
The period-over-period fluctuation in our loss on investments was primarily driven by changes in the fair value of our investments in privately held and publicly traded biotechnology companies.
The period-over-period fluctuation in our gain (loss) on investments was primarily driven by changes in the fair value of our investments in privately held and publicly traded biotechnology companies.
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. 69 Table of Contents ● 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.
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.
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. 68 Table of Contents Critical Accounting Estimates We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S.
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.
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, 2024, and our financial condition as of December 31, 2024.
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, 2025, and our financial condition as of December 31, 2025.
Other Obligations In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2024 for the purchase of services, capital equipment and materials as part of our normal course of business.
Other Obligations In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2025 for the purchase of services, capital equipment and materials as part of our normal course of business.
We expect our development expenses will continue to be stable as several late-stage studies end and we reallocate resources toward earlier stage programs. We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the various indications we may be studying.
We expect our development expenses will continue to stabilize as several late-stage studies end and we reallocate resources toward earlier stage programs. 65 We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the various indications we may be studying.
Refer to Part II, Item 7, Management’s Discussion and Analysis of Financial Condition and Results of Operations , in our 2023 Form 10-K for our results of operations for 2023 compared to 2022.
Refer to Part II, Item 7, Management's Discussion and Analysis of Financial Condition and Results of Operations , in our 2024 Form 10-K for our results of operations for 2024 compared to 2023.
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.
Because we are leading and conducting the Phase 3 development program, we are recognizing as R&D revenue the percentage 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.
The following table sets forth information on cost of sales (in millions): Year Ended December 31, 2024 2023 Cost of sales, excluding non-cash compensation expense related to equity awards $ 10.4 $ 8.7 Non-cash compensation expense related to equity awards 0.8 0.4 Total cost of sales $ 11.2 $ 9.1 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 cost of sales (in millions): Year Ended December 31, 2025 2024 Cost of sales, excluding non-cash compensation expense related to equity awards $ 14.0 $ 10.4 Non-cash compensation expense related to equity awards 1.9 0.8 Total cost of sales $ 15.9 $ 11.2 64 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.
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 benefit of $6.2 million for 2024 compared to an income tax expense of $32.3 million for 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 regarding our convertible debt. Income Tax Expense (Benefit) We recorded an income tax expense of $1.8 million for 2025 compared to an income tax benefit of $6.2 million for 2024.
Additionally, from our inception through December 31, 2024 , we have borrowed approximately $ 2.7 billion under long-term debt arrangements and received proceeds of approximately $0.5 billion from the sale of future royalties to finance a portion of our operations.
Additionally, from our inception through December 31, 2025, we have borrowed approximately $3.5 billion under long-term debt arrangements and received proceeds of approximately $0.5 billion from the sale of future royalties to finance a portion of our operations.
Royalty Revenue Monetization In 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.
Liability Related to Sale of Future Royalties In 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.
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 primarily associated with the manufacturing and distribution of TRYNGOLZA, TEGSEDI and WAYLIVRA and certain associated period costs.
Cost of Sales Our cost of sales is comprised of costs related to our commercial revenue, which consisted of manufacturing costs, transportation and freight, indirect overhead costs associated with the manufacturing and distribution of TRYNGOLZA, DAWNZERA, TEGSEDI and WAYLIVRA and associated period costs.
Our net loss per share increased for 2024 compared to 2023 primarily due to factors discussed in the sections above. 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 royalties and TEGSEDI and WAYLIVRA commercial revenue.
Our net loss per share decreased for 2025 compared to 2024 primarily due to factors discussed in the sections above. 68 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, WAINUA and QALSODY royalties and TEGSEDI and WAYLIVRA commercial revenue.
The following table sets forth information on research, development and patent expenses (in millions): Year Ended December 31, 2024 2023 Research, development and patent expenses, excluding non-cash compensation expense related to equity awards $ 809.1 $ 821.7 Non-cash compensation expense related to equity awards 92.4 77.9 Total research, development and patent expenses $ 901.5 $ 899.6 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.
The following table sets forth information on research, development and patent expenses (in millions): Year Ended December 31, 2025 2024 Research, development and patent expenses, excluding non-cash compensation expense related to equity awards $ 825.5 $ 809.1 Non-cash compensation expense related to equity awards 90.1 92.4 Total research, development and patent expenses $ 915.6 $ 901.5 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.
The following table sets forth information on manufacturing and development chemistry expenses (in millions): Year Ended December 31, 2024 2023 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards $ 57.7 $ 65.3 Non-cash compensation expense related to equity awards 9.4 8.8 Total manufacturing and development chemistry expenses $ 67.1 $ 74.1 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, decreased in 2024 compared to 2023 due to the timing of manufacturing performed by our contract manufacturing organizations for drug product related to several late-stage programs.
The following table sets forth information on manufacturing and development chemistry expenses (in millions): Year Ended December 31, 2025 2024 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards $ 87.3 $ 57.7 Non-cash compensation expense related to equity awards 7.8 9.4 Total manufacturing and development chemistry expenses $ 95.1 $ 67.1 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, increased in 2025 compared to 2024 due to the timing of manufacturing performed by our contract manufacturing organizations for drug product and active pharmaceutical ingredients related to several late-stage programs.
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details. 66 Table of Contents Loss on Investments We recorded a $2.9 million and $1.9 million loss on investments for 2024 and 2023, 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. Gain (Loss) on Investments We recorded a $10.2 million gain on investments and a $2.9 million loss on investments for 2025 and 2024, respectively.
Overview As noted in our Business Overview in Part I, Item 1, Business , 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 six marketed medicines: TRYNGOLZA, WAINUA, SPINRAZA, QALSODY, TEGSEDI and WAYLIVRA.
Overview As noted in our Business Overview in Part I, Item 1, Business , 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.
Revenue Recognition We earn revenue from several sources. The judgements and estimates we make vary between each source of our revenue.
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.
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.
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.
Operating Expenses The following table sets forth information on operating expenses (in millions): Year Ended December 31, 2024 2023 Operating expenses, excluding non-cash compensation expense related to equity awards $ 1,050.0 $ 1,035.7 Non-cash compensation expense related to equity awards 130.2 105.7 Total operating expenses $ 1,180.2 $ 1,141.4 Operating expenses, excluding non-cash compensation expense related to equity awards, increased slightly in 2024 compared to 2023.
Operating Expenses The following table sets forth information on operating expenses (in millions): Year Ended December 31, 2025 2024 Operating expenses, excluding non-cash compensation expense related to equity awards $ 1,191.5 $ 1,050.0 Non-cash compensation expense related to equity awards 133.9 130.2 Total operating expenses $ 1,325.4 $ 1,180.2 Operating expenses, excluding non-cash compensation expense related to equity awards, increased in 2025 compared to 2024.
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.
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.
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” ); and ● 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”).
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” ); and ● 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”). 71 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.
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) $ 610.3 $ 10.1 $ 600.2 0% Notes (principal payable) 632.5 — 632.5 Operating leases 260.3 20.9 239.4 Building mortgage payments (principal and interest payable) 9.6 0.5 9.1 Other obligations (principal and interest payable) 0.7 0.1 0.6 Total $ 1,513.4 $ 31.6 $ 1,481.8 Our contractual obligations consist primarily of our convertible debt.
Contractual Obligations Payments Due by Period (in millions) (selected balances described below) Total Less than 1 year More than 1 year 0% Notes due 2030 (principal payable) $ 770.0 $ - $ 770.0 1.75% Notes due 2028 (principal and interest payable) 600.2 10.1 590.1 0% Notes due 2026 (principal payable) 432.5 432.5 - Operating leases 484.8 35.5 449.3 Building mortgage payments (principal and interest payable) 9.1 0.5 8.6 Other obligations (principal and interest payable) 0.6 0.1 0.5 Total $ 2,297.2 $ 478.7 $ 1,818.5 Our contractual obligations consist primarily of our convertible debt.
In addition, R&D revenue decreased due to the timing of significant partner payments. WAINUA (Eplontersen) Collaboration with AstraZeneca Our financial results for the years ended December 31, 2024 and 2023 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and commercialize WAINUA for the treatment of ATTR.
WAINUA (Eplontersen) Collaboration with AstraZeneca Our financial results for the years ended December 31, 2025 and 2024 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and commercialize WAINUA for the treatment of ATTR.
The following table sets forth information on revenue and expenses under this collaboration (in millions): Year Ended December 31, 2024 2023 WAINUA joint development revenue $ 79.4 $ 126.4 Research and development expenses related to Phase 3 development expenses for WAINUA 107.2 150.8 Medical affairs expenses for WAINUA 7.1 4.1 Commercialization expenses for WAINUA 26.7 15.6 62 Table of Contents Our WAINUA joint development revenue in 2024 and 2023 includes a $30 million milestone payment from AstraZeneca that we earned when the MHRA approved WAINUA for ATTRv-PN in the UK as WAINZUA and a $50 million milestone payment from AstraZeneca that we earned when the FDA approved WAINUA for ATTRv-PN in the U.S., respectively.
We expect our medical affairs and commercialization expenses to increase as WAINUA advances toward the market under our collaboration with AstraZeneca. 63 The following table sets forth information on revenue and expenses under this collaboration (in millions): Year Ended December 31, 2025 2024 WAINUA joint development revenue $ 42.1 $ 79.4 Research and development expenses related to Phase 3 development of WAINUA 88.9 107.2 Medical affairs expenses for WAINUA 8.1 7.1 Commercialization expenses for WAINUA 30.3 26.7 Our WAINUA joint development revenue in 2024 included a $30 million milestone payment from AstraZeneca that we earned when the Medicines and Healthcare products Regulatory Agency, or MHRA, approved WAINUA for ATTRv-PN in the UK as WAINZUA.
During the same period, our long-term obligations did not change significantly. 67 Table of Contents The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of December 31, 2024. The table provides a breakdown of when obligations become due.
The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of December 31, 2025. The table provides a breakdown of when obligations become due.
The following table sets forth information on SG&A expenses (in millions): Year Ended December 31, 2024 2023 Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards $ 230.5 $ 205.1 Non-cash compensation expense related to equity awards 37.0 27.5 Total selling, general and administrative expenses $ 267.5 $ 232.6 SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2024 compared to 2023 due to the launches of WAINUA and TRYNGOLZA, including establishing the TRYNGOLZA field team in the second quarter of 2024, and advancing launch preparation activities for donidalorsen .
The following table sets forth information on SG&A expenses (in millions): Year Ended December 31, 2025 2024 Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards $ 352.0 $ 230.5 Non-cash compensation expense related to equity awards 41.9 37.0 Total selling, general and administrative expenses $ 393.9 $ 267.5 SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2025 compared to 2024 primarily due to the launches of TRYNGOLZA, DAWNZERA and WAINUA .
Net Loss and Net Loss per Share We generated a net loss of $453.9 million for 2024 compared to $366.3 million for 2023. Our net loss increased for 2024 compared to 2023 primarily due to factors discussed in the sections above . Basic and diluted net loss per share for 2024 were $3.04 compared to $2.56 for 2023.
Our net loss decreased for 2025 compared to 2024 primarily due to factors discussed in the sections above. Basic and diluted net loss per share for 2025 were $2.38 compared to $3.04 for 2024.
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): Year Ended December 31, 2024 2023 WAINUA $ 103.7 $ 115.5 TEGSEDI and WAYLIVRA 11.2 8.1 Olezarsen 147.4 138.3 Donidalorsen 16.6 24.9 Zilganersen 7.6 8.4 Ulefnersen 15.0 10.8 Other development projects 89.9 101.0 Development overhead expenses 135.9 123.3 Total drug development, excluding non-cash compensation expense related to equity awards 527.3 530.3 Non-cash compensation expense related to equity awards 41.2 34.5 Total drug development expenses $ 568.5 $ 564.8 Our development expenses, excluding non-cash compensation expense related to equity awards, were essentially flat in 2024 compared to 2023.
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): Year Ended December 31, 2025 2024 Eplontersen $ 87.6 $ 103.7 DAWNZERA 14.3 16.6 Olezarsen 87.1 147.4 Zilganersen 13.9 7.6 Obudanersen 31.9 16.6 Ulefnersen 11.1 15.0 Other development projects 81.1 84.5 Development overhead expenses 159.2 135.9 Total drug development expenses, excluding non-cash compensation expense related to equity awards 486.2 527.3 Non-cash compensation expense related to equity awards 42.5 41.2 Total drug development expenses $ 528.7 $ 568.5 Our development expenses, excluding non-cash compensation expense related to equity awards, decreased in 2025 compared to 2024 as several late-stage studies ended.
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.
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. 66 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.
This function is also responsible for making investments in complementary technologies to expand the reach of our technologies. 63 Table of Contents The following table sets forth information on drug discovery expenses (in millions): Year Ended December 31, 2024 2023 Drug discovery expenses, excluding non-cash compensation expense related to equity awards $ 114.4 $ 125.6 Non-cash compensation expense related to equity awards 18.4 16.2 Total drug discovery expenses $ 132.8 $ 141.8 Drug discovery expenses, excluding non-cash compensation expense related to equity awards, decreased in 2024 compared to 2023.
The following table sets forth information on drug discovery expenses (in millions): Year Ended December 31, 2025 2024 Drug discovery expenses, excluding non-cash compensation expense related to equity awards $ 125.2 $ 114.4 Non-cash compensation expense related to equity awards 16.2 18.4 Total drug discovery expenses $ 141.4 $ 132.8 Drug discovery expenses, excluding non-cash compensation expense related to equity awards, increased in 2025 compared to 2024 as we continued to advance our technologies discussed above.
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. 64 Table of Contents The following table sets forth information on medical affairs expenses (in millions): Year Ended December 31, 2024 2023 Medical affairs expenses, excluding non-cash compensation expense related to equity awards $ 27.2 $ 19.5 Non-cash compensation expense related to equity awards 4.7 3.4 Total medical affairs expenses $ 31.9 $ 22.9 Medical affairs expenses, excluding non-cash compensation expense related to equity awards, increased in 2024 compared to 2023 as we continued advancing our late-stage pipeline .
The following table sets forth information on medical affairs expenses (in millions): Year Ended December 31, 2025 2024 Medical affairs expenses, excluding non-cash compensation expense related to equity awards $ 32.0 $ 27.2 Non-cash compensation expense related to equity awards 5.4 4.7 Total medical affairs expenses $ 37.4 $ 31.9 Medical affairs expenses, excluding non-cash compensation expense related to equity awards, increased in 2025 compared to 2024 as we continued advancing our late-stage pipeline.
We expect SG&A expenses to increase as we continue to invest in our independent commercial launches. Investment Income Investment income for 2024 was $107.0 million compared to $89.0 million for 2023. The increase in investment income was primarily due to an increase in interest rates associated with our investments during a majority of 2024 compared to 2023.
We expect SG&A expenses to increase as we continue to invest in our independent commercial launches. Investment Income Investment income for 2025 was $97.8 million compared to $107.0 million for 2024.
The income tax benefit during 2024 primarily related to adjustments to prior year tax return positions for the royalty purchase agreement with Royalty Pharma and deductions related to foreign SPINRAZA royalties. The decrease in income tax expense for 2024 compared to 2023 primarily related to the impact of the Royalty Pharma transaction in 2023.
The income tax expense for 2025 primarily relates to state income taxes, partially offset by a federal tax benefit related to a capital loss carryback. The income tax benefit for 2024 primarily related to adjustments to prior year tax return positions for the royalty purchase agreement with Royalty Pharma and deductions related to foreign SPINRAZA royalties.
Non-cash compensation expense related to equity awards increased in 2024 compared to 2023 due to increased headcount and a higher stock price on the grant date of annual equity awards in 2024 compared to 2023. We believe non-cash compensation expense related to equity awards is not indicative of our operating results or cash flows from our operations.
We believe non-cash compensation expense related to equity awards is not indicative of our operating results or cash flows from our operations.
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 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).
Interest Expense The following table sets forth information on interest expense (in millions): Year Ended December 31, 2024 2023 Convertible senior notes: Non-cash amortization of debt issuance costs $ 6.1 $ 5.9 Interest expense payable in cash 10.5 6.4 Interest on mortgage for primary R&D and manufacturing facilities 0.4 0.4 Total interest expense $ 17.0 $ 12.7 Interest expense for 2024 was $ 17.0 million compared to $ 12.7 million for 2023 .
The decrease in investment income was primarily due to a decrease in interest rates associated with our investments during 2025 compared to 2024. 67 Interest Expense The following table sets forth information on interest expense (in millions): December 31, 2025 2024 Convertible notes: Non-cash amortization of debt issuance costs $ 6.3 $ 6.1 Interest expense payable in cash 10.1 10.5 Interest on mortgage for manufacturing facility 0.4 0.4 Other 0.5 - Total interest expense $ 17.3 $ 17.0 Interest Expense Related to Sale of Future Royalties We recorded $73.3 million and $73.5 million of interest expense related to the sale of future royalties in 2025 and 2024, respectively.
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.
Other Income (Expense) In 2025, we completed a $770.0 million offering of our 0% Notes due 2030 and used $267.6 million of the net proceeds to repurchase $200.0 million in principal of our 0% Notes due 2026 at a premium.
The following table sets forth information on R&D support expenses (in millions): Year Ended December 31, 2024 2023 Personnel costs $ 31.4 $ 27.2 Occupancy 28.5 28.7 Consulting 0.4 4.8 Patent expenses 5.3 4.3 Insurance 3.3 3.6 Computer software and licenses 8.4 2.7 Other 5.3 9.7 Total R&D support expenses, excluding non-cash compensation expense related to equity awards 82.6 81.0 Non-cash compensation expense related to equity awards 18.6 15.0 Total R&D support expenses $ 101.2 $ 96.0 R&D support expenses, excluding non-cash compensation expense related to equity awards, were essentially flat in 2024 compared to 2023. 65 Table of Contents 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.
The following table sets forth information on R&D support expenses (in millions): Year Ended December 31, 2025 2024 Personnel costs $ 33.1 $ 31.4 Occupancy 31.1 28.5 Computer software and licenses 14.4 8.4 Insurance 3.3 3.3 Patent expenses 6.4 5.3 Other 6.5 5.7 Total R&D support expenses, excluding non-cash compensation expense related to equity awards 94.8 82.6 Non-cash compensation expense related to equity awards 18.2 18.6 Total R&D support expenses $ 113.0 $ 101.2 R&D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2025 compared to 2024 primarily due to increased costs relating to computer software and licenses.
In addition, we began receiving commercial revenue from WAINUA royalties in 2024. From our inception through December 31, 2024, we have earned approximately $7.9 billion in revenue. We have also financed our operations through the sale of our equity securities, the issuance of long-term debt, the sale leaseback of facilities and the sale of future royalties.
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, 2025, we have raised net proceeds of approximately $2.8 billion from the sale of our equity securities.
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.
Refer to Part I, Item 1, Business , for further details on our business and key developments in our medicines.
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 .
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 . 69 Royalty Revenue Monetization In 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 the terms of the collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3 development program.
Under the terms of the collaboration agreement, AstraZeneca was responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program through December 31, 2025. After December 31, 2025, AstraZeneca is responsible for 75 percent and 87.5 percent of development costs in the U.S. and the rest of the world, respectively.
As of December 31, 2024, 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 $7.7 million. 70 Table of Contents Liability Related to Sale of Future Royalties In 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.
As of December 31, 2025, 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 $5.4 million.
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.
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.
We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and rare diseases. We currently have nine medicines in Phase 3 development and 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.
We currently have seven marketed medicines: TRYNGOLZA, DAWNZERA, WAINUA, SPINRAZA, QALSODY, TEGSEDI and WAYLIVRA. We also have a rich innovative late- and mid-stage pipeline in neurology, cardiometabolic diseases and select areas of high patient needs. We currently have nine medicines in Phase 3 development and additional medicines in early and mid-stage development .
Removed
Results of Operations Below we have included our results of operations for 2024 compared to 2023. Refer to Part II, Item 7, Management’s Discussion and Analysis of Financial Condition and Results of Operations, of our 2023 Form 10-K for our results of operations for 2023 compared to 2022.
Added
This increase was primarily driven by TRYNGOLZA product sales and higher royalty revenue. The remainder of our revenue came from programs under our R&D collaborations, including a $280 million upfront payment for the global license of sapablursen to Ono in the second quarter of 2025, reflecting the value that our pipeline and technology continues to generate.
Removed
SPINRAZA royalties in 2024 compared to 2023 were impacted from an annual order from a single country that did not recur in 2024. R&D revenue decreased in 2024 compared to 2023 primarily due to the decrease in WAINUA joint development revenue as development activities relating to ATTRv-PN wound down with the commercial launch of WAINUA.
Added
Research and development expenses related to the Phase 3 development of WAINUA decreased in 2025 compared to 2024 as development activities related to ATTRv-PN continued to wind down with the commercial launch of WAINUA.
Removed
We expect our medical affairs and commercialization expenses to increase as WAINUA advances toward the market under our collaboration with AstraZeneca.
Added
SG&A expenses increased year over year primarily due to the launches of TRYNGOLZA, DAWNZERA and WAINUA. Non-cash compensation expense related to equity awards were essentially flat year over year due to increased headcount offset by a lower stock price on the grant date of annual equity awards in 2025 compared to 2024.
Removed
SG&A expenses increased year over year primarily due to the launches of WAINUA and TRYNGOLZA, including establishing the TRYNGOLZA field team in the second quarter of 2024, and advancing launch preparation activities for donidalorsen. R&D expenses were essentially flat year over year as several late-stage studies ended.
Added
Costs of sales for recently launched products, such as TRYNGOLZA and DAWNZERA, does not include the full cost of manufacturing until we manufacture and sell additional inventory after exhausting pre-launch inventory, which we previously recorded as R&D expense.
Removed
In 2023, we recognized $15 million in R&D expense for licensing Vect-Horus’ platform technology.
Added
Selling, General and Administrative Expenses SG&A expenses include personnel, information technology systems and outside costs associated with the commercialization and pre-commercialization activities for our medicines and costs to support our company, our employees and our stockholders including, legal, human resources, investor relations and finance.
Removed
In addition, our cash available for investing increased due to the $489.1 million net proceeds we received from our public common stock offering in September 2024. Refer to Part IV, Item 15, Note 8, Stockholders’ Equity , in the Notes to the Consolidated Financial Statements for further details on the public offering.
Added
We also include fees we owe under our in-licensing agreements related to SPINRAZA and QALSODY and cost sharing payments associated with the co-commercialization activities under our WAINUA collaboration with AstraZeneca.
Removed
In June 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 included interest expense incurred for our 1.75% Notes.
Added
As a result of the repurchase, we recognized induced conversion expense of $16.3 million, which we recorded as other expense in our consolidated statement of operations for the year ended December 31, 2025.
Removed
Interest expense in 2024 included a full year of interest expense related to our 1.75% Notes. Interest Expense Related to Sale of Future Royalties We recorded $ 73.5 million and $ 68.8 million of interest expense related to the sale of future royalties in 2024 and 2023, respectively.
Added
The induced conversion expense is the difference between the amount paid to repurchase the 0% Notes due 2026 and the if-converted value of the notes at the time that the debt repurchase terms were finalized.
Removed
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.
Added
In July 2025, H.R.1 - 119th Congress was signed into law, introducing significant changes to U.S. federal tax law. The new law restores current expensing of domestic R&D costs and allows us to accelerate the deduction for a significant amount of such costs we capitalized since 2022.
Removed
We reflected the Royalty Pharma transaction 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. We continue to maintain a full valuation allowance on all our net deferred tax assets.
Added
These tax law changes did not have a material effect on our tax expense for the year ended December 31, 2025. 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 $381.4 million for 2025 compared to $453.9 million for 2024.
Removed
From the time we were founded through December 31, 2024 , we have raised net proceeds of approximately $ 2.6 billion from the sale of our equity securities, which includes our sale of 11.5 million shares of common stock for net proceeds of $489 million in September 2024.
Added
In addition, we began earning commercial revenue from TRYNGOLZA product sales in late December 2024 and DAWNZERA product sales in late August 2025. From our inception through December 31, 2025, we have earned approximately $8.9 billion in revenue.
Removed
Our working capital increased from 2023 to 2024 primarily due to a decrease in current liabilities as a result of lower deferred contract revenue as of December 31, 2024 compared to December 31, 2023.
Added
Our working capital decreased from 2024 to 2025 as we reclassified our 0% Notes due 2026 from non-current liabilities to current liabilities in the second quarter of 2025 because the notes are due in April 2026.
Removed
We have not entered into, nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules).
Added
During the same period, our long-term obligations increased due to the issuance of our 0% Notes due 2030, which was partially offset by the partial repurchase of our 0% Notes due 2026, in the fourth quarter of 2025 .
Removed
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.
Added
In addition, we also have a facility mortgage, facility leases, equipment financing arrangements and other obligations. In the third quarter of 2025, our build-to-suit lease in Carlsbad, California commenced, resulting in an increase to our contractual obligations related to operating leases.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

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Biggest changeAccordingly, 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, 2024 and will not be subject to any material risks arising from these changes in the foreseeable future .
Biggest changeAccordingly, 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, 2025 and will not be subject to any material risks arising from these changes in the foreseeable future.

Other IONS 10-K year-over-year comparisons