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What changed in IONIS PHARMACEUTICALS INC's 10-K — 2023 vs 2024

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Paragraph-level year-over-year comparison of IONIS PHARMACEUTICALS INC's 2023 and 2024 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 2024 report.

+510 added−626 removedSource: 10-K (2025-02-19) vs 10-K (2024-02-21)

Top changes in IONIS PHARMACEUTICALS INC's 2024 10-K

510 paragraphs added · 626 removed · 384 edited across 7 sections

Item 1. Business

Business — how the company describes what it does

216 edited+81 added−210 removed82 unchanged
Biggest changeIONIS-FB-L Rx We believe that the following medicines could compete with I ONIS-FB-L Rx in IgAN: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Tarpeyo (budesonide) Calliditas A corticosteroid indicated to reduce proteinuria in adults with primary IgAN Approved for IgAN Oral Filspari (Sparsentan) Travere An endothelin & angiotensin II receptor antagonist to reduce proteinuria in adults with primary IgAN Approved for IgAN Oral Atrasentan Novartis (Chinook) An endothelin A receptor antagonist Phase 3 (IgAN) Oral Iptacopan Novartis (Chinook) A factor B inhibitor of the alternative complement pathway Phase 3 (IgAN) 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 2 (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. 44 Table of Contents We believe that the following medicines could compete with I ONIS-FB-L Rx in GA: Medicine Company Medicine Description (1) Phase (1) Route of Administration (1) Ivervay (avacincaptad pegol) Iveric Bio A complement C5 inhibitor approved for GA secondary to AMD Approved (GA) Intravitreal Syfovre (pegcetacoplan) Apellis A complement C5 inhibitor approved for GA secondary to AMD Approved (GA) Intravitreal Tinlarebant Belite Bio A small molecule RBP4 antagonist Phase 3 (GA) Oral Danicopan Alexion A factor D inhibitor Phase 2 (GA) Oral PPY988 (GT005) Novartis A gene therapy with encoding for human complement factor I Phase 2 (GA) Intraocular AVD-104 Aviceda A glycomimetic nanoparticle Phase 2 (GA) Intravitreal ANX007 Annexon Bio A fragment antigen-binding (fab) antibody Phase 2 (GA) Intravitreal (1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.
Biggest changePelacarsen 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.
Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those tested and the FDA approved. The FDA does not regulate the behavior of physicians in their choice of treatments, but FDA regulations do impose stringent restrictions on manufacturers’ communications regarding off-label uses.
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.
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 36 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 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 10,266,822 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA United States 8,110,560 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA Europe 1910395 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Sequence and chemistry (full 2’-MOE) of SPINRAZA Europe 3308788 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Pharmaceutical compositions that include SPINRAZA United States 7,838,657 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2027 Oligonucleotides having sequence of SPINRAZA United States 8,361,977 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2030 Sequence and chemistry (full 2’-MOE) of SPINRAZA United States 8,980,853 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA United States 9,717,750 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA to a patient Europe 3449926 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Pharmaceutical compositions that include SPINRAZA for treating SMA Europe 3305302 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Antisense compounds including SPINRAZA for treating SMA United States 9,926,559 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2034 SPINRAZA doses for treating SMA United States 10,436,802 METHODS FOR TREATING SPINAL MUSCULAR ATROPHY 2035 SPINRAZA dosing regimen for treating SMA 30 Table of Contents Trademarks The name “SPINRAZA” is protected throughout the world by trademarks owned by our commercial partner Biogen.
Title Expiration Description of Claims United States 10,266,822 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA United States 8,110,560 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2025 Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA Europe 1910395 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Sequence and chemistry (full 2’-MOE) of SPINRAZA Europe 3308788 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2026 Pharmaceutical compositions that include SPINRAZA United States 7,838,657 SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES 2027 Oligonucleotides having sequence of SPINRAZA United States 8,361,977 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING 2030 Sequence and chemistry (full 2’-MOE) of SPINRAZA United States 8,980,853 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA United States 9,717,750 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Methods of administering SPINRAZA to a patient Europe 3449926 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Pharmaceutical compositions that include SPINRAZA for treating SMA Europe 3305302 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2030 Antisense compounds including SPINRAZA for treating SMA United States 9,926,559 COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT 2034 SPINRAZA doses for treating SMA United States 10,436,802 METHODS FOR TREATING SPINAL MUSCULAR ATROPHY 2035 SPINRAZA dosing regimen for treating SMA 21 Table of Contents Trademarks The name “SPINRAZA” is protected throughout the world by trademarks owned by our commercial partner Biogen.
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. 41 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 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.
If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, corrective advertising, consent decrees and the full range of civil and criminal penalties available to the FDA. Promotion of off-label uses of drugs can also implicate the false claims laws described below.
If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, including corrective advertising, consent decrees and the full range of civil and criminal penalties available to the FDA. Promotion of off-label uses of drugs can also implicate the false claims laws described below.
Other member states allow companies to fix their own prices for medicines but monitor and control company profits. The marketability of any medicine for which we receive regulatory approval for commercial sale may suffer if the government and third-party payers fail to provide adequate coverage and reimbursement.
Other member states allow companies to fix their own prices for medicines but monitor and control company profits. The marketability of any medicine for which we receive regulatory approval for commercial sale may suffer if the government or third-party payers fail to provide adequate coverage and reimbursement.
Other healthcare laws that may affect our ability to operate include, for example, the following: ● The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; ● Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and ● The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the HHS information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members. 39 Table of Contents Sales and Marketing Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid Services, other divisions of the HHS, the U.S.
Other healthcare laws that may affect our ability to operate include, for example, the following: ● The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; ● Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU and UK; and the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and ● The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the Centers for Medicare and Medicaid Services information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members. 29 Table of Contents Sales and Marketing Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid Services, other divisions of the HHS, the U.S.
Roche Huntington’s Disease In 2013, we entered into an agreement with Hoffmann-La Roche Inc and F. Hoffmann-La Roche Ltd, collectively Roche, to develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein.
Huntington’s Disease In 2013, we entered into an agreement with Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd, collectively Roche, to develop treatments for Huntington’s disease, or HD, based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational antisense medicine targeting HTT protein.
AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us. Over the term of the collaboration, we are eligible to receive an upfront payment, license fees, development milestone payments and regulatory milestone payments.
AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it has licensed from us. Over the term of the collaboration, we are eligible to receive an upfront payment, license fees, development milestone payments, regulatory milestone payments and sales milestone payments.
We currently have an integrated assessment of data from multiple LICA medicines and clinical programs which demonstrates that our LICA technology for liver targets can increase potency by 20-30-fold over our non-LICA antisense medicines.
We currently have an integrated assessment of data from multiple LICA medicines and clinical programs that demonstrates that our LICA technology for liver targets can increase potency by 20-30-fold over our non-LICA antisense medicines.
As discussed above, both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and regulations designed to contain or reduce the cost of healthcare, including new models aimed to lower of cost of drugs, promote accessibility, and improve quality of care and initiatives to control the price of prescription drugs using march-in rights under the Bayh-Dole Act. 40 Table of Contents The Foreign Corrupt Practices Act The U.S.
As discussed above, both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and regulations designed to contain or reduce the cost of healthcare, including new models aimed to lower of cost of drugs, promote accessibility, and improve quality of care and initiatives to control the price of prescription drugs using march-in rights under the Bayh-Dole Act. 30 Table of Contents The Foreign Corrupt Practices Act The U.S.
Examples of these include WAINUA, olezarsen and donidalorsen. SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein, which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA.
Examples of these include WAINUA, TRYNGOLZA and donidalorsen. SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein, which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA.
This enables us to leverage our expertise in nucleic acids and modified nucleic acid chemistry with the goal to enhance gene editing’s ability to treat diseases for which there are limited treatment options. Collaborative Arrangements We have established alliances with a cadre of leading global pharmaceutical companies.
This enables us to leverage our expertise in nucleic acids and modified nucleic acid chemistry with the goal to enhance gene editing’s ability to treat diseases for which there are limited treatment options. Collaborative Arrangements We have established alliances with a number of leading global pharmaceutical companies.
On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.
On December 8, 2023, the National Institute of Standards and Technology, or NIST, published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.
For example, third-party payers may limit coverage to specific products on an approved list, or formulary, which might not include all U.S. FDA-approved products for a particular indication. Moreover, a payer's decision to provide coverage for a medicine does not imply that an adequate reimbursement rate will be approved.
For example, third-party payers may limit coverage to specific products on an approved list, or formulary, which might not include all FDA-approved products for a particular indication. Moreover, a payer’s decision to provide coverage for a medicine does not imply that an adequate reimbursement rate will be approved.
On an annual basis, we monitor our pay equity status and market competitiveness, and perform a pay equity analysis that reviews pay equity by gender, ethnicity, race and age. Our 2023 pay equity analysis confirmed we do not have a statistically significant difference in pay for the same or similar work, regardless of gender, ethnicity, race or age.
On an annual basis, we monitor our pay equity status and market competitiveness, and perform a pay equity analysis that reviews pay equity by gender, ethnicity, race and age. Our 2024 pay equity analysis confirmed we do not have a statistically significant difference in pay for the same or similar work, regardless of gender, ethnicity, race or age.
We operate with integrity to help create a better, more sustainable future for all through environmental stewardship and responsible business practices and stakeholder interactions. • Innovation and R&D • Access and Affordability • Patient Advocacy and Engagement • Workplace Culture, Talent Attraction and Development • Diversity, Equity and Inclusion • Social Impact and Community Engagement • Environmental Sustainability • Governance and Integrity • Data Privacy and Cybersecurity Our CR initiatives are driven by our Chief Executive Officer and executive-level CR Steering Committee, or CR Committee.
We operate with integrity to help create a better, more sustainable future for all through environmental stewardship and responsible business practices and stakeholder interactions. • Innovation and R&D • Access and Affordability • Patient Advocacy and Engagement • Workplace Culture, Talent Attraction and Development • Inclusion and Belonging • Social Impact and Community Engagement • Environmental Sustainability • Governance and Integrity • Data Privacy and Cybersecurity Our CR initiatives are driven by our Chief Executive Officer and executive-level CR Steering Committee, or CR Committee.
Additional patent protection designed to protect bepirovirsen in other foreign jurisdictions are being pursued. With GSK’s license of bepirovirsen, we assigned our interest in these patents to GSK. The table below lists some key issued patents protecting bepirovirsen in the U.S. and Europe: Jurisdiction Patent No.
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.
In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2023, we have generated $85 million in payments under this collaboration.
In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through December 31, 2024, we have generated $85 million in payments under this collaboration.
Title Expiration Description of Claims United States 9,315,811 METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION 2032 Methods of treating HAE Europe 2717923 METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION 2032 Compounds for use in treating an inflammatory condition, including HAE United States 10,294,477 COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION 2035 Composition of donidalorsen Europe 3137091 COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION 2035 Composition of donidalorsen Zilganersen and GFAP We believe zilganersen is protected from generic competition in the U.S. until at least 2041.
Title Expiration Description of Claims United States 9,315,811 METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION 2032 Methods of treating HAE Europe 2717923 METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION 2032 Compounds for use in treating an inflammatory condition, including HAE United States 10,294,477 COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION 2035 Composition of donidalorsen Europe 3137091 COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION 2035 Composition of donidalorsen 23 Table of Contents Zilganersen and GFAP We believe zilganersen is protected from generic competition in the U.S. until at least 2041.
Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology.
Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology.
For example, in August 2022, President Biden signed the Inflation Reduction Act of 2022, or the IRA, into law, which includes key actions aimed at reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare and establish a price cap on such drugs, known as the Maximum Fair Price.
For example, in August 2022, the Inflation Reduction Act of 2022, or the IRA, was signed into law, which includes key actions aimed at reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare and establish a price cap on such drugs, known as the Maximum Fair Price.
In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through December 31, 2023, we have generated $60 million in payments under this collaboration. Commercialization Partnerships Otsuka In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize donidalorsen in Europe.
In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through December 31, 2024, we have generated more than $60 million in payments under this collaboration. Commercialization Partnerships Otsuka In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize donidalorsen in Europe.
There is no certainty that all employees and third-party business partners (including our contract research organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions.
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.
Our LICA medicines have also demonstrated consistently favorable safety and tolerability in clinical trials, including in our Phase 3 studies of WAINUA (for ATTRv-PN), olezarsen (for FCS patients) and donidalorsen (for HAE). Emerging Technology Advancements Our recent technology advancements have enabled us to create even more potent medicines amenable to more potential targets and tissue types.
Our LICA medicines have also demonstrated consistently favorable safety and tolerability in clinical trials, including in our Phase 3 studies of WAINUA (for ATTRv-PN), TRYNGOLZA (for FCS patients) and donidalorsen (for HAE). Emerging Technology Advancements Our recent technology advancements have enabled us to create even more potent medicines amenable to new potential targets and tissue types.
Additional patent protection designed to protect pelacarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting pelacarsen in the U.S. and Europe: Jurisdiction Patent No.
Additional patent protection designed to protect pelacarsen in other foreign jurisdictions is being pursued. The table below lists some key issued patents protecting pelacarsen in the U.S. and Europe: Jurisdiction Patent No.
In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.
In response to an October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center, which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.
In addition, we will pay Vect-Horus milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events. Other Agreements Alnylam Pharmaceuticals, Inc.
We will pay Vect-Horus milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events. Other Agreements Alnylam Pharmaceuticals, Inc.
In foreign jurisdictions, the drug approval process is similarly demanding. 37 Table of Contents 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. 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.
Our average employee turnover rate in 2023 was 7 percent, while the turnover for life sciences and medical device companies over this period was 23 percent according to a survey published by Radford – an Aon Hewitt Company. Given the uniqueness and complexity of our technology, it is critical to retain the knowledge and experience of outstanding long service employees.
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.
Given the lack of clarity in laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state authorities. Similar rigid restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries.
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.
Our partners include the following companies, among others: AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone payments. In addition, we are eligible to receive royalties under our partnerships.
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.
As described above, other healthcare laws that may affect our ability to operate include HIPAA, analogous state laws governing the privacy and security of health information, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, and the Physician Payments Sunshine Act.
As described above, other healthcare laws that may affect our operations include HIPAA, analogous state laws governing the privacy and security of health information, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, and the Physician Payments Sunshine Act.
For each program we work on, we choose the approach which demonstrates the best potential product profile for the indication we are pursuing. Our advanced LICA technology is a chemical technology we developed that involves attaching a molecule called a ligand that binds with receptors on the surface of cells in a highly specific manner.
For each program we work on, we choose the approach that demonstrates the best potential product profile for the indication we are pursuing. Our advanced LIgand-Conjugated Antisense, or LICA, technology is a chemical technology we developed that involves attaching a molecule called a ligand that binds with receptors on the surface of cells in a highly specific manner.
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 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 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.
Under the agreement, we are responsible for advancing the two programs through preclinical studies and Roche is responsible for clinical development, manufacturing and commercialization of the medicines if they receive regulatory approval. Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments and sales milestone payments.
Under the agreement, we are responsible for advancing the two programs through preclinical studies and Roche is responsible for clinical development, manufacturing and commercialization of the medicines. Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments and sales milestone payments.
Over the term of the collaboration, we are eligible to receive an upfront payment, license fee, development and approval milestone payments and sales milestone payments. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties ranging from mid to high teens for sales outside the U.S.
Over the term of the collaboration, we are eligible to receive an upfront payment, development and approval milestone payments and sales milestone payments. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.
Commercial Operations We have established sales and marketing capabilities to support our commercial launch of WAINUA in the U.S. and anticipated near-term commercial launches of olezarsen and donidalorsen.
Commercial Operations We have established sales and marketing capabilities to support our commercial launch of WAINUA and TRYNGOLZA in the U.S. and anticipated near-term commercial launch of donidalorsen.
We have also added capabilities to utilize RNA interference, or RNAi, and potentially gene editing in addition to our novel antisense technology, which gives us the potential to deliver medicines to a greater number of people living with serious diseases. 20 Table of Contents Overview of Ionis’ Technology All of the medicines currently in our clinical pipeline use our antisense technology — an innovative platform for discovering first-in-class and/or best-in-class medicines.
We have also added capabilities to utilize small interfering RNA, or siRNA, and potentially gene editing in addition to our novel antisense technology, which gives us the potential to deliver medicines to a greater number of people living with serious diseases. 11 Table of Contents Overview of Ionis’ Technology All of the medicines currently in our clinical pipeline use our antisense technology — an innovative platform for discovering first-in-class and/or best-in-class medicines.
Our antisense technology is also broadly applicable to many additional antisense mechanisms including decreasing toxic RNAs. We also now use small interfering RNA (siRNA) technology, in addition to antisense technology, in the development of new medicines. Like antisense, siRNA medicines target RNA, and can decrease the production of specific proteins involved in disease.
Our antisense technology is also broadly applicable additional antisense mechanisms including decreasing toxic RNAs. We also now use siRNA technology, in addition to antisense technology to develop new medicines. Like antisense, siRNA medicines target RNA, and can decrease the production of specific proteins involved in disease.
Pursuant to our collaboration with GSK, GSK is responsible for any further bepirovirsen drug supply. IONIS-FB-L Rx We supplied API for the IONIS-FB-L Rx Phase 1 and Phase 2 IgAN programs. Pursuant to our collaboration with Roche, Roche is responsible for any further drug supply for the IONIS-FB-L Rx program.
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.
From January 2005 to January 2008 he served as our Vice President, Drug Development Operations and from January 2003 to January 2005, as our Vice President, Development Chemistry and Operations. Mr. Birchler joined Ionis in 1995 as Senior Scientist/Senior Research Associate. Prior to joining Ionis, Mr.
From January 2008 to March 2022, Mr. Birchler served as our Senior Vice President, Drug Development Operations. From January 2005 to January 2008 he served as our Vice President, Drug Development Operations and from January 2003 to January 2005, as our Vice President, Development Chemistry and Operations. Mr. Birchler joined Ionis in 1995 as Senior Scientist/Senior Research Associate.
Vect-Horus In December 2023, we entered into a license agreement with Vect-Horus to provide us with worldwide, exclusive license for a specified number of targets using Vect-Horus’ platform technology ”VECTrans” for systemic delivery of RNA-targeted therapeutics that can cross the blood-brain barrier and address targets in the central nervous system. As a result, we paid Vect-Horus to license its technologies.
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.
Our Technology For three decades through our innovations in science and technology, we have enhanced the profiles of RNA-targeted medicines and pursued new opportunities in emerging areas of genetic medicine. Our recent technology advancements have enabled us to advance programs with the potential for extended dosing and delivery to new tissues, such as muscle.
Our Technology For three decades through our innovations in science and technology, we have enhanced the profiles of RNA-targeted medicines in addition to advancing new approaches in genetic medicine. Our recent technology advancements have enabled us to advance programs with the potential for extended dosing and delivery to new tissues, such as muscle.
Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics.
Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.
Employees and Human Capital As of February 15, 2024, we employed 927 people, the vast majority of whom reside in the U.S. A significant number of our management and professional employees have had prior experience with pharmaceutical, biotechnology or medical product companies.
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.
Birchler was employed by CIBA Vision Corp. and Burroughs Wellcome Pharmaceuticals in various engineering, development and commercial positions. 47 Table of Contents C. FRANK BENNETT, Ph.D. Executive Vice President, Chief Scientific Officer Dr. Bennett has served as Ionis’ Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr. Bennett was promoted to Chief Scientific Officer.
Prior to joining Ionis, Mr. Birchler was employed by CIBA Vision Corp. and Burroughs Wellcome Pharmaceuticals in various engineering, development and commercial positions. C. FRANK BENNETT, Ph.D. Executive Vice President, Chief Scientific Officer Dr. Bennett has served as Ionis’ Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr. Bennett was promoted to Chief Scientific Officer.
In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement.
In addition, we are eligible to receive tiered royalties up to 10 percent on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement.
Geary served as our Executive Vice President, Development and from August 2008 to March 2020, was our Senior Vice President, Development. From August 2003 to August 2008, Dr. Geary served as our Vice President, Preclinical Development. From November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr.
From August 2003 to August 2008, Dr. Geary served as our Vice President, Preclinical Development. From November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr.
We believe antisense technology is well suited to address hyperlipoproteinemia(a) because it specifically targets the RNA that codes for all forms of the Apo(a) molecule. It is estimated that there are more than eight million people living with CVD and elevated levels of Lp(a).
We believe antisense technology is well suited to address hyperlipoproteinemia(a) because it specifically targets the RNA that codes for all forms of the Apo(a) molecule. It is estimated that there are more than eight million people living with CVD and elevated levels of Lp(a). Our partner, Novartis, is responsible for ongoing development and commercialization of pelacarsen worldwide.
In exchange for such rights, Alnylam gave us a technology access fee, participation in fees from Alnylam’s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics.
In exchange for such rights, we are eligible to earn a technology access fee, participate in fees from Alnylam’s partnering programs and earn future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics.
Over the term of the collaboration, we are eligible to receive an upfront payment, a license fee, development milestone payments, regulatory milestone payments and sales milestone payments. In addition, we are also eligible to receive tiered royalties from the high teens to 20 percent on net sales.
Over the term of the collaboration, we are eligible to receive an upfront payment, a license fee, a development milestone payment, regulatory milestone payments and sales milestone payments. We are also eligible to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen .
We are focused on developing a unique and innovative approach to bring our medicines to patients living with serious diseases. We have built core capabilities and a commercial platform with the ability to scale as needed to meet our current and future commercialization needs. We plan to build our field sales teams as we approach each of our launches.
We are focused on developing a unique and innovative approach to bring our medicines to patients living with serious diseases. We have built core capabilities and a commercial platform with the ability to scale as needed to meet our current and future commercialization needs.
WAYLIVRA’s approval in Brazil for FPL was based on efficacy and safety data from the Phase 3 BROADEN study in patients with FPL. Our Innovative Pipeline of Investigational Medicines As a pioneer in RNA-targeted therapeutics, we continue to drive innovation with a leading pipeline in neurology, cardiology and other areas of high patient need.
WAYLIVRA’s approval in Brazil for FPL was based on efficacy and safety data from the Phase 3 BROADEN study in patients with FPL. Our Innovative Late-Stage Pipeline of Ionis-Owned Investigational Medicines As a pioneer in RNA-targeted therapeutics, we continue to drive innovation with a leading pipeline in neurology, cardiology and select diseases of high unmet need.
HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions, including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world, affecting nearly 300 million people and resulting in approximately 900,000 deaths annually.
HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions, including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world, affecting more than 250 million people and resulting in more than 1 million deaths annually.
Gene Editing and Metagenomi Collaboration In 2022, we entered into a collaboration with Metagenomi that leverages our extensive expertise in RNA-targeted therapeutics and Metagenomi’s versatile next-generation gene editing systems to pursue a mix of validated and novel genetic targets with the goal of discovering and developing new drugs.
Gene Editing and Metagenomi Collaboration In 2022, we entered into a collaboration with Metagenomi that leverages our extensive expertise in RNA-targeted therapeutics and Metagenomi’s next-generation gene editing systems to pursue a mix of validated and novel genetic targets with the goal of discovering and developing new drugs. These targets have the potential to expand therapeutic options for patients.
Research and Development Partners AstraZeneca In addition to our collaboration for WAINUA, we have a collaboration with AstraZeneca focused on discovering and developing treatments for cardiovascular, renal and metabolic diseases, which we formed in 2015. Under our collaboration, AstraZeneca has licensed multiple medicines from us.
Cardiovascular, Renal and Metabolic Collaboration We also have a collaboration with AstraZeneca focused on discovering and developing treatments for cardiovascular, renal and metabolic diseases, which we formed in 2015. Under our collaboration, AstraZeneca has licensed multiple medicines from us.
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.
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.
The collaboration includes territory-specific development, commercial and medical affairs cost-sharing provisions. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S.
AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. AstraZeneca is responsible for the vast majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S.
Gene editing is highly complementary and synergistic with RNA-targeted therapeutics. Both platforms rely on the same nucleic acid hybridization principals to precisely target nucleases to either RNA, in the case of RNase H and siRNA drugs, or to DNA in the case of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems.
Both platforms rely on the same nucleic acid hybridization principals to precisely target nucleases to either RNA, in the case of RNase H and siRNA drugs, or to DNA in the case of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems.
Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients. It is estimated that there are approximately 350 patients with FUS-ALS in G7 countries.
Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients.
From inception through December 31, 2023, we have generated more than $425 million in payments under this collaboration, including a milestone payment for the approval of WAINUA in the U.S. and revenue we earned from cost sharing provisions.
From inception through December 31, 2024, we have generated more than $520 million in payments under this collaboration, including milestone payments for the approval of WAINUA in the U.S. and UK, revenue we earned from cost sharing provisions and royalties.
In 2023, we established three strategic CR pillars that we believe are most important to our business: Ionis Corporate Responsibility Strategic Pillars Innovate to improve the lives of people with serious diseases Empowering our employees and communities Operating responsibly and sustainably We innovate across the business and work tirelessly to discover, develop and deliver important new medicines for people with serious diseases.
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.
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.
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.
Additional patent applications to protect WAINUA in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting WAINUA in the U.S. and Europe: Jurisdiction Patent No.
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.
Title Expiration Description of Claims Europe 1622597 MODULATION OF APOLIPOPROTEIN C-III EXPRESSION 2024 Antisense sequence and chemistry of WAYLIVRA Europe 2441449 MODULATION OF APOLIPOPROTEIN C-III EXPRESSION 2024 Antisense compounds that hybridize within the nucleotide region of apo-CIII targeted by WAYLIVRA Europe 3002007 MODULATION OF APOLIPOPROTEIN C-III EXPRESSION 2024 Antisense compounds complementary to an apo-CIII nucleic acid for use in therapy United States 9,157,082 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION 2032 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL 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 Europe 2956176 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS 2034 Apo-CIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or FCS Trademark The name “WAYLIVRA” is protected by trademark in Europe.
Title Expiration Description of Claims United States 9,157,082 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION 2032 Methods of using apo-CIII antisense compounds for reducing pancreatitis and chylomicronemia and increasing HDL 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 Europe 2956176 MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS 2034 Apo-CIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or FCS Trademark The name “WAYLIVRA” is protected by trademark in Europe.
Corporate Responsibility and Environmental, Social and Governance Initiatives We believe operating responsibly and sustainably creates long-term value for our company and our stakeholders. We recognize the importance of Corporate Responsibility, or CR, and Environmental, Social and Governance, or ESG, initiatives as it relates to our business strategy and risk assessment.
Ulefnersen We believe there are no medicines in clinical development for FUS-ALS. Corporate Responsibility Initiatives We believe operating responsibly and sustainably creates long-term value for our company and our stakeholders. We recognize the importance of Corporate Responsibility, or CR, and Environmental, Social and Governance, or ESG, initiatives as it relates to our business strategy and risk assessment.
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.
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.
We will share more details on our updated CR framework, goals and ESG initiatives in our 2023 CR Report, which will be published in April 2024 and available on our website. Nothing in the report or on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K.
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.
The QALSODY NDA and MAA included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study evaluating ascending dose levels, the Phase 3 VALOR study, and the Phase 3 OLE study, as well as 12-month integrated results from the Phase 3 VALOR study and the Phase 3 OLE study.
The 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 safety of SPINRAZA over this extended follow-up period was consistent with previously reported findings. 6 Table of Contents The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized, placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an OLE study for patients with SMA who participated in prior SPINRAZA studies.
The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized, placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an OLE study for patients with SMA who participated in prior SPINRAZA studies.
If the government were to allege or convict us or our executive officers of violating these laws, our business could be harmed. In addition, private individuals can bring similar actions.
If the government alleged, or subsequently settled or convicted us or our executive officers of violating these laws, our business could be harmed. In addition, private individuals can bring similar actions.
Additionally in June 2023, GSK presented durable response data from the Phase 2 B-Sure long-term follow-up study of bepirovirsen in complete responder patients from the Phase 2b B-Clear study of patients with HBV. Bepirovirsen had a favorable safety and tolerability profile supportive of continued development.
Additionally in June 2023, GSK presented durable response data from the Phase 2 B-Sure long-term follow-up study of bepirovirsen in complete responder patients from the Phase 2b B-Clear study of patients with HBV.
O’Neil served as our Executive Vice President, Legal & General Counsel and Chief Compliance Officer. From January 2013 to March 2020, Mr. O’Neil served as our Senior Vice President, Legal and General Counsel. From September 2010 to January 2013, Mr.
From January 2013 to March 2020, Mr. O’Neil served as our Senior Vice President, Legal and General Counsel. From September 2010 to January 2013, Mr. O’Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel.
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.
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.
We have also diversified the approaches we can use in designing our medicines in order to reach more patients with severe diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including our Bicycle LICA technology, siRNA technology and MsPA backbone chemistry.
We have also diversified the approaches we can use in designing our medicines to reach more patients with severe diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including Bicycle technology, siRNA technology and MsPA backbone chemistry. And through our Metagenomi collaboration, we added the potential to use gene editing, which modifies DNA.
Some symptoms can be managed with existing drugs; however, there are no approved disease modifying therapies. In December 2021, we initiated the Phase 1/2 study, HALOS, of ION582 in patients with AS. The study is an open label dose-escalation study enrolling approximately 50 patients designed to assess the safety, tolerability and activity of multiple ascending doses of ION582 administered intrathecally.
Some symptoms can be managed with existing drugs; however, there are no approved disease modifying therapies. 8 Table of Contents We are conducting the ongoing open label Phase 1/2 study, HALOS, of ION582 in patients with AS designed to assess the safety, tolerability and activity of multiple ascending doses of ION582 administered intrathecally.
Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, healthcare reform legislation has strengthened these laws.
Despite our best efforts to comply with applicable law and regulations, due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws.
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 IONIS-FB-L Rx and Factor B We believe IONIS-FB-L Rx is protected from generic competition in the U.S. and Europe until at least 2035.
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.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeFor example: ● Onasemnogene abeparvovec and risdiplam compete with SPINRAZA; ● Taldefgrobep alfa, Evrysdi + GYM329 and NMD670 could compete with SPINRAZA; ● Patisiran, tafamidis, tafamidis meglumine and vutrisiran compete with TEGSEDI and WAINUA; ● Acoramidis, NTLA-2001 and NNC6019-0001 could compete with TEGSEDI and WAINUA; ● ARO-APOC3 and pegozafermin could compete with WAYLIVRA and olezarsen; ● Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor subcutaneous, garadacimab, deucrictibant, NTLA-2002 and STAR-0215 could compete with donidalorsen; ● Olpasiran, zerlasiran, lepodisiran and muvalaplin could compete with pelacarsen; ● NI-005/AP-101 could compete with QALSODY; ● VIR-2218 + PEG-IFN-α, VIR-3434 ± VIR-2218 ± PEG-IFN-α, VIR-2218 + BRII-179, NI-204VIR-2218 + GS-9688 + nivolumab, AB-729, imdusiran + Peg-IFNa-2α + NA, xalnesiran + RG6084 + NA, xalnesiran + NA, xalnesiran + pegIFN + NA, xalnesiran + RO7049389 + NA, xalnesiran + ruzotolimod + NA, RO7049389 + ruzotolimod + NA could complete with bepirovirsen; and ● Budesonide, sparsentan, atrasentan, iptacopan, zigakibart, sibeprenlimab, atacicept, ravulizumab, vemircopan, felzartamab, povetacicept, avacincaptad pegol, pegcetacoplan, tinlarebant, danicopan, GT005, AVD-104 and ANX007 could compete with IONIS-FB-L Rx .
Biggest changeFor example: ● Onasemnogene abeparvovec and risdiplam compete with SPINRAZA; ● Acoramidis, patisiran, tafamidis, tafamidis meglumine and vutrisiran compete with WAINUA; ● Nexiguran ziclumeran, ALXN2220 and NNC6019-0001 could compete with WAINUA; ● Plozasiran, pegozafermin and NST-1024 could compete with TRYNGOLZA and WAYLIVRA; ● Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor subcutaneous, garadacimab, deucrictibant, NTLA-2002 and STAR-0215 could compete with donidalorsen; ● Olpasiran, zerlasiran, lepodisiran and muvalaplin could compete with pelacarsen; ● NI-005/AP-101 could compete with QALSODY; ● VIR-2218, VIR-3434, BRII-179, AB-729, selgantolimod, bersacapavir, REP 2139-Mg and VTP-300 could complete with bepirovirsen; ● Budesonide, sparsentan, atrasentan, iptacopan, zigakibart, sibeprenlimab, atacicept, ravulizumab, vemircopan, felzartamab, telitacicept and povetacicept could compete with sefaxersen; and ● GTX-102, alogabat and NNZ-2591 could compete with ION582.
If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face restrictive regulatory actions or incur other harm to our business. Additionally, the use of artificial intelligence, or AI, based software is increasingly being used in the biopharmaceutical industry.
If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face restrictive regulatory actions or incur other harm to our business. Additionally, artificial intelligence, or AI, based software is increasingly being used in the biopharmaceutical industry.
If any of our medicines in Phase 3 clinical studies do not show sufficient efficacy in patients with the targeted indication, or if such studies are discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.
If any of our medicines in Phase 3 clinical studies do not show sufficient safety and efficacy in patients with the targeted indication, or if such studies are discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.
The call spread transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes or 0.125% Notes or offset any cash payments we are required to make in excess of the principal amount of the converted 0% Notes or 0.125% Notes, as the case may be.
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.
In addition, if we choose to rely on third parties to assist us in commercializing our medicines, we may not be able to enter into collaborations or hire consultants or external service providers on acceptable financial terms, or at all.
If we choose to rely on third parties to assist us in commercializing our medicines, we may not be able to enter into collaborations or hire consultants or external service providers on acceptable financial terms, or at all.
Even if approval is obtained on a medicine that has been designated as an orphan drug, we may lose orphan drug exclusivity if the FDA or EMA determines that the request for designation was materially defective or if we cannot assure sufficient quantity of the applicable medicine to meet the needs of patients with the rare disease or condition, or if a competitor is able to gain approval for the same medicine in a safer or more effective form or that makes a major contribution to patient care.
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.
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. 58 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 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.
Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, wars, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed.
Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, war, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed.
Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material. 59 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 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.
These competitive developments could make our medicines, including our commercial medicines and our medicines in development, obsolete or non-competitive. 51 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.
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.
As of December 31, 2023, we had cash, cash equivalents and short-term investments equal to $2.3 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including our commercial medicines, or to license certain medicines and proprietary technologies, we will need additional funding in the future.
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.
For planning purposes, we estimate and may disclose the timing of a variety of clinical, regulatory and other milestones, such as when we anticipate a certain medicine will enter clinical trials, when we anticipate completing a clinical study, or when we anticipate filing an application for, or obtaining, marketing authorization, or when we or our partners plan to commercially launch a medicine.
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.
Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do or more successfully commercialize their products. There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain geographic markets of products against targets that are also targets of products in our development pipeline.
Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do or more successfully commercialize their products. There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain geographic markets of products against targets that are also targets of products in our development pipeline or of medicines we are commercializing.
It is unclear how future litigation and healthcare reform measures will impact the ACA and our business. 50 Table of Contents 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.
It is unclear how future litigation and healthcare reform measures will impact the ACA and our business. 41 Table of Contents 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.
The degree of market acceptance for our medicines, including our commercial medicines and our medicines in development, depends upon a number of factors, including the: ● receipt and scope of marketing authorizations; ● establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over competing products; ● cost and effectiveness of our medicines compared to other available therapies; ● patient convenience of the dosing regimen for our medicines; and ● reimbursement policies of government and third-party payers.
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.
Since corporate partnering is a significant part of our strategy to fund the advancement and commercialization of our development programs, if any of our collaborative partners fail to fund our collaborative programs, or if we cannot obtain additional partners, we may have to delay or stop progress on our drug development programs.
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.
We will now and continuing into the foreseeable future need to invest significant financial resources to develop capabilities to commercialize medicines on our own and expect that our income in the future will be driven primarily by commercial sales.
We will now and continuing into the foreseeable future need to invest significant financial resources to commercialize medicines on our own and expect that our income in the future will be driven primarily by commercial sales.
If we are not successful in executing this expansion, it could limit our ability to meet our manufacturing requirements and commercial objectives in the future. In addition, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our medicines, called oligonucleotides, on a commercial scale for the systemic administration of a medicine.
If we are not successful in executing this expansion, it could limit our ability to meet our manufacturing requirements and commercial objectives in the future. 44 Table of Contents In addition, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our medicines, called oligonucleotides, on a commercial scale for the systemic administration of a medicine.
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 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.
Use of AI based software may lead to the release of confidential proprietary information, which may impact our ability to realize the benefit of our intellectual property. Risks related to our securities and the global credit markets If we do not progress in our programs as anticipated, the price of our securities could decrease.
Use of AI based software may lead to the release of confidential proprietary information, which may impact our ability to realize the benefit of our intellectual property. 52 Table of Contents Risks related to our securities and the global credit markets If we do not progress in our programs as anticipated, the price of our securities could decrease.
This happened in connection with the conditional marketing approval for WAYLIVRA in the EU, as the EC is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA.
This happened in connection with the conditional marketing approval for WAYLIVRA in the EU, as the European Commission is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA.
In addition, under accelerated approval the FDA is requiring completion of the ongoing Phase 3 trial for QALSODY to confirm the clinical benefit of QALSODY. Moreover, our commercial medicines are chemically similar to each other.
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.
The addition of any of these shares into the public market may have an adverse effect on the price of our securities. 62 Table of Contents In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and 0.125% Notes, the counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments, including over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock.
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 response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.
In response to an October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center that will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.
There are a number of factors that could cause a clinical study to fail or be delayed, including: ● the clinical study may produce negative or inconclusive results; ● regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements; ● we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on subjects or lack of efficacy in the trial; ● we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies; ● enrollment in our clinical studies may be slower than we anticipate; ● we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we rely, may not identify, recruit or train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study; ● the institutional review board for a prospective site might withhold or delay its approval for the study; ● people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the clinical study process or personal issues; ● a clinical study site may deviate from the protocol for the study; ● the cost of our clinical studies may be greater than we anticipate; ● our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and ● the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed. 55 Table of Contents Further, the FDA or other regulatory authorities could request, among other things, additional information or commitments before we can start or continue a clinical study, protocol amendments, increased safety monitoring, additional product labeling information, and post-approval commitments.
There are a number of factors that could cause a clinical study to fail or be delayed, including: ● the clinical study may produce negative or inconclusive results; ● regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements; ● we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on subjects or lack of efficacy in the trial; ● we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies; ● enrollment in our clinical studies may be slower than we anticipate; ● we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we rely, may not identify, recruit or train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study; ● the institutional review board for a prospective site might withhold or delay its approval for the study; ● people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the clinical study process or personal issues; ● a clinical study site may deviate from the protocol for the study; ● the cost of our clinical studies may be greater than we anticipate; ● our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and ● the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed.
As of December 31, 2023, we had an accumulated deficit of approximately $1.8 billion and stockholders’ equity of approximately $0.4 billion. Most of our income has historically come from collaborative arrangements, including commercial revenue from royalties and R&D revenue, with additional income from research grants and the sale or licensing of our patents, as well as interest income.
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.
The same is true of other unused tax attributes, such as tax credits. Under the current U.S. federal income tax law, U.S. federal NOLs generated in taxable years beginning after December 31, 2017 may be carried forward indefinitely, but the deductibility of such U.S. federal NOLs is limited to 80 percent of taxable income.
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.
The potential impacts of climate change may also include increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we currently manufacture most of our research and clinical supplies in a manufacturing facility located in Carlsbad, California.
The potential impacts of climate change may also include increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we currently manufacture most of our research and clinical supplies in a manufacturing facility located in Carlsbad, California, and various regions within California have recently experienced numerous catastrophic wildfires.
Furthermore, we and our partners may not successfully commercialize additional medicines. 49 Table of Contents Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, we may not be able to sell our medicines in that market.
Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, we may not be able to sell our medicines in that market.
As a result, we are potentially exposed to varying natural disaster or extreme weather risks such as hurricanes, tornadoes, fires, droughts, floods, or other events that may result from the impact of climate change on the environment.
As a result, we are potentially exposed to varying natural disaster or extreme weather risks such as fires, hurricanes, tornadoes, droughts, floods, or other events that may result from the impact of climate change on the environment, any of which could impact our business and manufacturing operations.
Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, announcements of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers’ reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines. 61 Table of Contents Broad market factors may materially harm the market price of our common stock irrespective of our operating performance.
Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, financing transactions, announcements of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers’ reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines.
Risks related to pandemics, climate change and other events Our business may be adversely affected by pandemics, climate change, extreme weather events, earthquakes, wars, civil or political unrest, terrorism or other catastrophic events.
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.
Because we have international operations, we are subject to numerous risks associated with international business activities, including : ● compliance with differing or unexpected regulatory requirements for our medicines and foreign employees; ● complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems; ● difficulties in staffing and managing foreign operations; ● in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic partners; ● foreign government taxes, regulations and permit requirements; ● U.S. and foreign government tariffs, trade and export restrictions, price and exchange controls and other regulatory requirements; ● anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions; ● economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, in particular foreign countries or globally; ● fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing business in another country; ● compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad; ● workforce uncertainty in countries where labor unrest is more common than in the U.S.; and ● changes in diplomatic and trade relationships. 63 Table of Contents Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate, including the United Kingdom’s Bribery Act 2010.
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.
While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework. It is unclear whether or how these selected models or similar policy initiatives will impact prescription drug pricing in the future.
While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework. It is unclear whether or how these selected models or similar policy initiatives will impact prescription drug pricing in the future, particularly in light of the recent U.S. presidential and congressional elections.
In 2021, we completed a $632.5 million offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0 million.
In 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.
There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these suppliers will need to increase their scale of production to meet our projected needs for commercial manufacturing. Further, we must continue to improve our manufacturing processes to allow us to reduce our drug costs.
There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these suppliers will need to increase their scale of production to meet our projected needs for commercial manufacturing.
Our business partners face similar risks and any security breach 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 could adversely affect our security posture.
In connection with the issuance of the 0% Notes and 0.125% Notes, we entered into certain call spread transactions covering 10.9 million shares and 6.6 million shares, respectively, that we expect will offset the dilution to holders of common stock upon any conversion of those notes.
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.
Risks related to cybersecurity, social media and artificial intelligence We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks. We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to operate our business.
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.
We also received a Notice of Non-Compliance Withdrawal Letter, or Non-W, from Health Canada for WAYLIVRA in November 2018. 54 Table of Contents The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many reasons, including: ● such authorities may disagree with the design or implementation of our clinical studies; ● we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for any indication; ● such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in countries where the standard of care is potentially different from the U.S.; ● we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks to support approval; ● such authorities may disagree with the interpretation of data from preclinical or clinical studies; ● such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial supplies for our medicines; and ● the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly change in a manner rendering our clinical data insufficient for approval.
The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many reasons, including: ● such authorities may disagree with the design or implementation of our clinical studies; ● we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for any indication; ● such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in countries where the standard of care is potentially different from the U.S.; ● we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks to support approval; ● such authorities may disagree with the interpretation of data from preclinical or clinical studies; ● such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial supplies for our medicines; and ● the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly change in a manner rendering our clinical data insufficient for approval. 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.
In addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue developing the infrastructure required to successfully commercialize our medicines, including the expansion of our manufacturing capabilities. All of these activities will require significant cash.
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, while we do not have any clinical trial sites in Ukraine or Gaza, we do have a limited number of clinical trial sites in Russia and Israel that may be materially impacted by the ongoing wars between Russia and Ukraine and military conflicts in Israel and the surrounding areas, as well as related political or economic responses and counter-responses by various global actors, or collectively, conflicts in Eastern Europe and the Middle East, and could result in difficulties enrolling or completing our clinical trials in such areas on schedule.
In addition, while we do not have any clinical trial sites in Russia, Ukraine or Gaza, we do have a limited number of clinical trial sites in Israel that may be materially impacted by the ongoing military conflicts in Israel and elsewhere in the Middle East and could result in difficulties enrolling or completing our clinical trials in such areas on schedule.
For example, recent events such as the COVID-19 pandemic, the ongoing conflicts in Eastern Europe and the Middle East, and the failure of Silicon Valley Bank have caused disruptions of global financial markets and resulted in increased volatility in the trading price of our common stock. In addition, industry factors may materially harm the market price of our common stock.
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.
There are significant risks involved in building and managing a sales organization, including our ability to hire, retain and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed sales and marketing team.
We will need to establish and maintain effective sales teams for each of our independently launched medicines and there are significant risks involved in managing a sales organization, including our ability to hire, retain and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed sales and marketing team.
The FDA has granted orphan drug designation to olezarsen for the treatment of patients with FCS, to ulefnersen for the treatment of patients with FUS-ALS, and to ION582 for the treatment of patients with Angelman syndrome.
The FDA 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.
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.
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.
Non-compliance could significantly delay or prevent receipt of marketing authorizations for our medicines, including authorizations for our commercial medicines and our medicines in development, or could result in enforcement action after authorization that might limit the commercial success of our medicines, including our commercial medicines and our medicines in development.
We, our partners and our contract manufacturers may not comply or maintain compliance with cGMP, or similar foreign regulations. Non-compliance could significantly delay or prevent receipt of marketing authorizations for our medicines, including authorizations for our commercial medicines and our medicines in development, or could result in enforcement action after authorization that might limit the commercial success of our medicines.
If we cannot continue to secure additional collaborative partners, our revenues could decrease and the development of our medicines could suffer. Our corporate partners are developing and funding many of the medicines in our development pipeline.
However, we may not be able to negotiate favorable collaborative arrangements for these drug programs. If we cannot continue to secure additional collaborative partners, our revenues could decrease and the development of our medicines could suffer. Our corporate partners are developing and funding many of the medicines in our development pipeline.
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.
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.
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.
In addition to receiving funding, we enter into collaborative arrangements with third parties to: ● conduct clinical studies; ● seek and obtain marketing authorizations; and ● manufacture and commercialize our medicines. 47 Table of Contents 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.
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.
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.
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.
To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add key development resources. We plan to continue to rely on additional collaborative arrangements to develop and commercialize some of our unpartnered medicines. However, we may not be able to negotiate favorable collaborative arrangements for these drug programs.
To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add key development resources. While we are now commercializing some of our medicines independently, we still plan to continue to rely on additional collaborative arrangements to develop and commercialize some of our unpartnered medicines.
Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead to additional compliance costs and impact the manner in which we operate our business. 64 Table of Contents Risks related to taxes Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.
Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead to additional compliance costs and impact the manner in which we operate our business.
If any of these occur, it could affect our partner’s commitment to the collaboration with us and could delay or otherwise negatively affect the commercialization of our medicines, including QALSODY, SPINRAZA, WAINUA, bepirovirsen, donidalorsen, IONIS-FB-L Rx and pelacarsen. We may not be able to benefit from orphan drug designation for our medicines.
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.
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.
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.
We manufacture the finished drug product for TEGSEDI, WAINUA and WAYLIVRA at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA and QALSODY. The facilities and the equipment we, our partners and our contract manufacturers use to research, develop and manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace.
The facilities and the equipment we, our partners and our contract manufacturers use to research, develop and manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace.
If any subcommittee cannot reach unanimous agreement on any matter within its respective scope of authority, such matter may be referred to the JSC for resolution.
If any subcommittee cannot reach unanimous agreement on any matter within its respective scope of authority, such matter may be referred to the JSC for resolution. If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize WAINUA.
Although we possess property damage and business interruption insurance coverage, this insurance may not be sufficient to cover all of our potential losses and may not continue to be available to us on acceptable terms, or at all. In addition, our development and commercialization activities could be harmed or delayed by a shutdown of the U.S. government, including the FDA.
Although we possess property damage and business interruption insurance coverage, this insurance may not be sufficient to cover all of our potential losses and may not continue to be available to us on acceptable terms, or at all.
Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition. Risks related to compliance with laws Our operations are subject to extensive legal and regulatory requirements affecting the health care industry.
Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition.
In the past, we have invested in clinical studies of medicines that have not met the primary clinical endpoints in their Phase 3 studies or have been discontinued for other reasons.
As a result, such data should be viewed with caution until the final data are available. In the past, we have invested in clinical studies of medicines that have not met the primary clinical endpoints in their Phase 3 studies or have been discontinued for other reasons.
Nasdaq, and the market for biotechnology companies in particular, have historically experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable.
In addition, industry factors may materially harm the market price of our common stock. Nasdaq, and the market for biotechnology companies in particular, have historically experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of the particular companies affected.
If we continue to engage third parties to assist us in the commercialization of our medicines, our product revenues and profitability may be lower than if we commercialized such medicines ourselves. If the market does not accept our medicines, including our commercial medicines and our medicines in development, we are not likely to generate substantial revenues or become consistently profitable.
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.
If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize WAINUA. 53 Table of Contents If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our products profitably.
If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our products profitably.
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.
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.
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 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.
Any failure to effectively build or maintain the infrastructure required to successfully commercialize our medicines, including our sales, marketing, market access, distribution, and related capabilities, or scale-up our existing support functions, could adversely impact the revenue we generate from our medicines.
Any failure to establish or maintain an effective commercialization infrastructure, including our sales, marketing, market access, distribution, and related capabilities, scale-up our existing support functions, or effectively integrate new functional areas, could adversely affect our ability to successfully commercialize our medicines.
The FDA and EMA have granted orphan drug designation to WAINUA for the treatment of patients with ATTR, to donidalorsen for the treatment of patients with HAE, to TEGSEDI for the treatment of patients with ATTRv-PN, to WAYLIVRA for the treatment of patients with FCS, to tominersen for the treatment of patients with HD, and to ION356 for the treatment of patients with Pelizaeus-Merzbacher disease.
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.
However, the anti-dilutive effect of the convertible note hedges is offset by certain warrant transactions we entered into in connection with the issuance of the 0% Notes and the 0.125% Notes.
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.
If we are unable to establish effective marketing, sales, market access, distribution, and related functions, or enter into agreements with third parties to commercialize our medicines, we may not be able to generate revenue from our medicines.
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.
We rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and WAINUA and drug product for WAYLIVRA. Any delays or disruption to our own or third-party commercial manufacturing capabilities could limit the commercial success of our medicines.
Delays or disruption to our own or third-party commercial manufacturing capabilities for any reason could limit the commercial success of our medicines.
We are dependent on the principal members of our management and scientific staff, and as we move towards commercializing medicines on our own, we will become increasingly dependent on the principal members of our commercial team. We do not have employment agreements with any of our employees that would prevent them from leaving us.
We are dependent on the principal members of our management, scientific and commercial staff. We do not have employment agreements with any of our employees that would prevent them from leaving us. The loss of our key management, scientific or commercial employees might slow the achievement of important research and development or commercial goals.
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.
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.
A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health information, could harm our reputation, delay progress on the development of our medicines, compel us to comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue.
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.
If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including our commercial medicines and our medicines in development, our revenue will be limited. In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of coverage and reimbursement from third-party payers.
In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of coverage and reimbursement from third-party payers.
Likewise, data privacy or security incidents or breaches by employees or others may pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our employees, patients, customers or other business partners may be exposed to unauthorized persons or to the public.
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.
The FDA and other regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
The FDA and other regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability. 43 Table of Contents In addition, when approved, the FDA or a foreign regulatory authority may condition approval on the performance of post-approval clinical studies or patient monitoring, which could be time consuming and expensive.
While we have invested, and continue to invest, in the protection of our data and information technology infrastructure, our efforts may not prevent service interruptions or identify breaches in our systems that could adversely affect our business and operations and result in the loss of critical or sensitive information, which could result in financial, legal, business or reputational harm to us.
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.
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general may not accept or use any of the medicines that we or our partners may develop. For example, TEGSEDI requires periodic blood and urine monitoring and is available in the U.S. only through a risk evaluation and mitigation strategy, or REMS program.
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general may not accept or use any of the medicines that we or our partners may develop.
The global credit and financial markets have experienced extreme volatility and disruptions recently, including as a result of the COVID-19 pandemic, ongoing conflicts in Eastern Europe and the Middle East, and the failure of Silicon Valley Bank.
Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, financial condition or stock price. The global credit and financial markets have experienced extreme volatility and disruptions recently, including as a result of the ongoing conflicts in Eastern Europe and the Middle East.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeDepending on the environment and system, we have implemented and maintain various technical, physical, and organizational measures, processes, standards, and policies designed to manage and mitigate material risks from cybersecurity threats to our critical technologies, including, for example: ● incident response plan; ● disaster recovery/business continuity plans; ● risk assessments; ● encryption of certain data; ● network security and access controls for certain systems; ● physical security; ● asset management, tracking and disposal; ● systems monitoring; and ● employee training.
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.
Our assessment and management of material risks from cybersecurity threats are integrated into the Company’s overall risk management processes. For example, cybersecurity risk is assessed as a component of the Company’s enterprise risk management program.
Our assessment and management of material risks from cybersecurity threats are integrated into the Company’s overall risk management processes. For example, cybersecurity risk is assessed as a component of our enterprise risk management program.
Our cybersecurity incident response plan is designed to escalate cybersecurity incidents, depending on the circumstances, to our senior management team and Audit Committee of the Board of Directors.
Our cybersecurity incident response plan is designed to escalate certain cybersecurity incidents, depending on the circumstances, to our senior management team and Audit Committee of the Board of Directors.
Our Senior Vice President, Information Technology is responsible for hiring appropriate personnel, helping to integrate cybersecurity risk considerations into the Company’s overall risk management strategy, communicating key priorities to relevant personnel, helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security assessments and other security-related reports.
Our Senior Vice President, Information Technology is responsible for hiring appropriate personnel, helping to integrate cybersecurity risk considerations into our overall risk management strategy, communicating key priorities to relevant personnel, helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security assessments and other security-related reports.
In addition, we have developed a process whereby our senior management will evaluate material risks from cybersecurity threats against our overall business objectives and will report certain cybersecurity incidents to the Audit Committee of the Board of Directors, which evaluates our overall enterprise risk.
In addition, we have developed a process whereby our senior management evaluates material risks from cybersecurity threats against our overall business objectives and reports certain cybersecurity incidents to the Audit Committee of the Board of Directors, which evaluates our overall enterprise risk. We use third-party providers to perform various functions throughout our business, such as application providers and hosting companies.
We use third-party service providers to perform various functions throughout our business, such as application providers and hosting companies. We use third-party service providers to assist us from time to time to identify, assess, and manage material risks from cybersecurity threats, including, for example, legal counsel, cybersecurity consultants, cybersecurity software providers, penetration testing firms, and forensic investigators.
We use third-party providers to assist us from time to time in an effort to identify, assess, and manage material risks from cybersecurity threats, including, for example, legal counsel, cybersecurity consultants, cybersecurity software providers, penetration testing firms, and forensic investigators.
Risk Factors in this Annual Report on Form 10-K, including the risk factor titled “ We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks .” Governance Our Board of Directors addresses the Company’s cybersecurity risk management as part of its general oversight function.
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.
As part of such process, the Audit Committee of the Board of Directors receives regular reports from our Senior Vice President, Information Technology concerning the Company’s significant cybersecurity threats and risks and the processes the Company has implemented to address them. 66 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. 58 Table of Contents
The Audit Committee of the Board of Directors is responsible for overseeing the Company’s cybersecurity risk management processes, including oversight and mitigation of risks from cybersecurity threats.
The Audit Committee of the Board of Directors is responsible for overseeing our cybersecurity risk management processes, including oversight and mitigation of risks from cybersecurity threats. The Audit Committee also oversees our internal audit department and management’s internal controls over financial reporting, including with respect to cybersecurity.
These processes are designed to identify, assess, and manage material risks that may result from cybersecurity threats and apply to our critical technologies inclusive of networks, third party hosted services, communications systems, hardware, software, and critical data, including intellectual property and confidential information that is proprietary, strategic, or competitive in nature. 65 Table of Contents Our Information Technology department, led by our Senior Vice President, Information Technology, helps to detect, respond to, and manage cybersecurity threats and risks by monitoring and evaluating our threat environment using various manual and automated tools in certain environments and systems and other methods including, for example: ● analyzing reports of certain threats and actors; ● conducting scans of the threat environment; ● evaluating our and our industry’s risk profile; ● evaluating certain threats reported to us; ● conducting internal and external audits; ● conducting threat assessments for certain internal and external threats; and ● conducting vulnerability assessments to identify vulnerabilities.
These processes are designed to identify, assess, and manage material risks that may result from cybersecurity threats and apply to our critical technologies inclusive of networks, third party hosted services, communications systems, hardware, software, and critical data, including intellectual property and confidential information that is proprietary, strategic, or competitive in nature.
Our cybersecurity risk assessment and management processes are implemented and maintained by our Senior Vice President, Information Technology, who is an information technology professional with healthcare and digital certifications and has over 25 years of relevant experience, and other employees in our Information Technology department who are certified security professionals and have relevant experience.
Our cybersecurity risk assessment and management processes are implemented and maintained by our Senior Vice President, Information Technology, who holds an undergraduate degree in Computer Engineering and has served in information technology and security roles dedicated to the pharmaceutical and biotechnology sector for approximately 18 years, including serving as the Chief Information Officer of two public biopharmaceutical companies.
Removed
For a description of the risks from cybersecurity threats that may materially affect the Company and how they may do so, see our risk factors under Part 1. Item 1A.
Added
The Company maintains a risk-based approach and process designed to identify and oversee cybersecurity risks presented by third parties, including vendors, service providers and other external users of the Company’s systems, as well as the systems of third parties that could materially impact our business if there is a cybersecurity incident affecting those third-party systems.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeProperties As of February 15, 2024, the following are the primary facilities in which we operate: Property Description Location Square Footage Owned or Leased Initial Lease Term End Date Lease Extension Options Laboratory and office space facility 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 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.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeFiscal year ending December 31. 68 Table of Contents COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index, and the Nasdaq Biotechnology Index Dec-18 Dec-19 Dec-20 Dec-21 Dec-22 Dec-23 Ionis Pharmaceuticals, Inc. $ 100.00 $ 111.75 $ 104.59 $ 56.29 $ 69.87 $ 93.58 Nasdaq Composite Index $ 100.00 $ 136.69 $ 198.10 $ 242.03 $ 163.28 $ 236.17 Nasdaq Biotechnology Index $ 100.00 $ 125.11 $ 158.17 $ 158.20 $ 142.19 $ 148.72 ___________ (1) This section is not “soliciting material,” is not deemed “filed” with the SEC, is not subject to the liabilities of Section 18 of the Exchange Act and is not to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, whether made before or after the date hereof and irrespective of any general incorporation language in any such filing.
Biggest changeCOMPARISON 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 .
Item 5. Market for Registrant ’ s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities Market Information and Dividends Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol “IONS.” As of February 15, 2024, there were approximately 476 stockholders of record of our common stock.
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.
The total return assumes reinvestment of dividends. * $100 invested on December 31, 2018 in stock or index, including reinvestment of dividends.
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.
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.
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.
Performance Graph (1) Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 2018 in our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index.
We 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.

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 2023 and 2022 (in millions): Year Ended December 31, 2023 2022 Total revenue $ 787.6 $ 587.4 Total operating expenses $ 1,141.4 $ 997.6 Loss from operations $ (353.7 ) $ (410.2 ) Net loss $ (366.3 ) $ (269.7 ) Cash, cash equivalents and short-term investments $ 2,331.2 $ 1,986.9 69 Table of Contents Revenue Total revenue for 2023 was $787.6 million compared to $587.4 million in 2022 and was comprised of the following (in millions): Year Ended December 31, 2023 2022 Revenue: Commercial revenue: SPINRAZA royalties $ 240.4 $ 242.3 Other commercial revenue: TEGSEDI and WAYLIVRA revenue, net 34.9 30.1 Licensing and other royalty revenue 33.3 31.0 Total other commercial revenue 68.2 61.1 Total commercial revenue 308.6 303.4 R&D revenue: Amortization from upfront payments 125.3 68.6 Milestone payments 100.5 74.0 License fees 116.8 37.0 Other services 10.0 27.6 Collaborative agreement revenue 352.6 207.2 WAINUA joint development revenue 126.4 76.8 Total R&D revenue 479.0 284.0 Total revenue $ 787.6 $ 587.4 Commercial revenues in 2023 were relatively consistent compared to 2022.
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.
The period-over-period fluctuation in our loss on investments was primarily driven by changes in the fair value of our investments in publicly traded and privately held biotechnology companies.
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.
As AstraZeneca is responsible for the majority of the medical affairs and commercial costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling, general and administrative, or SG&A, expenses, respectively.
As AstraZeneca is responsible for the vast majority of the medical affairs and commercial costs in the U.S. and all costs associated with bringing WAINUA to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling, general and administrative, or SG&A, expenses, respectively.
We discuss such risks, uncertainties and other factors throughout this report and specifically under Item 1A of Part I of this report, Risk Factors .
We discuss such risks, uncertainties and other factors throughout this report and specifically under Part I, Item 1A, Risk Factors .
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.
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.
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.
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.
We discuss the estimates we make related to the relative stand-alone selling price of a license in detail above under “Allocating the transaction price to each of our performance obligations.” 78 Table of Contents Estimated Liability for Clinical Development Costs We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world.
We discuss the estimates we make related to the relative stand-alone selling price of a license in detail above under “Allocating the transaction price to each of our performance obligations.” Estimated Liability for Clinical Development Costs We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world.
In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements included in Item 8 of Part II of this report.
In addition, the following review should be read in conjunction with the information presented in our consolidated financial statements and the related notes to our consolidated financial statements included in Part II, Item 8, Financial Statements and Supplementary Data , of this report.
Other Obligations In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2023 for the purchase of services, capital equipment and materials as part of our normal course of business.
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.
The R&D revenue we recognize each period is comprised of several types of revenue, including amortization from upfront payments, milestone payments, license fees and other services that are recognized immediately or amortized over the period in which we satisfy our performance obligation. Each of these types of revenue require us to make various judgements and estimates.
The R&D revenue we recognize each period is comprised of several types of revenue, including amortization from upfront payments, milestone payments, license fees and other services that we recognize immediately or amortize over the period in which we satisfy our performance obligation. Each of these types of revenue require us to make various judgements and estimates.
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details regarding our convertible debt. Income Tax Expense (Benefit) We recorded an income tax expense of $32.3 million for 2023 compared to $11.7 million for 2022.
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.
The following table sets forth information on cost of sales (in millions): Year Ended December 31, 2023 2022 Cost of sales, excluding non-cash compensation expense related to equity awards $ 8.7 $ 13.4 Non-cash compensation expense related to equity awards 0.4 0.7 Total cost of sales $ 9.1 $ 14.1 Research, Development and Patent Expenses Our research, development and patent expenses consist of expenses for drug discovery, drug development, medical affairs, manufacturing and development chemistry and R&D support expenses.
The following table sets forth information on 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.
Overview As noted in our Business Overview in Part I of this report, for three decades, we have invented medicines that we believe bring better futures to people with serious diseases. Today, as a pioneer in RNA-targeted medicines, we continue to drive innovation in RNA therapies. We currently have five marketed medicines: SPINRAZA, QALSODY, WAINUA, TEGSEDI and WAYLIVRA.
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.
The table provides a breakdown of when obligations become due. We provide a more detailed description of the major components of our debt in Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements .
We provide a more detailed description of the major components of our debt in Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements .
The following table sets forth information on research, development and patent expenses (in millions): Year Ended December 31, 2023 2022 Research, development and patent expenses, excluding non-cash compensation expense related to equity awards $ 821.7 $ 759.4 Non-cash compensation expense related to equity awards 77.9 73.7 Total research, development and patent expenses $ 899.6 $ 833.1 71 Table of Contents 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, 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.
Liability Related to Sale of Future Royalties In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively.
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.
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details. Loss on Investments We recorded a $1.9 million and $7.3 million loss on investments for 2023 and 2022, respectively.
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.
We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and other areas of high patient need. We currently have nine medicines in Phase 3 development and multiple additional medicines in early and mid-stage development . Refer to Part I, Item 1, Business , for further details on our business and key developments in our medicines.
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.
Contractual Obligations Payments Due by Period (in millions) (selected balances described below) Total Less than 1 year More than 1 year 1.75% Notes (principal and interest payable) $ 620.3 $ 10.1 $ 610.2 0% Notes (principal payable) 632.5 — 632.5 0.125% Notes (principal and interest payable) 44.6 44.6 — Building mortgage payments (principal and interest payable) 10.2 0.5 9.7 Operating leases 279.5 20.4 259.1 Other obligations (principal and interest payable) 0.8 0.1 0.7 Total $ 1,587.9 $ 75.7 $ 1,512.2 Our contractual obligations consist primarily of our convertible debt.
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.
The following table sets forth information on revenue and expenses under this collaboration (in millions): Year Ended December 31, 2023 2022 WAINUA joint development revenue $ 126.4 $ 76.8 Research and development expenses related to Phase 3 development expenses for WAINUA 150.8 147.1 Medical affairs expenses for WAINUA 4.1 2.0 Commercialization expenses for WAINUA 15.6 2.6 70 Table of Contents Our WAINUA joint development revenue in 2023 includes a $50 million milestone payment from AstraZeneca that we earned when the FDA approved WAINUA for ATTRv-PN in the U.S.
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 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.
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.
Additionally, from our inception through December 31, 2023 , we have borrowed approximately $ 2.7 billion under long-term debt arrangements and received proceeds of $0.5 billion from the sale of future royalties to finance a portion of our operations. Our cash, cash equivalents and short-term investments, working capital and long-term obligations increased from 2022 to 2023.
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.
In addition, we expect to receive commercial revenue from WAINUA royalties beginning in 2024. From our inception through December 31, 2023, we have earned approximately $7.2 billion in revenue. We have also financed our operations through the sale of our equity securities, the issuance of long-term debt and the sale of future royalties.
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.
Item 7. Management ’ s Discussion and Analysis of Financial Condition and Results of Operations This financial review presents our operating results for each of the two years in the period ended December 31, 2023, and our financial condition as of December 31, 2023. Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021.
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.
Further, we internally evaluate the performance of our operations excluding it. Cost of Sales Our cost of sales is comprised of costs related to our commercial revenue, which consisted of manufacturing costs, including certain fixed costs, transportation and freight, indirect overhead costs associated with the manufacturing and distribution of TEGSEDI and WAYLIVRA and certain associated period costs.
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.
Milestone Payments When recognizing revenue related to milestone payments, we typically make the following judgements and estimates: ● Whether a milestone payment is probable (discussed in detail above under “Determining the transaction price, including any variable consideration” ); ● Whether a milestone payment relates to services we are performing or if our partner is performing the services; ● If we are performing services, we recognize revenue over our estimated period of performance in a similar manner to the amortization of upfront payments (discussed above under “R&D Services with Upfront Payments”); and ● Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner achieves the milestone event and we do not have a performance obligation.
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”).
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.
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.
In 2022, we manufactured higher quantities of API to support launch preparation activities for WAINUA, olezarsen and donidalorsen. Refer to the section titled, Manufacturing , in Part I, Item 1, Business , for further details on the activities and types of costs we incur in our manufacturing process.
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.
Net Loss and Net Loss per Share We generated a net loss of $366.3 million for 2023 compared to $269.7 million for 2022. Our net loss increased for 2023 compared to 2022 primarily due to factors discussed in the sections above .
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.
Interest Expense The following table sets forth information on interest expense (in millions): Year Ended December 31, 2023 2022 Convertible senior notes: Non-cash amortization of debt issuance costs $ 5.9 $ 5.3 Interest expense payable in cash 6.4 0.7 Interest on mortgage for primary R&D and manufacturing facilities 0.4 2.1 Total interest expense $ 12.7 $ 8.1 In 2023, we completed a $575.0 million offering of our 1.75% Notes and repurchased $504.4 million in principal of our 0.125% Notes.
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 .
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, 2023 2022 WAINUA $ 115.5 $ 103.9 TEGSEDI and WAYLIVRA 8.1 10.6 Olezarsen 138.3 68.1 Donidalorsen 24.9 14.1 Zilganersen 8.4 5.6 Ulefnersen 10.8 8.4 Other development projects 101.0 123.5 Development overhead expenses 123.3 92.0 Total drug development, excluding non-cash compensation expense related to equity awards 530.3 426.2 Non-cash compensation expense related to equity awards 34.5 31.5 Total drug development expenses $ 564.8 $ 457.7 Our development expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to our advancing late-stage pipeline and full or nearly full enrollment of many of our Phase 3 studies.
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.
WAINUA (Eplontersen) Collaboration with AstraZeneca Our financial results for the years ended December 31, 2023 and 2022 reflected the cost-sharing provisions related to our collaboration with AstraZeneca to develop and commercialize WAINUA for the treatment of ATTR.
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.
The following is a summary of the critical accounting estimates we make with respect to our revenue. 77 Table of Contents Research and development revenue under collaborative agreements We recognize R&D revenue from numerous collaboration agreements. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&D services, and manufacturing services.
Research and development revenue under collaborative agreements We recognize R&D revenue from numerous collaboration agreements. Our collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&D services, and manufacturing services.
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , for further details on this transaction. Other Income (Expense) In 2023, we completed a $575.0 million offering of our 1.75% Notes and used $488.2 million of the net proceeds to repurchase $504.4 million in principal of our 0.125% Notes.
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.
The following table sets forth information on manufacturing and development chemistry expenses (in millions): Year Ended December 31, 2023 2022 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards $ 65.3 $ 76.2 Non-cash compensation expense related to equity awards 8.8 9.9 Total manufacturing and development chemistry expenses $ 74.1 $ 86.1 Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022.
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 medical affairs expenses (in millions): Year Ended December 31, 2023 2022 Medical affairs expenses, excluding non-cash compensation expense related to equity awards $ 19.5 $ 15.9 Non-cash compensation expense related to equity awards 3.4 2.0 Total medical affairs expenses $ 22.9 $ 17.9 Medical affairs expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 as we continued advancing our late-stage pipeline .
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 SG&A expenses (in millions): Year Ended December 31, 2023 2022 Selling, general and administrative expenses, excluding non-cash compensation expense related to equity awards $ 205.1 $ 124.4 Non-cash compensation expense related to equity awards 27.5 25.9 Total selling, general and administrative expenses $ 232.6 $ 150.3 SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022 primarily due to increased expenses related to our go-to-market activities for WAINUA, olezarsen and donidalorsen.
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 .
Results of Operations Below we have included our results of operations for 2023 compared to 2022. Refer to our 2022 Form 10-K for our results of operations for 2022 compared to 2021.
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.
Basic and diluted net loss per share for 2023 were $2.56 compared to $1.90 for 2022. 75 Table of Contents Liquidity and Capital Resources We have financed our operations primarily from research and development collaborative agreements. We also financed our operations from commercial revenue from SPINRAZA and QALSODY royalties and TEGSEDI and WAYLIVRA commercial revenue.
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.
The following table sets forth information on drug discovery expenses (in millions): Year Ended December 31, 2023 2022 Drug discovery expenses, excluding non-cash compensation expense related to equity awards $ 125.6 $ 181.3 Non-cash compensation expense related to equity awards 16.2 16.2 Total drug discovery expenses $ 141.8 $ 197.5 Drug discovery expenses, excluding non-cash compensation expense related to equity awards, decreased in 2023 compared to 2022.
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.
From the time we were founded through December 31, 2023 , we have raised net proceeds of approximately $ 2.1 billion from the sale of our equity securities.
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.
The following table sets forth information on R&D support expenses (in millions): Year Ended December 31, 2023 2022 Personnel costs $ 27.2 $ 21.2 Occupancy 28.7 19.2 Consulting 4.8 0.8 Patent expenses 4.3 4.7 Insurance 3.6 3.8 Computer software and licenses 2.7 1.9 Other 9.7 8.2 Total R&D support expenses, excluding non-cash compensation expense related to equity awards 81.0 59.8 Non-cash compensation expense related to equity awards 15.0 14.1 Total R&D support expenses $ 96.0 $ 73.9 73 Table of Contents R&D support expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022.
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.
We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the various indications we may be studying. Furthermore, as we obtain results from trials, we may elect to discontinue clinical trials for certain drug candidates in certain indications in order to focus our resources on more promising drug candidates or indications.
Furthermore, as we obtain results from trials, we may elect to discontinue clinical trials for certain drug candidates in certain indications in order to focus our resources on more promising drug candidates or indications. Our Phase 1 and Phase 2 programs are clinical research programs that fuel our Phase 3 pipeline.
Although we may characterize a medicine as “in Phase 1” or “in Phase 2,” it does not mean that we are conducting a single, well-defined study with dedicated resources. Instead, we allocate our internal resources on a shared basis across numerous medicines based on each medicine’s particular needs at that time. This means we are constantly shifting resources among medicines.
Instead, we allocate our internal resources on a shared basis across numerous medicines based on each medicine’s particular needs at that time. This means we are constantly shifting resources among medicines.
Our Phase 1 and Phase 2 programs are clinical research programs that fuel our Phase 3 pipeline. When our medicines are in Phase 1 or Phase 2 clinical trials, they are in a dynamic state in which we may adjust the development strategy for each medicine.
When our medicines are in Phase 1 or Phase 2 clinical trials, they are in a dynamic state in which we may adjust the development strategy for each medicine. Although we may characterize a medicine as “in Phase 1” or “in Phase 2,” it does not mean that we are conducting a single, well-defined study with dedicated resources.
As of December 31, 2023, a hypothetical 10 percent increase in our liability for preclinical and clinical development costs would have resulted in an increase in our loss before income tax benefit and accrued liabilities of approximately $10.6 million.
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.
In addition, we recorded a one-time expense of $20 million when we terminated a build-to-suit lease agreement in August 2023. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments , in the Notes to the Consolidated Financial Statements for further details on the lease termination .
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 .
As a result, beginning in the second quarter of 2023, our interest expense related to our convertible notes increased because we began incurring interest expense for our 1.75% Notes. 74 Table of Contents Interest Expense Related to Sale of Future Royalties We recorded $ 68.8 million of interest expense related to the sale of future royalties in 2023 as a result of the Royalty Pharma transaction, in which we sold a minority interest in our future SPINRAZA and pelacarsen royalties to Royalty Pharma for a $500 million upfront payment and $625 million of potential future payments.
These amounts are related to the Royalty Pharma Investments, or Royalty Pharma, transaction, in which we sold a minority interest in our future SPINRAZA and pelacarsen royalties to Royalty Pharma for a $500 million upfront payment and $625 million of potential future payments.
Operating Expenses The following table sets forth information on operating expenses (in millions): Year Ended December 31, 2023 2022 Operating expenses, excluding non-cash compensation expense related to equity awards $ 1,035.7 $ 897.3 Non-cash compensation expense related to equity awards 105.7 100.3 Total operating expenses $ 1,141.4 $ 997.6 Our operating expenses, excluding non-cash compensation expense related to equity awards, increased in 2023 compared to 2022, primarily due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee we paid to Vect-Horus.
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.
Investment Income Investment income for 2023 was $89.0 million compared to $25.3 million for 2022. The increase in investment income was primarily due to an increase in interest rates associated with our investments in debt securities and an increase in our cash available for investment during 2023 compared to 2022.
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.
As discussed above, in 2023, we repurchased $504.4 million in principal of our 0.125% Notes. In the third quarter of 2023, we closed a real estate transaction and received $32.4 million. In the second quarter of 2023, we issued $575.0 million of 1.75% Notes (due in June 2028).
In 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.
To analyze and compare our results of operations to other similar companies, we believe it is important to exclude non-cash compensation expense related to equity awards from our operating expenses. We believe non-cash compensation expense related to equity awards is not indicative of our operating results or cash flows from our operations.
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.
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. 72 Table of Contents 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.
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.
The resulting tax liability is partially offset by the utilization of our R&D tax credits. The increase in income tax expense for 2023 compared to 2022 relates primarily to the impact of the Royalty Pharma transaction. We continue to maintain a full valuation allowance on all our net deferred tax assets.
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.
In the first quarter of 2023, we received an upfront payment of $500.0 million when we entered into a royalty purchase agreement with Royalty Pharma and recorded a corresponding long-term liability related to the sale of future royalties. The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of December 31, 2023.
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.
Removed
Commercial revenue for 2023 included $240 million from SPINRAZA royalties, which were relatively consistent compared to 2022. Our commercial revenue in 2023 also included royalties from QALSODY U.S. product sales. Our R&D revenue increased in 2023 compared to 2022 primarily due to continued success with our pipeline and technology.
Added
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.
Removed
As a result, we earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from our new collaborations with Otsuka, Roche and Novartis.
Added
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.
Removed
Our R&D expenses increased as we advanced our pipeline, which included an increase in the costs associated with our clinical studies as most of our Phase 3 studies were either fully enrolled or approaching full enrollment at the end of 2023. Our SG&A expenses increased due to expenses related to our launch preparation activities for WAINUA, olezarsen and donidalorsen.
Added
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.
Removed
In 2022, we recognized $80 million for licensing Metagenomi’s gene editing technologies.
Added
In 2023, we recognized $15 million in R&D expense for licensing Vect-Horus’ platform technology.
Removed
The increase was primarily related to increased occupancy, personnel and consulting costs to support advancing our pipeline and our technology. In October 2022, we executed a sale and leaseback transaction for our headquarters in Carlsbad, California. As a result, beginning in the fourth quarter of 2022, our occupancy costs increased because we began incurring rent expense for these facilities.
Added
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.
Removed
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.
Added
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.
Removed
Our cash balance increased due to the $500.0 million upfront payment we received in January 2023 from our royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, net proceeds we received from the debt offering in June 2023 and payments from partners.
Added
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.
Removed
These increases were partially offset by the repurchase of $504.4 million in principal of our 0.125% Notes during 2023.
Added
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.
Removed
Gain on Sale of Real Estate In 2022, we closed a purchase and sale agreement with a real estate investor in which we sold and leased back the facilities at our headquarters location in Carlsbad, California for a total purchase price of $263.4 million and recorded a gain of $150.1 million in 2022, resulting in income tax expense of $8.8 million.
Added
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.
Removed
The primary drivers of our income tax expense despite our full year pretax loss relate to the requirement for taxpayers to amortize research and development expenditures over five years pursuant to Internal Revenue Code, or IRC, Section 174 beginning in 2022 under the Tax Cuts and Jobs Act of 2017, or TCJA, and the impact of the royalty purchase agreement with Royalty Pharma, which we reflected as a taxable sale which required us to include the proceeds from the sale, net of currently deductible issuance costs, as taxable income in 2023.
Removed
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 . 76 Table of Contents Royalty Revenue Monetization In January 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively.

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, 2023 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, 2024 and will not be subject to any material risks arising from these changes in the foreseeable future .

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