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What changed in ALNYLAM PHARMACEUTICALS, INC.'s 10-K — 2023 vs 2024

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Paragraph-level year-over-year comparison of ALNYLAM 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.

+846 added−918 removedSource: 10-K (2025-02-13) vs 10-K (2024-02-15)

Top changes in ALNYLAM PHARMACEUTICALS, INC.'s 2024 10-K

846 paragraphs added · 918 removed · 605 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

299 edited+117 added−212 removed115 unchanged
Biggest changeKey 2023 and Recent Highlights TTR Franchise • ONPATTRO (patisiran) and AMVUTTRA (vutrisiran)– hATTR Amyloidosis with Polyneuropathy ◦ Achieved global net product revenues for ONPATTRO and AMVUTTRA for the full year 2023 of $354.5 million and $557.8 million, respectively ◦ Attained over 4,060 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2023 • Vutrisiran – hATTR Amyloidosis with Polyneuropathy ◦ Presented nine-month results from the randomized treatment extension period of the HELIOS-A study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy • Patisiran – ATTR Amyloidosis with Cardiomyopathy ◦ Presented 18-month results from the APOLLO-B Phase 3 study of patisiran in patients with ATTR amyloidosis with cardiomyopathy ◦ Presented new 24-month results from an interim analysis of the open-label extension period of the APOLLO-B Phase 3 study of patisiran in patients with ATTR amyloidosis with cardiomyopathy ◦ Received CRL from the FDA for the sNDA for patisiran for the treatment of the cardiomyopathy of ATTR amyloidosis • Vutrisiran – ATTR Amyloidosis with Cardiomyopathy ◦ Announced updates to the statistical analysis plan for the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy, including updates to the primary and secondary endpoint structure, as well as study exposure; Topline results expected to be available in late June or early July 2024 • ALN-TTRsc04 – ATTR Amyloidosis ◦ Presented positive initial topline results from the Phase 1 study in healthy volunteers Commercial/Late-Stage Pipeline • GIVLAARI (givosiran) – Acute Hepatic Porphyria ◦ Recognized GIVLAARI global net revenue of $219.3 million for the year ended December 31, 2023 7 Table of Con tents ◦ Attained over 650 patients worldwide on commercial GIVLAARI treatment as of December 31, 2023 • OXLUMO (lumasiran) – Primary Hyperoxaluria Type 1 ◦ Recognized OXLUMO global net revenue of $109.8 million for the year ended December 31, 2023 ◦ Attained over 430 patients worldwide on commercial OXLUMO treatment as of December 31, 2023 • Leqvio (inclisiran) – Hypercholesterolemia (in collaboration with Novartis) ◦ Our collaborator, Novartis, continued the launch of Leqvio, with focus on patient on-boarding, removing access hurdles and enhancing medical education • Fitusiran – Hemophilia (in collaboration with Sanofi) ◦ Our collaborator, Sanofi, reported positive data from the Phase 3 ATLAS-OLE study of fitusiran, in development for the treatment of hemophilia A or B, with or without inhibitors, and an NDA submission with the FDA is expected in 2024 Early-Stage and Pre-Clinical Pipeline • Zilebesiran – Hypertension ◦ Completed enrollment in the KARDIA-2 Phase 2 study, evaluating the safety and efficacy of zilebesiran in patients with uncontrolled hypertension when added on top of another antihypertensive medication ◦ Reported positive topline results from the KARDIA-1 Phase 2 dose-ranging study of zilebesiran • ALN-APP – Cerebral Amyloid Angiopathy and Autosomal Dominant Alzheimer’s Disease ◦ Reported positive interim results from the ongoing single ascending dose part of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease ◦ Announced that the FDA has provided clearance to initiate the multiple-dose part (Part B) of the ongoing Phase 1 study of ALN-APP Corporate Highlights • Finance ◦ Ended 2023 with $2.44 billion in cash, cash equivalents and marketable securities • Business ◦ Entered into global strategic collaboration with Roche for the co-development and co-commercialization of zilebesiran 8 Table of Con tents RNAi Therapeutics – A New Class of Innovative Medicines Overview of RNAi Therapeutics In recent years, a tremendous amount of progress has been made in effectively delivering RNAi therapeutics to targeted organs and cells, and we believe Alnylam has been the leader of this advancement.
Biggest changeParallel filings for regulatory approval have also been submitted in all major regions, including Europe and Japan ▪ The FDA has accepted the sNDA and set an action goal date of March 23, 2025, under PDUFA • Nucresiran (formerly ALN-TTRsc04) – ATTR Amyloidosis ◦ Received Orphan Drug Designation from the FDA and announced positive interim Phase 1 data of nucresiran in patients with ATTR amyloidosis Commercial/Late-Stage Pipeline • GIVLAARI (givosiran) – Acute Hepatic Porphyria ◦ Recognized GIVLAARI global net revenue of $255.9 million for the year ended December 31, 2024 • OXLUMO (lumasiran) – Primary Hyperoxaluria Type 1 ◦ Recognized OXLUMO global net revenue of $167.1 million for the year ended December 31, 2024 • Leqvio (inclisiran) – Hypercholesterolemia (in collaboration with Novartis) ◦ Our collaborator, Novartis, continued the launch of Leqvio, with a focus on increasing account and patient adoption, and continuing medical education • Fitusiran – Hemophilia (in collaboration with Sanofi) ◦ Our collaborator, Sanofi, continued to advance fitusiran, an investigational RNAi therapeutic in development for the treatment of hemophilia A and B, with or without inhibitors, and the FDA has set a PDUFA target action date of March 28, 2025 Early-Stage and Preclinical Pipeline • Zilebesiran – Hypertension ◦ Initiated Phase 1 studies of zilebesiran + REVERSIR for hypertension • Mivelsiran – Cerebral Amyloid Angiopathy and Alzheimer’s Disease ◦ Announced positive initial results from the multiple dose portion of the Phase 1 study of mivelsiran in patients with Alzheimer’s disease • ALN-HTT02 – Huntington’s Disease ◦ Initiated a Phase 1 study of ALN-HTT02 in adult patients with Huntington’s disease Corporate Highlights • Finance ◦ Ended 2024 with $2.69 billion in cash, cash equivalents and marketable securities 7 Table of Contents RNAi Therapeutics – A Class of Innovative Medicines Overview of RNAi Therapeutics Alnylam was founded in 2002 to translate the discovery of RNAi into a new class of medicines, which we refer to as RNAi therapeutics.
Additional granted and pending patents in the U.S., Europe and other countries may be available. ** Expiration dates listed here do not account for any patent term extensions, supplemental protection certificates or pediatric extensions that may be available.
Additional granted and pending patents in the U.S., Europe and other countries may be available. ** Expiration dates listed here do not account for any patent term extensions, supplemental protection certificates or pediatric extensions that may be available.
We expect to continue to rely on third-party CMOs for the supply of drug substance and drug product, including ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as other product candidates, for the next several years, including the launch of our additional product candidates and to supply the needs of our collaborators.
We expect to continue to rely on third-party CMOs for the supply of drug substance and drug product, including for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as other product candidates, for the next several years, including the launch of our additional product candidates and to supply the needs of our collaborators.
We are continuing to augment the key components of a global commercial organization with a focus on successfully launching our commercially approved products around the world and preparing for the anticipated commercial launches of additional RNAi therapeutics, assuming successful development and regulatory approval.
We are continuing to augment the key components of our global commercial organization with a focus on successfully launching our commercially approved products around the world and preparing for the anticipated commercial launches of additional RNAi therapeutics, assuming successful development and regulatory approval.
ITEM 1. BUSINESS Overview Alnylam Pharmaceuticals, Inc. (also referred to as Alnylam, we, our or us) is a global commercial-stage biopharmaceutical company developing novel therapeutics based on ribonucleic acid interference, or RNAi. RNAi is a naturally occurring biological pathway within cells for sequence-specific silencing and regulation of gene expression.
ITEM 1. BUSINESS Overview Alnylam Pharmaceuticals, Inc. (also referred to as Alnylam, the Company, we, our or us) is a global commercial-stage biopharmaceutical company developing novel therapeutics based on ribonucleic acid interference, or RNAi. RNAi is a naturally occurring biological pathway within cells for sequence-specific silencing and regulation of gene expression.
Abbreviated Applications and 505(b)(2) Applications Once an NDA is approved, the product covered thereby becomes a listed drug that can, in turn, be relied upon by potential competitors in support of approval of an abbreviated NDA, or ANDA, or a 505(b)(2) application.
Abbreviated Applications and 505(b)(2) Applications Once an NDA is approved, the product covered thereby becomes a reference listed drug that can, in turn, be relied upon by potential competitors in support of approval of an abbreviated NDA, or ANDA, or a 505(b)(2) application.
In July 2023, we entered into a Collaboration and License Agreement, or the Roche Collaboration and License Agreement, with F. Hoffmann-La Roche Ltd. and Genentech, Inc. or, collectively, Roche, pursuant to which we established a worldwide, strategic collaboration for the joint development and commercialization of zilebesiran.
In 2023, we entered into a Collaboration and License Agreement, or the Roche Collaboration and License Agreement, with F. Hoffmann-La Roche Ltd. and Genentech, Inc. or, collectively, Roche, pursuant to which we established a worldwide, strategic collaboration for the joint development and commercialization of zilebesiran.
Reducing APP protein production is expected to reduce the secretion of Aβ peptides that aggregate into extracellular amyloid deposits in AD and CAA and reduce the intraneuronal APP cleavage products that trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in AD.
Reducing APP protein production is expected to reduce the secretion of Aβ peptides that aggregate into extracellular amyloid deposits in AD and CAA and reduce the intraneuronal APP cleavage products that may trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in AD.
In July 2023, we entered into the Roche Collaboration and License Agreement with Roche, pursuant to which we established a worldwide, strategic collaboration for the joint development of pharmaceutical products containing zilebesiran.
In July 2023, we entered into the Roche Collaboration and License Agreement, pursuant to which we and Roche established a worldwide, strategic collaboration for the joint development of pharmaceutical products containing zilebesiran.
As a condition of NDA approval, the FDA may require post-approval evaluations, sometimes referred to as Phase 4 trials, or other surveillance to monitor the drug’s safety or effectiveness and may impose other conditions, including labeling restrictions, such as a Boxed Warning, and/or distribution and use restrictions through a Risk Evaluation and Mitigation Strategy, or REMS, all of which can materially affect the potential market and profitability of the product.
As a condition of NDA approval, the FDA may require post-approval evaluations, including Phase 4 trials, or other surveillance to monitor the drug’s safety or effectiveness and may impose other conditions, including labeling restrictions, such as a Boxed Warning, and/or distribution and use restrictions through a Risk Evaluation and Mitigation Strategy, or REMS, all of which can materially affect the potential market and profitability of the product.
For more information regarding the Roche Collaboration and License Agreement, including the ongoing or expected financial and accounting impact on our business, please see Note 4, Net Revenues from Collaborations, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K. Novartis.
For more information regarding the Roche Collaboration and License Agreement, including the ongoing or expected financial and accounting impact on our business, please see Note 4, Net Revenues from Collaborations, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K. Regeneron.
For more information regarding the Regeneron Collaboration, including the ongoing or expected financial and accounting impact on our business, please see Note 4, Net Revenues from Collaborations, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K. Roche .
For more information regarding the Regeneron Collaboration, including the ongoing or expected financial and accounting impact on our business, please see Note 4, Net Revenues from Collaborations, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K. Sanofi.
We expect these collaborations to provide us with financial support in the form of upfront cash payments, license fees, equity investments, research, development, and sales and marketing support and/or funding, milestone payments and/or royalties or profit sharing based on sales of RNAi therapeutics. Below is a brief description of our key collaborations. Product Collaborations Regeneron.
We expect these collaborations to provide us with financial support in the form of upfront cash payments, license fees, equity investments, research, development, and sales and marketing support and/or funding, milestone payments and/or royalties or profit sharing based on sales of RNAi therapeutics. Below is a brief description of our key collaborations. Product Collaborations Roche .
Post-Approval Controls The holder of a marketing authorisation must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.
Post-Approval Controls The holder of a marketing authorization must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.
All new MAAs must include a risk management plan, or RMP, describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product. The regulatory authorities may also impose specific obligations as a condition of the marketing authorisation.
All new MAAs must include a risk management plan, or RMP, describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product. The regulatory authorities may also impose specific obligations as a condition of the marketing authorization.
Leqvio (inclisiran), our fifth product, is being developed and commercialized by our collaborator Novartis AG, or Novartis, and has received marketing authorization from the European Commission, or EC, for the treatment of adults with hypercholesterolemia or mixed dyslipidemia and from the FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, or HeFH, or clinical atherosclerotic cardiovascular disease, or ASCVD, who require additional lowering of low-density lipoprotein cholesterol, or LDL-C.
Leqvio (inclisiran), our fifth product, is being developed and commercialized by our collaborator Novartis AG, or Novartis, and has received marketing authorization from the European Commission, or EC, for the treatment of adults with hypercholesterolemia or mixed dyslipidemia and from the FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, or HeFH, or clinical atherosclerotic cardiovascular 5 Table of Contents disease, or ASCVD, who require additional lowering of low-density lipoprotein cholesterol, or LDL-C.
Similarly, our board of directors regularly provides input on important decisions relating to these matters, including with respect to employee compensation and benefits, talent retention and development. Corporate Information Alnylam Pharmaceuticals, Inc. is a Delaware corporation that was formed in May 2003.
Similarly, our board of directors regularly provides input on important decisions relating to these matters, including with respect to employee compensation and benefits, succession planning, talent retention and development. Corporate Information Alnylam Pharmaceuticals, Inc. is a Delaware corporation that was formed in May 2003.
In September 2023, we reported positive topline results from KARDIA-1, with zilebesiran meeting the primary endpoint and demonstrating greater than 15mmHg reduction of systolic blood pressure at three months of treatment compared to placebo at the two highest single doses evaluated.
In September 2023, we reported positive topline results from the KARDIA-1 clinical trial, with zilebesiran meeting the primary endpoint and demonstrating greater than 15mmHg reduction of systolic blood pressure at three months of treatment compared to placebo at the two highest single doses evaluated.
In 2012, we established a manufacturing facility in Cambridge, Massachusetts and have developed GMP capabilities and processes for the manufacture of patisiran formulated bulk drug product for late-stage clinical trial use and commercial supply. We expect to continue to manufacture commercial supply for formulated bulk drug product for ONPATTRO in this facility for the foreseeable future.
In 2012, we established a manufacturing facility in Cambridge, Massachusetts and have developed GMP capabilities and processes for the manufacture of patisiran formulated bulk drug product for late-stage clinical trial use and commercial supply. We expect to continue to manufacture commercial supply for formulated bulk drug product for ONPATTRO in this facility for the near future.
In December 2020, we began GMP operations, and we believe this facility will enable us to initiate manufacturing for multiple new early-stage programs over the next few years, as well as provide us the manufacturing capabilities to support our late-stage and select commercial programs in the future.
In December 2020, we began GMP operations, and we believe this facility will enable us to initiate manufacturing for multiple new early-stage programs over the next few years, as well as provide us the manufacturing capabilities to support select late-stage clinical and commercial programs in the future.
Our focus is on clinical indications where there is a high unmet need, a genetically validated target, early biomarkers for the assessment of clinical activity in Phase 1 clinical studies, and a definable path for drug development, regulatory approval, patient access and commercialization.
Our focus is on clinical indications where there is a high unmet need, a genetically validated target, early biomarkers for the assessment of clinical activity in Phase 1 clinical trials, and a definable path for drug development, regulatory approval, patient access and commercialization.
Such risk-minimization measures or post-authorisation obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorisation safety studies. RMPs and PSURs are routinely available to third parties requesting access, subject to limited redactions.
Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies. RMPs and PSURs are routinely available to third parties requesting access, subject to limited redactions.
The complete response letter describes the deficiencies that the FDA has identified in an application and may recommend actions that the applicant can take to address the deficiencies. Such actions may include, among other things, conducting additional safety or efficacy studies.
T he complete response letter describes the deficiencies that the FDA has identified in an application and may recommend actions that the applicant can take to address the deficiencies. Such actions may include, among other things, conducting additional safety or efficacy studies.
Sanofi presented positive results from the ATLAS-A/B and ATLAS-INH Phase 3 studies of fitusiran in December 2021, and in July 2022, Sanofi presented positive results from the Phase 3 ATLAS-PPX study evaluating the efficacy and safety of once-monthly fitusiran (80 mg) in adults and adolescents with severe hemophilia A or B who were previously treated with prior factor or bypassing agent prophylaxis.
Sanofi presented positive results from the ATLAS-A/B and ATLAS-INH Phase 3 clinical trials of fitusiran in December 2021, and in July 2022, Sanofi presented positive results from the Phase 3 ATLAS-PPX study evaluating the efficacy and safety of once-monthly fitusiran (80 mg) in adults and adolescents with severe hemophilia A or B who were previously treated with prior factor or bypassing agent prophylaxis.
In 2023, Sanofi presented positive results from the ATLAS-OLE Phase 3 extension study of fitusiran, demonstrating a substantially improved safety profile and consistent bleed protection in people with hemophilia A or B, with or without inhibitors. Specifically, the risk of thrombosis was reduced, with rates comparable to those reported in the general hemophilia population.
In 2023, Sanofi presented positive results from the ATLAS-OLE Phase 3 extension clinical trial of fitusiran, demonstrating a substantially improved safety profile and consistent bleed protection in people with hemophilia A or B, with or without inhibitors. Specifically, the risk of thrombosis was reduced, with rates comparable to those reported in the general hemophilia population.
Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing daily oral medications and daily peak and trough effects, resulting in inconsistent blood pressure control and an increased risk for stroke, heart attack and premature death.
Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing daily oral medications and daily peak and trough effects, resulting 14 Table of Contents in inconsistent blood pressure control and an increased risk for stroke, heart attack and premature death.
For novel drug products or drug products that present difficult questions of safety or efficacy, the FDA may refer the application to an advisory committee, which is typically in the form of a panel that includes independent clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved.
For novel drug products or drug products that present difficult questions of safety or efficacy, the FDA may refer the application to an advisory committee, which is typically in the form of a panel that includes independent clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.
The FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada. In response, authorities in Canada have passed rules designed to safeguard the Canadian drug supply from shortages.
The FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada. 30 Table of Contents In response, authorities in Canada have passed rules designed to safeguard the Canadian drug supply from shortages.
Foreign Corrupt Practices Act of 1977, as amended, or FCPA, and similar anti-bribery laws in non-U.S. jurisdictions generally prohibit companies and their officers, directors, employees and intermediaries from offering or making improper payments to non-U.S. officials for the purpose of obtaining or retaining business.
Foreign Corrupt Practices Act of 1977, as amended, or FCPA, and similar anti-bribery laws in non-U.S. jurisdictions generally prohibit companies and their officers, directors, employees and intermediaries from offering or making 31 Table of Contents improper payments to non-U.S. officials for the purpose of obtaining or retaining business.
For such products, the results of appropriate pre-clinical studies or clinical trials must be provided, and guidelines from the EMA detail the type of supplementary data to be provided for different types of biological product.
For such products, the results of appropriate preclinical studies or clinical trials must be provided, and guidelines from the EMA detail the type of supplementary data to be provided for different types of biological product.
Orphan medicinal product designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following marketing authorisation.
Orphan medicinal product designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following marketing authorization.
We believe that the current supply capacity we have established externally, together with the internal capabilities we developed to support pre-clinical development, our existing facility for patisiran formulated bulk drug product and our Norton manufacturing facility, will be sufficient to meet our and our collaborators’ anticipated needs for the next several years.
We believe that the current supply capacity we have established externally, together with the internal capabilities we developed to support preclinical development, our existing facility for patisiran formulated bulk drug product and our Norton manufacturing facility, will be sufficient to meet our and our collaborators’ anticipated needs for the next several years.
Competition for Our Business in General The competition we face can be grouped into three broad categories: • other companies working to develop RNAi and microRNA therapeutic products; • companies developing technology known as antisense, which, like RNAi, attempts to silence the activity of specific genes by targeting the mRNAs copied from them; and • marketed products and development programs for therapeutics that treat the same diseases for which we are marketing products or developing treatments.
The competition we face can be grouped into three broad categories: • other companies working to develop RNAi and microRNA therapeutic products; • companies developing technology known as antisense, which, like RNAi, attempts to silence the activity of specific genes by targeting the mRNAs copied from them; and • marketed products and development programs for therapeutics that treat the same diseases for which we are marketing products or developing treatments.
There are several approved products for the treatment of hemophilia, including: Factor VIII replacement products, Factor IX replacement products, factor replacement products with extended half-lives, and a bispecific antibody that mimicks Factor VIII.
Hemophilia. There are several approved products for the treatment of hemophilia, including: Factor VIII replacement products, Factor IX replacement products, factor replacement products with extended half-lives, and a bispecific antibody that mimics Factor VIII.
Key provisions of the IRA include the following, among others: • The IRA requires manufacturers to pay rebates for Medicare Part B and Part D drugs whose price increases exceed inflation; 33 Table of Con tents • The IRA eliminates the “donut hole” under Medicare Part D beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and requiring manufacturers to subsidize, through a newly established manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs below the out-of-pocket maximum and 20% once the out-of-pocket maximum has been reached. • The IRA delays the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries. • The IRA directs allows the Centers for Medicare and Medicaid Services, or CMS, to engage in price-capped negotiation for certain Medicare Part B and Part D products.
Key provisions of the IRA include the following, among others: • The IRA requires manufacturers to pay rebates for Medicare Part B and Part D drugs whose net price increases exceed inflation; • The IRA eliminates the “donut hole” under Medicare Part D beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and requiring manufacturers to subsidize, through a manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs below the out-of-pocket maximum and 20% once the out-of-pocket maximum has been reached. • The IRA delays the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries. • The IRA directs allows the Centers for Medicare and Medicaid Services, or CMS, to engage in price-capped negotiation for certain Medicare Part B and Part D products.
Manufacturing Medicinal products may only be manufactured in the EU, or imported into the EU from another country, by the holder of a manufacturing authorisation from the competent national authority.
Manufacturing Medicinal products may only be manufactured in the EU, or imported into the EU from another country, by the holder of a manufacturing authorization from the competent national authority.
In response to this directive, the HHS Secretary announced, and the Center for Medicare and Medicaid Innovation is developing, new models intended to lower drug costs under Medicare and Medicaid, including designing new payment methods for drugs approved under accelerated approval, in consultation with the FDA, to encourage timely confirmatory trial completion and improve access to post-market safety and efficacy data with the goal of reducing Medicare spending on drugs that have no confirmed clinical benefit; creating a list of generic drugs for which the out-of-pocket Part D costs will be capped at $2 a month per drug, and establishing new approach for administering outcomes-based agreements for cell and gene therapies.
For instance, the Center for Medicare and Medicaid Innovation is developing, new models intended to lower drug costs under Medicare and Medicaid, including designing new payment methods for drugs approved under accelerated approval, in consultation with the FDA, to encourage timely confirmatory trial completion and improve access to post-market safety and efficacy data with the goal of reducing Medicare spending on drugs that have no confirmed clinical benefit; creating a list of generic drugs for which the out-of-pocket Part D costs will be capped at $2 a month per drug; and establishing new approach for administering outcomes-based agreements for cell and gene therapies.
We monitor the capacity availability for the manufacture of drug substance and drug product and believe that our supply agreements with our CMOs and the lead times for new supply agreements would allow us to access additional capacity to meet our and our collaborators’ currently anticipated needs.
We monitor the capacity availability for the manufacture of drug substance and drug product and believe that our supply agreements with our CMOs and the lead times for new supply agreements would allow us to access additional capacity to meet our and our 35 Table of Contents collaborators’ currently anticipated needs.
Any actual bonus payout is based solely on our performance against our corporate goals in the case of executive officers and is based on a combination of individual performance and corporate performance (or regional or national commercial performance metrics, as applicable) in the case of all other employees.
Any actual bonus payout is based solely on our performance against our corporate goals in the case of our executive leadership team and is based on a combination of individual performance and corporate performance (or regional or national commercial performance metrics, as applicable) in the case of all other employees.
AGT is the most upstream precursor in the renin-angiotensin-aldosterone system, a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established 16 Table of Con tents anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.
AGT is the most upstream precursor in the renin-angiotensin-aldosterone system, a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.
In addition, we intend to disclose on our web site any amendments to, or waivers from, our code of business conduct and ethics that are required to be disclosed pursuant to SEC rules. The SEC maintains an Internet website that contains reports, proxy and information statements, and other information regarding Alnylam and other issuers that file electronically with the SEC.
We intend to disclose on our website any amendments to, or waivers from, our code of business conduct and ethics that are required to be disclosed pursuant to SEC rules. The SEC maintains an Internet website that contains reports, proxy and information statements, and other information regarding Alnylam and other issuers that file electronically with the SEC.
However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically takes a year or more.
However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically may take a year or more.
As part of our Alnylam P 5 x25 strategy, we have multiple drivers of future growth, including the development of transformative medicines to treat prevalent disease. In addition to Leqvio, we are advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, in development for the treatment of hypertension.
In addition to our marketed products, as part of our Alnylam P 5 x25 strategy, we have multiple drivers of future growth, including the development of transformative medicines to treat prevalent disease. In addition to Leqvio, we are advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen in development for the treatment of hypertension.
FDA approval of an NDA is required before commercial distribution of a new drug may begin in the U.S. An NDA must include the results of extensive nonclinical, clinical and other testing, as described above, a compilation of data relating to the product’s pharmacology, CMC information, proposed labeling and other information.
FDA approval of an NDA is required before commercial distribution of a new drug may begin in the U.S. An NDA must include the results of extensive nonclinical, clinical and other testing, as described above, a compilation of data relating to the product’s pharmacology, information related to the product’s chemistry and manufacturing, proposed labeling and other information.
In addition to the federal anti-kickback law, many states have their own laws that are analogous to the federal anti-kickback law, but may apply regardless of whether any federal or state healthcare program business is involved.
In addition to the Federal Anti-Kickback Statute, many states have their own laws that are analogous to the Federal Anti-Kickback Statute, but may apply regardless of whether any state healthcare program business is involved.
We also make available on our website the charters of our audit committee, people, culture and compensation committee, nominating and corporate governance committee, and science and technology committee, as well as our corporate governance guidelines and our code of business conduct and ethics.
We also make available on our website the charters of our audit committee, people, culture and compensation committee, nominating and corporate governance committee, and science and technology committee, as well as our corporate governance guidelines and 37 Table of Contents our code of business conduct and ethics.
As of October 2016, the EMA began publishing clinical data (including clinical study reports) on the agency’s website following the grant, denial or withdrawal of an MAA for a centralised marketing authorisation, subject to procedures for limited redactions and protection against unfair commercial use.
As of October 2016, the EMA began publishing clinical data (including clinical study reports) on the agency’s website following the grant, denial or withdrawal of an MAA for a centralized marketing authorization, subject to procedures for limited redactions and protection against unfair commercial use.
Leqvio (inclisiran) — Hypercholesterolemia Our RNAi therapeutic Leqvio, developed and commercialized by our collaborator, Novartis, is the first and only siRNA therapy (or RNAi therapeutic) to lower LDL-C, and is the first RNAi therapeutic approved for a highly prevalent disease.
Our RNAi therapeutic Leqvio, developed and commercialized by our collaborator, Novartis, is the first and only siRNA therapy (or RNAi therapeutic) to lower LDL-C, and is the first RNAi therapeutic approved for a prevalent disease.
None of our employees in the U.S. are represented by a labor union or covered by collective bargaining agreements, and we believe our relationship with our employees is good. During 2023, we enhanced our capabilities by adding approximately 100 new full-time employees.
None of our employees in the U.S. are represented by a labor union or covered by collective bargaining agreements, and we believe our relationship with our employees is good. During 2024, we enhanced our capabilities by adding approximately 200 new full-time employees.
For 36 Table of Con tents medicines that do not fall within these categories, an applicant may voluntarily submit an application for a centralized marketing authorisation to the EMA, as long as the CHMP agrees that (i) the medicine concerned contains a new active substance, (ii) the medicine is a significant therapeutic, scientific, or technical innovation, or (iii) the authorisation of the medicine under the centralized procedure would be in the interest of public health.
For medicines that do not fall within these categories, an applicant may voluntarily submit an application for a centralized marketing authorization to the EMA, as long as the CHMP agrees that (i) the medicine concerned contains a new active substance, (ii) the medicine is a significant therapeutic, scientific, or technical innovation, or (iii) the authorization of the medicine under the centralized procedure would be in the interest of public health.
We face a broad spectrum of current and potential competitors, ranging from very large, global pharmaceutical companies with significant resources, to biotechnology companies with resources and expertise comparable to our own, to smaller biotechnology companies with fewer resources and less expertise than those we currently possess.
For our marketed and discovery assets, we face a broad spectrum of current and potential competitors, ranging from very large, global pharmaceutical companies with significant resources, to biotechnology companies with resources and expertise comparable to our own, to smaller biotechnology companies with fewer resources and less expertise than those we currently possess.
Various laws, regulations and recommendations relating to safe working conditions, laboratory practices, the experimental use of animals, and the purchase, storage, movement, import, export and use and disposal of hazardous or potentially hazardous 35 Table of Con tents substances are or may be applicable to our activities.
Various laws, regulations and recommendations relating to safe working conditions, laboratory practices, the experimental use of animals, and the purchase, storage, movement, import, export and use and disposal of hazardous or potentially hazardous substances are or may be applicable to our activities.
Based on our expertise in RNAi therapeutics and broad intellectual property estate, we have formed collaborations with leading pharmaceutical and life sciences companies to support our development and commercialization efforts, including Regeneron, Roche, Novartis (which acquired our collaborator The Medicines Company, or MDCO, in 2020), Sanofi, Vir Biotechnology, Inc., or Vir, Dicerna Pharmaceuticals, Inc.
Based on our expertise in RNAi therapeutics and broad intellectual property estate, we have formed collaborations with leading pharmaceutical and life sciences companies to support our development and commercialization efforts, including Roche, Regeneron, Sanofi, and Novartis (which acquired our collaborator The Medicines Company, or MDCO, in 2020) .
However, if, under certain situations, the agreed initial PSP included nonclinical and/or pediatric clinical studies that were expected to have been completed before submission of the NDA, BLA, or supplement, failure of the sponsor to complete these agreed studies in a timely manner may result in a refusal to file.
If, under certain situations, the agreed initial PSP included nonclinical and/or pediatric clinical studies that were expected to have been completed before submission 27 Table of Contents of the NDA or supplement, failure of the sponsor to complete these agreed studies in a timely manner may result in a refusal to file.
For purposes of 30 Table of Con tents large molecule drugs, the FDA defines “same drug” as a drug that contains the same principal molecular structural features, but not necessarily all of the same structural features, and is intended for the same use as the previously approved drug.
For purposes of large molecule drugs, the FDA defines “same drug” as a drug that contains the same principal molecular structural features, but not necessarily all of the same structural features, and is intended for the same use as the previously approved drug.
In connection with our EMA approval on September 15, 2022, the EMA granted AMVUTTRA Marketing Exclusivity and ODE until September 15, 2032. 23 Table of Con tents GIVLAARI Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam 8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9133461 United States Compositions of Matter & Methods of Use 5/14/2033 Alnylam/Icahn School of Medicine at Mount Sinai 9150605 United States Compositions of Matter 8/28/2025 Ionis Pharmaceuticals 9631193 United States Methods of Use 3/15/2033 Alnylam/Icahn School of Medicine at Mount Sinai 9708615 United States Compositions of Matter & Methods of Use 3/8/2024 Alnylam 10119143 United States Compositions of Matter & Methods of Use 10/3/2034 Alnylam/Icahn School of Medicine at Mount Sinai 10125364 United States Compositions of Matter & Methods of Use 3/15/2033 Alnylam/Icahn School of Medicine at Mount Sinai 10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam 10273477 United States Compositions of Matter 3/8/2024 Alnylam 2836595 Europe Compositions of Matter & Methods of Use 4/10/2033 Alnylam/Icahn School of Medicine at Mount Sinai 2336317 Europe Compositions of Matter 6/14/2024 Alnylam _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
In connection with our EMA approval on September 15, 2022, the EMA granted AMVUTTRA marketing exclusivity and ODE until September 15, 2032. 20 Table of Contents GIVLAARI Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam 8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam 9133461 United States Compositions of Matter & Methods of Use 5/14/2033 Alnylam/Icahn School of Medicine at Mount Sinai 9150605 United States Compositions of Matter 8/28/2025 Ionis Pharmaceuticals 9631193 United States Methods of Use 3/15/2033 Alnylam/Icahn School of Medicine at Mount Sinai 10119143 United States Compositions of Matter & Methods of Use 10/3/2034 Alnylam/Icahn School of Medicine at Mount Sinai 10125364 United States Compositions of Matter & Methods of Use 3/15/2033 Alnylam/Icahn School of Medicine at Mount Sinai 10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam 2836595 Europe Compositions of Matter & Methods of Use 4/10/2033 Alnylam/Icahn School of Medicine at Mount Sinai _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
The Federal Food, Drug, and Cosmetic Act, or FDCA, and other federal and state statutes and regulations govern, among other things, the research, development, testing, approval, manufacture, storage, record keeping, reporting, labeling, marketing and distribution of drug products.
The Federal Food, Drug, and Cosmetic Act, or FDCA, and other federal and state statutes and regulations govern, among other things, the research, development, testing, approval, manufacture, storage, record keeping, reporting, labeling, advertising, promotion, marketing, import, export, and distribution of drug products.
Nevertheless, Recordati S.p.A has two products, PANHEMATIN and NORMOSANG, that are approved in the U.S. and EU, respectively, for the treatment of acute porphyria attacks, and some physicians may prescribe these therapies off-label for the prophylactic treatment of AHP. Primary Hyperoxaluria.
GIVLAARI is currently the only approved therapy for prophylactic treatment of AHP in the U.S. and EU. Nevertheless, Recordati S.p.A has two products, PANHEMATIN and NORMOSANG, that are approved in the U.S. and EU, respectively, for the treatment of acute porphyria attacks, and some physicians may prescribe these therapies off-label for the prophylactic treatment of AHP. Primary Hyperoxaluria.
Under the original agreement, Ionis licensed to us its patent estate related to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi products in exchange for a previously disclosed technology access fee, participation in fees for our collaboration programs and future milestone and royalty payments from us for programs that incorporate Ionis’ intellectual property.
Under the original agreement, Ionis licensed to us its patent estate related to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi products in exchange for a technology access fee, participation in fees for our collaboration programs and future milestone and royalty payments from us for programs that 18 Table of Contents incorporate Ionis’ intellectual property.
It is possible that changes in insurer policies regarding co-pay coupons and patient assistance programs and/or the introduction and enactment of new legislation or regulatory action could restrict or otherwise negatively affect these co-pay coupon programs and patient support programs, which could result in fewer patients using affected products, and therefore could have a material adverse effect on pharmaceutical manufacturers’ sales, business, and financial condition.
It is possible that further changes in insurer policies regarding co-pay coupons and patient assistance programs and/or new legislation or regulatory action, or decisions regarding enforcement of such action, could restrict or otherwise negatively affect these co-pay coupon programs and patient support programs, which could result in fewer patients using affected products, and therefore could have a material adverse effect on pharmaceutical manufacturers’ sales, business, and financial condition.
Annual cash bonus targets are based on grade level and are communicated as a percentage of base salary. Equity compensation grants are made based on grade level, geography, and performance.
Annual cash bonus targets are based on grade level and are communicated as a percentage of base salary. Equity compensation awards are based on grade level, geography, and performance.
Comprised of components such as risk assessment and monitoring; policies, procedures, and guidance; training and communications; dedicated resources; and systems and processes supporting activities such as third party relationships and investigations and remediation; our program and related controls are built to enhance our business processes, structures, and controls across our global operations, and to empower ethical decision making.
Comprised of components such as risk assessment and monitoring; policies, procedures, and guidance; training and communications; dedicated resources; and systems and processes supporting activities such as third party engagements and investigations and remediation, and the Company’s enterprise risk management program; our program and related controls are built to enhance our business processes, structures, and controls across our global operations, and to empower ethical decision making.
During this period, the competent authorities may not accept or approve any similar medicinal product for the same therapeutic indication, unless (i) the second medicinal product is safer, more effective or otherwise clinically superior to the authorised orphan product; (ii) the marketing authorisation holder for the authorised product consents to a second orphan medicinal product application; or (iii) the marketing authorisation holder for the authorised product cannot supply enough orphan medicinal product.
During this period, the competent authorities may not accept or approve a similar medicinal product for the same approved therapeutic indication, unless (i) the second medicinal product is safer, more effective or otherwise clinically superior to the authorized orphan product; (ii) the marketing authorization holder for the authorized product consents to a second orphan medicinal product application; or (iii) the marketing authorization holder for the authorized product cannot supply enough orphan medicinal product.
Data Exclusivity MAAs for generic medicinal products do not need to include the results of pre-clinical studies and clinical trials, but instead can refer to the data included in the marketing authorisation of a reference product for which regulatory data exclusivity has expired.
Data Exclusivity MAAs for generic medicinal products do not need to include the results of preclinical studies and clinical trials, but instead can refer to such data included in the marketing authorization of a reference product for which regulatory data exclusivity has expired.
For the treatment of individuals with inhibitors, there is an approved Factor VIIa replacement product and an activated prothrombin complex concentrate, as well as a bispecific antibody that mimicks Factor VIII. In addition, there are new, innovative molecules currently in development for treatment of hemophilia A and B, both with and without inhibitors.
For the treatment of individuals with inhibitors, there is an approved Factor VIIa replacement product and an activated prothrombin complex concentrate, as well as a bispecific antibody that mimics Factor VIII. In addition, new, innovative molecules have been recently approved or are currently in development for treatment of hemophilia A and B, both with and without inhibitors.
For OXLUMO, we established a new VBA component called a Patient Need Adjustment with the effect of providing payers with greater budget certainty for medicines administered across a broad range of patient age groups by paying a rebate if the average number of vials utilized by a plan member exceeds an established threshold.
For OXLUMO, we offer a VBA component called a patient need adjustment that provides payers with greater budget certainty for medicines administered across a broad range of patient age groups by paying a rebate if the average number of vials utilized by a plan member exceeds an established threshold.
The results of nonclinical testing are submitted to the FDA as part of an IND, together with chemistry, manufacturing and controls, or CMC, information, analytical and stability data, a proposed clinical trial protocol and other information. Clinical testing in humans may not commence until an IND is in effect.
The results of nonclinical testing are submitted to the FDA as part of an IND, together with chemistry, manufacturing and controls information, analytical and stability data, a proposed clinical trial protocol and other information. Clinical testing in humans may not commence until an IND is in effect. Nonclinical testing typically continues even after the IND is submitted.
Manufacturers can be held liable under false claims laws, even if they do not submit claims to the government, where they are found to have caused submission of false claims by, among other things, providing incorrect coding or billing advice about their products to customers that file claims, or by engaging in kickback arrangements or off-label promotion with customers that file claims.
Manufacturers can be held liable under false claims laws, even if they do not submit claims to the government, where they are found to have caused submission of false claims by, among other things, providing incorrect coding or billing advice about their products to customers that file claims, providing inaccurate reporting regarding pricing or other product data in connection with their government price reporting, or by engaging in kickback arrangements or off-label promotion with customers that file claims.
For delivery to the central nervous system, or CNS, and the eye (ocular delivery), we are utilizing an alternative conjugate approach based on a hexadecyl (C16) moiety as a lipophilic ligand. During 2023, we continued to advance approaches for heart, skeletal muscle, and adipose tissue delivery of siRNAs.
For delivery to the central nervous system, or CNS, and the eye (ocular delivery), we are utilizing an alternative conjugate approach based on a hexadecyl (C16) moiety as a lipophilic ligand. We are also advancing approaches for heart, skeletal muscle and adipose tissue delivery of siRNAs.
AHP refers to a family of ultra-rare, genetic diseases characterized by potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP is comprised of four types: acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and aminolevulinic acid dehydratase-deficiency porphyria.
Our Other Marketed Products GIVLAARI (givosiran) — Acute Hepatic Porphyria (AHP) AHP refers to a family of ultra-rare, genetic diseases characterized by potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP is comprised of four types: acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and aminolevulinic acid dehydratase-deficiency porphyria.
The centralized procedure is compulsory for medicinal products that (1) are derived from biotechnology processes, (2) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders, viral diseases or autoimmune diseases and other immune dysfunctions, (3) are orphan medicinal products or (4) are advanced therapy medicinal products, such as gene or cell therapy medicines.
The centralized procedure is compulsory for medicinal products that (1) are developed by biotechnology processes including advanced therapy medicinal products such as gene and cell therapies, (2) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders, viral diseases or autoimmune diseases and other immune dysfunctions or (3) are orphan medicinal products.
In connection with the collaboration, Blackstone agreed to provide us up to $2.00 billion in financing, including $1.00 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and zilebesiran (formerly ALN-AGT) pursuant to the funding agreement finalized in August 2020.
In connection with the collaboration, Blackstone agreed to provide us up to $2.00 billion in financing, including $1.00 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and zilebesiran pursuant to a co-development agreement that was executed in August 2020.
Clinical trials to support NDAs are typically conducted in three sequential phases, which may overlap or be combined. • In Phase 1, the initial introduction of the drug into healthy human subjects or patients, the drug is tested primarily to assess safety, tolerability, pharmacokinetics, pharmacological actions and metabolism associated with increasing doses. • Phase 2 usually involves trials in a limited patient population, to assess the optimum dosage and dose regimen, identify possible adverse effects and safety risks, and provide preliminary support for the efficacy of the drug in the indication being studied. 27 Table of Con tents • Phase 3 clinical trials further evaluate the drug’s clinical efficacy, side effects and safety in an expanded patient population, typically at geographically dispersed clinical trial sites, to establish the overall benefit-risk relationship of the drug and to provide adequate information for the labeling of the drug.
Clinical trials to support NDAs are typically conducted in three sequential phases, which may overlap or be combined. • In Phase 1, the initial introduction of the drug into a limited number of healthy human subjects or patients, the drug is tested primarily to assess safety, tolerability, pharmacokinetics, pharmacological actions and metabolism associated with increasing doses. • Phase 2 usually involves trials in a limited patient population with the specified disease or condition the drug is intended to treat to assess the optimum dosage and dose regimen, identify possible adverse effects and safety risks, and to preliminarily evaluate the efficacy of the drug in the indication being studied. • Phase 3 clinical trials further evaluate the drug’s clinical efficacy, side effects and safety in an expanded patient population, typically at geographically dispersed clinical trial sites, to establish the overall benefit-risk relationship of the drug and to provide an adequate basis for regulatory approval and labeling of the drug.
Hoffmann-La Roche Ltd.; Silence Therapeutics plc and its collaborators, AstraZeneca plc, Jiangsu Hansoh Pharmaceuticals Group Co., Ltd., and Mallinckrodt plc; Arbutus Biopharma Corp., or Arbutus; Sylentis, S.A.U., or Sylentis; and Novo Nordisk and its collaborators, Boehringer Ingelheim and Eli Lilly and Company.
Hoffmann-La Roche Ltd.; Silence Therapeutics plc and its collaborators, AstraZeneca plc, Jiangsu Hansoh Pharmaceuticals Group Co., Ltd., and Mallinckrodt plc; Arbutus Biopharma Corp., or Arbutus; Sylentis, S.A.U., or Sylentis; Novo Nordisk and its collaborators, Aro Biotherapeutics, Boehringer Ingelheim, and Eli Lilly and Company; and our collaborators Regeneron, Sanofi and Vir.
We are continuing to advance other extrahepatic delivery approaches, including delivery to muscle and adipose cells. In addition, we are exploring peptide and antibody-based approaches for targeted siRNA delivery to new tissues in collaboration with PeptiDream to discover and develop peptide-siRNA conjugates for targeted delivery of RNAi therapeutics to a broader range of extrahepatic tissues.
We are continuing to advance other extrahepatic delivery approaches, including delivery to muscle and adipose cells. In addition, we are exploring peptide and antibody-based approaches for targeted siRNA delivery to new tissues as part of our collaboration with PeptiDream, Inc., which aims to discover and develop novel conjugates for targeted delivery of RNAi therapeutics to a broader range of tissues.
In addition, in connection with our FDA approval on November 23, 2020, the FDA granted OXLUMO NCE exclusivity until November 23, 2025, and ODE until November 23, 2027. In connection with our EMA approval on November 19, 2020, the EMA granted OXLUMO Marketing Exclusivity and ODE until November 19, 2030.
In addition, in connection with our FDA approval on November 23, 2020, the FDA granted OXLUMO NCE exclusivity until November 23, 2025, and ODE until November 23, 2027.
Notwithstanding the above definitions, a drug that is “clinically superior” to an orphan drug will not be considered the “same drug” and thus will not be blocked by Orphan Drug Exclusivity.
However, a drug that is “clinically superior” to an orphan drug will not be considered the “same drug” and thus will not be blocked by orphan drug exclusivity.
Patisiran, approved in the EU in August 2018, givosiran, approved in the EU in March 2020, lumasiran, approved 37 Table of Con tents in the EU in November 2020, as well as vutrisiran, approved in the EU in September 2022 and fitusiran have been granted orphan medicinal product designation.
Patisiran, approved in the EU in August 2018, givosiran, approved in the EU in March 2020, lumasiran, approved in the EU in November 2020, as well as vutrisiran, approved in the EU in September 2022 and fitusiran have been granted orphan medicinal product designation.
The executive order also directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.
Among other things, the executive order directed the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.
For example, the FDA granted Orphan Drug Designation for patisiran and vutrisiran as therapeutic approaches for the treatment of ATTR amyloidosis, givosiran as a therapeutic approach for AHP, lumasiran as a therapeutic approach for PH1, and inclisiran as a therapeutic approach for HoFH.
For example, the FDA granted orphan drug designation for patisiran, vutrisiran and nucresiran as therapeutic approaches for the treatment of ATTR amyloidosis, givosiran as a therapeutic approach for AHP, lumasiran as a therapeutic approach for PH1, and inclisiran as a therapeutic approach for homozygous familial hypercholesterolemia.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changePenalties are three times the amount of the claims in question plus civil monetary penalties. • The federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer of remuneration to a Medicare or Medicaid beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or Medicaid, unless an exception applies. • The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created, among other provisions, federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and, in any matter involving a health care benefit program, knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services.
Biggest changePenalties are three times the amount of the claims in question plus civil monetary penalties. • The federal civil monetary penalties laws, which generally impose civil fines for, among other things, the offering or transfer of remuneration to a Medicare or Medicaid beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or Medicaid.
As discussed above, under our agreement with Blackstone, if the revenues generated by the royalties received by Blackstone from us with respect to Leqvio sales do not reach a certain level by the end of 2029, Blackstone will be entitled to a higher royalty percentage beginning in 2030, which would have an adverse impact on our royalty revenues beginning in 2030.
As discussed above, under our agreement with Blackstone Royalties, if the revenues generated by the royalties received by Blackstone Royalties from us with respect to Leqvio sales do not reach a certain level by the end of 2029, Blackstone Royalties will be entitled to a higher royalty percentage beginning in 2030, which would have an adverse impact on our royalty revenues beginning in 2030.
Disputes may arise in the future with respect to the ownership of rights to technology or products developed with collaborators, which could have an adverse effect on our ability to develop and commercialize any affected product candidate.
Disputes may arise in the future with respect to the ownership of rights to technology or products developed with our collaborators, which could have an adverse effect on our ability to develop and commercialize any affected product candidate.
In addition, if we have a dispute with a collaborator over the ownership of technology or other matters, or if a collaborator terminates its collaboration with us, for breach or otherwise, or determines not to pursue the research, development and/or commercialization of the affected product or product candidate, it could delay our development of product candidates, result in the need for additional company resources to develop product candidates, require us to expend time and resources to develop expanded sales and marketing capabilities on a more expedited timeline, make it more difficult for us to attract new collaborators and could adversely affect how we are perceived in the business and financial communities.
In addition, if we have a dispute with a collaborator over the ownership of technology or other matters, or if a collaborator terminates its collaboration with us, for breach or otherwise, or determines not to pursue the research, development and/or commercialization of the affected product or product candidate, it could delay our development of product candidates, result in the need for additional company resources to develop our product candidates, require us to expend time and resources to develop expanded sales and marketing capabilities on a more expedited timeline, make it more difficult for us to attract new collaborators and adversely affect how we are perceived in the business and financial communities.
Moreover, a collaborator, or in the event of a change in control of a collaborator or the assignment of a collaboration agreement to a third party, the successor entity or assignee, as in the case of MDCO and Novartis, could determine that it is in its interests to: • pursue alternative technologies or develop alternative products, either on its own or jointly with others, that may be competitive with the products on which it is collaborating with us or which could affect its commitment to the collaboration with us; • pursue higher-priority programs or change the focus of its development programs, which could affect the collaborator’s commitment to us; or • if it has marketing rights, choose to devote fewer resources to the marketing of our product candidates, if any are approved for marketing, than it does for product candidates developed without us.
Moreover, a collaborator, or in the event of a change in control of a collaborator or the assignment of a collaboration agreement to a third party, the successor entity or assignee, as in the case of MDCO and Novartis, could determine that it is in its interests to: • pursue alternative technologies or develop alternative products, either on its own or jointly with others, that may be competitive with the products on which it is collaborating with us or which could affect its commitment to its collaboration with us; • pursue higher-priority programs or change the focus of its development programs, which could affect the collaborator’s commitment to us; or • if it has marketing rights, choose to devote fewer resources to the marketing of our product candidates, if any are approved for marketing, than it does for product candidates developed without us.
Given our dependence on a limited number of CMOs to supply our commercial products and clinical candidates, and the ongoing utilization of our own facilities, any delay or setback in the manufacture of our products could impede ongoing clinical and commercial supply, which could materially and adversely impact our business, prospects, operating results or financial condition.
Given our dependence on a limited number of CMOs to supply our commercial products and clinical candidates, and the ongoing utilization of our own facilities, any delay or setback in the manufacture of our products could impede ongoing clinical and commercial supply, which could materially and adversely impact our business, prospects, operating results and financial condition.
If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face regulatory actions or incur other harm to our business. Our business and operations could suffer in the event of system failures or unauthorized or inappropriate use of or access to our systems.
If any of these events were to occur or if we otherwise fail to comply with applicable regulations, we could face regulatory actions or incur liability or other harm to our business. Our business and operations could suffer in the event of system failures or unauthorized or inappropriate use of or access to our systems.
Delays or difficulties in patient enrollment, or difficulties retaining trial participants, including as a result of the availability of existing approved treatments or other investigational treatments or safety concerns, including the impact of pandemics or other public health emergencies, can result in increased costs, longer development times or termination of a clinical trial.
Delays or difficulties in patient enrollment, or difficulties retaining trial participants, including as a result of the availability of existing approved treatments or other investigational treatments, safety concerns, or the impact of pandemics or other public health emergencies, can result in increased costs, longer development times or termination of a clinical trial.
Failure to obtain and maintain broad patent scope and all available regulatory exclusivities and to maximize patent term restoration or extension on patents covering our product candidates and products may lead to loss of exclusivity and generic entry resulting in a loss of market share and/or revenue. We license patent rights from third-party owners.
Failure to obtain and maintain broad patent scope and all available regulatory exclusivities and to maximize patent term restoration or extension on patents covering our products and product candidates may lead to loss of exclusivity and generic entry resulting in a loss of market share and/or revenue. We license patent rights from third-party owners.
In addition, the FDA has the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, plan as part of its review of an NDA, or after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug, such as limiting prescribing to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients who meet certain safe-use criteria and requiring treated patients to enroll in a registry.
In addition, the FDA has the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, as part of its review of an NDA, or after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug, such as limiting prescribing to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients who meet certain safe-use criteria and requiring treated patients to enroll in a registry.
Business interruptions from future pandemics or public health emergencies, including staffing shortages, raw material or other supply chain shortages, production slowdowns and disruptions in delivery systems, may also adversely impact the third parties we or our collaborators rely on in the U.S. and abroad to sufficiently manufacture our approved products and to produce product candidates in quantities we require, which may impair our commercialization efforts, our research and development activities and the potential commercialization of our product candidates.
Business interruptions from pandemics or public health emergencies, including staffing shortages, raw material or other supply chain shortages, production slowdowns and disruptions in delivery systems, may also adversely impact the third parties we or our collaborators rely on in the U.S. and abroad to sufficiently manufacture our approved products and to produce product candidates in quantities we require, which may impair our commercialization efforts, our research and development activities and the potential commercialization of our product candidates.
For example, our agreement with Novartis relating to the development and commercialization of inclisiran worldwide may be terminated by Novartis at any time upon four months’ prior written notice, provided if the agreement is terminated by Novartis for convenience, Novartis must grant a license to us under certain technology developed in the course of its (or MDCO’s) activities under the agreement, subject to a royalty to be negotiated between the parties.
Our agreement with Novartis relating to the development and commercialization of inclisiran worldwide may be terminated by Novartis at any time upon four months’ prior written notice, provided if the agreement is terminated by Novartis for convenience, Novartis must grant a license to us under certain technology developed in the course of its (or MDCO’s) activities under the agreement, subject to a royalty to be negotiated between the parties.
If we are unsuccessful in accomplishing the objectives set forth above, we may not be able to develop product candidates, successfully commercialize our approved products or any future products, raise capital, if needed, repay our indebtedness, achieve financial self-sustainability or continue our operations. We have a history of losses and may never become and remain profitable.
If we are unsuccessful in accomplishing the objectives set forth above, we may not be able to develop product candidates, successfully commercialize our approved products or any future products, raise capital, if needed, repay our indebtedness, achieve financial self-sustainability or continue our operations. We have a history of losses and may not become and remain profitable.
In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. These measures could reduce the demand for our products, once approved, or put pressure on our product pricing.
Such reforms could have a material and adverse effect on our anticipated revenues from one or more of our approved products or other product candidates that we may successfully develop and for which we may obtain regulatory approval and may affect our business, prospects, operating results and financial condition and our ability to develop drug candidates.
Such reforms could have a material and adverse effect on our anticipated revenues for one or more of our approved products or other product candidates that we may successfully develop and for which we may obtain regulatory approval and may affect our business, prospects, operating results and financial condition and our ability to develop drug candidates.
RNAi is a relatively new scientific field, the commercial exploitation of which has resulted in many different patents and patent applications from organizations and individuals seeking to obtain patent protection in the field. We have obtained grants and issuances of RNAi patents and have licensed many of these patents from third parties on an exclusive basis.
RNAi is a relatively new and growing scientific field, the commercial exploitation of which has resulted in many different patents and patent applications from organizations and individuals seeking to obtain patent protection in the field. We have obtained grants and issuances of RNAi patents and have licensed many of these patents from third parties on an exclusive basis.
Although we depend heavily on these parties, we control only limited aspects of their activity and therefore, we cannot be assured that these third parties will adequately perform all of their contractual obligations to us in compliance with regulatory and other legal requirements and our internal policies and procedures.
Although we depend heavily on these parties, we control only limited aspects of their activity and therefore, we cannot be assured that these third parties will adequately perform their contractual obligations to us in compliance with regulatory and other legal requirements and our internal policies and procedures.
Under the IRA’s Price Negotiation Program, a FDA approval for vutrisiran for treatment of Stargardt Disease would cause us to lose the orphan exemption for AMVUTTRA from Medicare price negotiation. As a result, in October 2022, we announced we would not pursue a Phase 3 clinical trial to study vutrisiran for treatment of Stargardt Disease.
Under the IRA’s Price Negotiation Program, an FDA approval for vutrisiran for treatment of Stargardt Disease would cause us to lose the orphan exemption for AMVUTTRA from Medicare price negotiation. As a result, in October 2022, we announced we would not pursue a Phase 3 clinical trial to study vutrisiran for the treatment of Stargardt Disease.
If we fail to comply with our obligations under any licenses or related agreements, we may be required to pay damages and could lose license or other rights that are necessary for developing, commercializing and protecting our RNAi technology, as well as our approved products and product candidates.
If we fail to comply with our obligations under any licenses or related agreements, we may be required to pay damages and could lose license or other rights that are necessary for developing, commercializing and protecting our RNAi technology, as well as our products and product candidates.
The manufacturing processes for our products and any other product candidates that we may develop is subject to the FDA and foreign regulatory authority approval process and we will need to meet, and will need to contract with CMOs who can meet, all applicable FDA and foreign regulatory authority requirements on an ongoing basis.
The manufacturing processes for our products and any other product candidates that we may develop is subject to the FDA and foreign regulatory authority approval processes and we will need to meet, and will need to contract with CMOs who can meet, all applicable FDA and foreign regulatory authority requirements on an ongoing basis.
If we do not comply with laws regulating the protection of the environment and health and human safety, our business, prospects, operating results and financial condition could be adversely affected. Our research, development and manufacturing involve the use of hazardous materials, chemicals and various radioactive compounds.
If we do not comply with laws regulating the protection of the environment and health and human safety, our business, prospects, operating results and financial condition could be adversely affected. Our research, development and manufacturing activities involve the use of hazardous materials, chemicals and various radioactive compounds.
To the extent that any disruption, security breach or unauthorized or inappropriate use or access to our systems were to result in a loss of or damage to our data, or inappropriate disclosure of confidential or proprietary information, including but not limited to patient, employee or vendor information, we could incur notification obligations to affected individuals and government agencies, liability, including potential lawsuits from patients, collaborators, employees, stockholders or other third parties, and liability under foreign, federal and state laws that protect the privacy and security of personal information, and the development and potential commercialization of our product candidates could be delayed.
To the extent that any disruption, security breach or unauthorized or inappropriate use or access to our systems were to result in a loss of or damage to our data, or inappropriate disclosure of confidential or proprietary information, including but not limited to patient, employee or vendor information, we could incur notification obligations to affected individuals and government agencies, face potential lawsuits from patients, collaborators, employees, stockholders or other third parties, and incur liability under foreign, federal and state laws that protect the privacy and security of personal information, and the development and potential commercialization of our products and product candidates could be delayed.
Among other things, these provisions: • establish a classified board of directors such that all members of our board of directors are not elected at one time; • establish a prohibition on actions by our stockholders by written consent; • authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; • allow the authorized number of our directors to be changed only by resolution of our board of directors. • limit who may call a special meetings of stockholders; • require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to case to amend or repeal certain provisions of our charter or bylaws; • limit the manner in which stockholders can remove directors from our board of directors; and • establish advance notice requirements for election to our board of directors and for proposing matters that can be acted upon at stockholder meetings.
Among other things, these provisions: • establish a classified board of directors such that all members of our board of directors are not elected at one time; • establish a prohibition on actions by our stockholders by written consent; • authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our board of directors; • allow the authorized number of our directors to be changed only by resolution of our board of directors. • limit who may call a special meeting of stockholders; • require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to cast to amend or repeal certain provisions of our charter or bylaws; • limit the manner in which stockholders can remove directors from our board of directors; and • establish advance notice requirements for election to our board of directors and for proposing matters that can be acted upon at stockholder meetings.
The terms of any financing we may be required to pursue in the future may adversely affect the holdings or the rights of our stockholders. If we raise additional funds by issuing equity securities, further dilution to our existing stockholders will result.
The terms of any financing we may be required to pursue in the future may adversely affect the holdings or the rights of our stockholders. If we raise additional funds by issuing equity securities, dilution to our existing stockholders will result.
We may not be successful in entering into future collaborations on terms favorable to us due to various factors, including our ability to demonstrate improved product profiles from our new technologies, including our IKARIA platform, our ability to successfully demonstrate proof-of-concept for our technology in humans in certain tissues or disease areas, our ability to demonstrate the safety and efficacy of our specific product candidates, our ability to manufacture or have third parties manufacture RNAi therapeutics, the strength of our intellectual property portfolio and/or concerns around challenges or potential challenges to our intellectual property portfolio.
We may not be successful in entering into future collaborations on terms favorable to us due to various factors, including our ability to demonstrate improved product profiles from our new technologies, our ability to successfully demonstrate proof-of-concept for our technology in humans in certain tissues or disease areas, our ability to demonstrate the safety and efficacy of our specific product candidates, our ability to manufacture or have third parties manufacture RNAi therapeutics, the strength of our intellectual property portfolio and/or concerns around challenges or potential challenges to our intellectual property portfolio.
Many of our competitors have: • substantially greater financial, technical and human resources than we have; • more extensive experience in pre-clinical testing, conducting clinical trials, obtaining regulatory approvals, and in manufacturing, marketing and selling drug products; • product candidates that are based on previously tested or accepted technologies; • multiple products that have been approved or are in late stages of development; and • collaborative arrangements in our target markets with leading companies and research institutions.
Many of our competitors have: • substantially greater financial, technical and human resources than we have; • more extensive experience in preclinical testing, conducting clinical trials, obtaining regulatory approvals, and in manufacturing, marketing and selling drug products; • product candidates that are based on previously tested or accepted technologies; • multiple products that have been approved or are in late stages of development; and • collaborative arrangements in our target markets with leading companies and research institutions.
Moreover, any adverse actions by Novartis with respect to the MDCO License Agreement or disputes with Novartis regarding the MDCO License Agreement could adversely impact our ability to comply with our obligations under our agreements with Blackstone.
Moreover, any adverse actions by Novartis with respect to the MDCO License Agreement or disputes with Novartis regarding the MDCO License Agreement could adversely impact our ability to comply with our obligations under our agreements with Blackstone Royalties.
When such disclosures occur, there is a risk that study enrollment may be adversely impacted, we fail to monitor and comply with applicable AE reporting obligations or that we may not be able to defend our business in the face of the political and market pressures generated by social media due to restrictions on what we may say about our investigational products.
When such disclosures occur, there is a risk that trial enrollment may be adversely impacted, that we may fail to monitor and comply with applicable AE reporting obligations or that we may not be able to defend our business in the face of the political and market pressures generated by social media due to restrictions on what we may say about our investigational products.
Because certain U.S. patent applications are confidential until the patents issue, such as applications filed prior to November 29, 2000, or applications filed after such date which will not be filed in foreign countries, third parties may have filed patent applications for subject matter covered by our pending patent applications without our being aware of those applications, and our patent applications may not have priority over those applications.
Because certain U.S. patent applications are confidential until the patents issue, such as applications filed prior to November 29, 2000, or applications filed after such date that will not be filed in foreign countries, third parties may have filed patent applications for subject matter covered by our pending patent applications without our being aware of those applications, and our patent applications may not have priority over those applications.
Moreover, we expect that a number of our collaborations will provide that royalties payable to us for licenses to our intellectual property may be offset by amounts paid by our collaborators to third parties who have competing or superior intellectual property positions in the relevant fields, which could result in significant reductions in our revenues from products developed through collaborations.
Moreover, we expect that a number of our collaboration agreements will provide that royalties payable to us for licenses to our intellectual property may be offset by amounts paid by our collaborators to third parties who have competing or superior intellectual property positions in the relevant fields, which could result in significant reductions in our revenues from products developed through collaborations.
Other factors we believe will materially affect market acceptance of our products include: • the timing of our receipt of any marketing approvals, the terms of any approvals and the countries in which approvals are obtained; • the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any; • relative convenience, dosing regimen and ease of administration of our product candidates; • the willingness of patients to accept potentially new routes of administration or new or different therapeutic approaches and mechanisms of action; • the success of our physician education programs; • the availability of adequate government and third-party payor reimbursement; • the pricing of our products, particularly as compared to alternative treatments, and the market perception of such prices and any price increase that we may implement in the future; and • availability of alternative effective treatments for the diseases that our product candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
The factors we believe will materially affect market acceptance of our products include: • the timing of our receipt of any marketing approvals, the terms of any approvals and the countries in which approvals are obtained; • the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any; • relative convenience, dosing regimen and ease of administration of our product candidates; • the willingness of patients to accept potentially new routes of administration or new or different therapeutic approaches and mechanisms of action; 55 Table of Contents • the success of our physician education programs; • the availability of adequate government and third-party payor reimbursement; • the pricing of our products, particularly as compared to alternative treatments, and the market perception of such prices and any price increase that we may implement in the future; and • availability of alternative effective treatments for the diseases that our product candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
This will require us to build upon the success we have had in a range of challenging activities, including continued platform innovation, pre-clinical testing and clinical trial stages of development, obtaining regulatory approval and reimbursement for our novel product candidates and manufacturing, marketing and selling our approved products.
This will require us to build upon the success we have had in a range of challenging activities, including continued platform innovation, preclinical testing and clinical trial stages of development, obtaining regulatory approval and reimbursement for our novel product candidates and manufacturing, marketing and selling our approved products.
Moreover, we cannot be certain that our collaborators, including Novartis, will continue to successfully execute their obligations under our collaboration agreements and generate collaboration and royalty revenues for us. To become and remain profitable, we must succeed in discovering, developing and commercializing novel product candidates with significant market potential.
Moreover, we cannot be certain that our collaborators, including Roche and Novartis, will continue to successfully execute their obligations under our collaboration agreements and generate collaboration and royalty revenues for us. To remain profitable, we must succeed in discovering, developing and commercializing novel product candidates with significant market potential.
Our current collaborations allow, and we expect that any future collaborations will allow, either party to terminate the collaboration for a material breach by the other party. In addition, our collaborators may have additional termination rights for convenience with respect to the collaboration or a particular program under the collaboration, under certain circumstances.
Our current collaborations allow, and we expect that any future collaborations will allow, either party to terminate the collaboration for a material breach by the other party. In addition, our collaborators may have additional termination rights for convenience with respect to the collaboration as a whole or a particular program under the collaboration, under certain circumstances.
If we fail to obtain a required license and are unable to design around a patent, we may be unable to effectively market some of our technology and products, which could limit our ability to generate revenues or achieve profitability and possibly prevent us from generating revenue sufficient to sustain our operations.
If we fail to obtain a required license and are unable to design around a patent, we may be unable to effectively market some of our technology and products, which could limit our ability to generate revenues or maintain profitability and possibly prevent us from generating revenue sufficient to sustain our operations.
If Blackstone does not receive royalty payments in respect of global sales of Leqvio equaling at least $1.00 billion by December 31, 2029, Blackstone’s interest in Leqvio royalties will increase to 55% (and our interest will decrease to 45%) effective January 1, 2030.
If Blackstone does not receive royalty payments in respect of global sales of Leqvio equaling at least $1.00 billion by December 31, 2029, Blackstone Royalties’ interest in Leqvio royalties will increase to 55% (and our interest will decrease to 45%) effective January 1, 2030.
Specifically, we have stated that we will not raise the price of any product for which we receive marketing approval over the rate of inflation, as determined by the consumer price index for urban consumers (approximately 3.4% currently) ) absent a significant value driver.
Specifically, we have stated that we will not raise the price of any product for which we receive marketing approval over the rate of inflation, as determined by the consumer price index for urban consumers (approximately 3.5% currently) absent a significant value driver.
If licenses are not available to us or not available on reasonable terms, we or our licensees may not be able to market the affected products or conduct the desired activities. Our strategy depends on our ability to rapidly identify and seek patent protection for our discoveries.
If licenses are not available to us or not available on reasonable terms or at all, we or our licensees may not be able to market the affected products or conduct the desired activities. Our strategy depends on our ability to rapidly identify and seek patent protection for our discoveries.
Ionis is also developing antisense drugs using ligand-conjugated GalNAc technology licensed from us, and these drugs have been shown to have increased potency at lower doses in clinical and pre-clinical studies, compared with antisense drugs that do not use such licensed GalNAc technology.
Ionis is also developing antisense drugs using ligand-conjugated GalNAc technology licensed from us, and these drugs have been shown to have increased potency at lower doses in clinical and preclinical studies, compared with antisense drugs that do not use such licensed GalNAc technology.
As discussed in the Risk Factor captioned “If we or our collaborators, CMOs or service providers fail to comply with healthcare laws and regulations, or legal obligations related to privacy, data protection and information security, we or they could be subject to enforcement actions, which could negatively impact our ability to develop, market and sell our products and may harm our reputation,” these laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements.
As discussed in the Risk Factor above captioned “If we or our collaborators, CMOs or service providers fail to comply with healthcare laws and regulations, or legal obligations related to privacy, data protection and information security, we or they could be subject to enforcement actions, which could negatively impact our ability to develop, market and sell our products and may harm our reputation,” these 63 Table of Contents laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements.
We have been expanding our manufacturing capabilities, and to continue to commercialize our approved products, continue to develop our current product candidates, apply for regulatory approvals and, if approved, commercialize future products, we will need to continue to develop our internal manufacturing capabilities and/or contract or otherwise arrange for any necessary external manufacturing capabilities.
We have been expanding our manufacturing capabilities, and in order to continue to commercialize our approved products, continue to develop our current product candidates, apply for regulatory approvals and, if approved, commercialize future products, we will need to continue to develop our internal manufacturing capabilities and/or contract or otherwise arrange for any necessary external manufacturing capabilities.
The full extent to which COVID-19, or any future pandemic or public health emergency, will negatively affect our operations, financial performance, and stock price will depend on future developments that are highly uncertain and cannot be predicted.
The full extent to which any pandemic or public health emergency, will negatively affect our operations, financial performance, and stock price will depend on future developments that are highly uncertain and cannot be predicted.
If our operations are found to be in violation of any of the aforementioned requirements, we may be subject to penalties, including civil or criminal penalties (including individual imprisonment), criminal prosecution, monetary damages, the curtailment or restructuring of our operations, or exclusion from participation in government contracting, healthcare reimbursement or other government programs, including Medicare and Medicaid, or the imposition of a corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services, or the OIG, any of which could materially and adversely affect our business, prospects, operating results or financial condition.
If our operations are found to be in violation of any of the aforementioned requirements, we may be subject to penalties, including civil or criminal penalties (including individual imprisonment), criminal prosecution, monetary damages, the curtailment or restructuring of our operations, or exclusion from participation in government contracting, healthcare reimbursement or other government programs, including Medicare and Medicaid, or the imposition of a corporate integrity agreement with the Office of Inspector General of the Department of HHS, or the OIG, any of which could materially and adversely affect our business, prospects, operating results or financial condition.
Risks Related to Our Dependence on Third Parties • We may be unable to maintain existing or enter into new collaborations with other companies that can provide business and scientific capabilities and funds for the development and commercialization of certain of our product candidates. • If any collaborator materially amends, terminates or fails to perform its obligations under agreements with us, the development and commercialization of certain of our product candidates could be delayed or terminated. • We expect to continue to grow our manufacturing capabilities and resources and we must incur significant costs to develop this expertise and/or rely on third parties to manufacture our products. • We rely on third parties to conduct our clinical trials, and if such third parties fail to fulfill their obligations, our development plans may be adversely affected.
Risks Related to Our Dependence on Third Parties • We may be unable to maintain existing or enter into new collaborations with other companies that can provide business and scientific capabilities and funds for the development and commercialization of certain of our product candidates. • If any collaborator materially amends, terminates or fails to perform its obligations under agreements with us, the development and commercialization of certain of our product candidates could be delayed or terminated. • We expect to incur significant costs as we continue to grow our manufacturing capabilities and resources and develop manufacturing expertise; in the meantime, we rely, and expect to continue to rely, on third parties to manufacture our products. • We rely on third parties to conduct our clinical trials, and if such third parties fail to fulfill their obligations, our development plans may be adversely affected.
In the U.S., the rules dealing with federal, state, and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the U.S. Treasury Department. Changes to tax laws (which changes may have retroactive application) could adversely affect us or holders of our common stock.
In the U.S., the rules dealing with federal, state, and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the U.S. Treasury Department. Changes to tax laws (which changes may have 42 Table of Contents retroactive application) could adversely affect us or holders of our common stock.
If the payment we receive for our products, or the reimbursement provided for such products, is inadequate in light of our significant development and other costs, or if reimbursement is denied, our return on investment could be adversely affected. In addition, we have stated publicly that we intend to grow through continued scientific innovation rather than arbitrary price increases.
If the payment we receive for our products, or the reimbursement provided for such products, is inadequate in light of our significant development and other costs, or if reimbursement is denied, our return on investment could be adversely affected. In addition, we have stated publicly that we intend to grow through continued scientific innovation rather than more substantial price increases.
Therefore, even if we successfully develop and commercialize products, we may be unable to achieve or maintain profitability. Confidentiality agreements with employees and others may not adequately prevent disclosure of trade secrets and other proprietary information.
Therefore, even if we successfully develop and commercialize products, we may be unable to maintain profitability. Confidentiality agreements with employees and others may not adequately prevent disclosure of trade secrets and other proprietary information.
In some cases, the delivery technology we utilize is highly specialized or proprietary, and for technical and/or legal reasons, we may have access to only one or a limited number of potential manufacturers for such delivery technology. In addition, the scale-up of our delivery technologies could be very difficult and/or take significant time.
In some cases, the delivery technology we utilize is highly specialized or proprietary, and for technical and/or 45 Table of Contents legal reasons, we may have access to only one or a limited number of potential manufacturers for such delivery technology. In addition, the scale-up of our delivery technologies could be very difficult and/or take significant time.
For certain product candidates, we have formed collaborations to fund all or part of the costs of drug development and commercialization, such as our collaborations with Regeneron, Roche, Novartis, Vir, Dicerna and Sanofi.
For certain product candidates, we have formed collaborations to fund all or part of the costs of drug development and commercialization, such as our collaborations with Roche, Regeneron, Sanofi and Novartis.
In addition, our cost-sharing responsibility for any approved product covered by Medicare Part D could be significantly greater under the newly designed Part D benefit structure compared to the pre-IRA benefit design.
In addition, our cost-sharing responsibility for any approved product covered by Medicare Part D could be significantly greater under the IRA Part D benefit structure compared to the pre-IRA benefit design.
Similar to RNAi therapeutics, antisense drugs target mRNAs in order to suppress the activity of specific genes. Akcea Therapeutics, Inc., a wholly owned subsidiary of Ionis, has received marketing approval for an antisense drug, inotersen for the treatment of adult hATTR amyloidosis patients with stage 1 or stage 2 polyneuropathy.
Similar to RNAi therapeutics, antisense drugs target mRNAs in order to suppress the activity of specific genes. Akcea Therapeutics, Inc., a wholly owned subsidiary of Ionis, has received marketing approval for an antisense drug, inotersen for the treatment of adult 69 Table of Contents hATTR amyloidosis patients with stage 1 or stage 2 polyneuropathy.
As a result, any factor that has an adverse impact on sales of Leqvio could affect our ability to meet the $1.00 billion repayment threshold in this timeframe, which in turn would have a negative impact on the percentage of the Leqvio royalty stream that we are entitled to retain.
As 41 Table of Contents a result, any factor that has an adverse impact on sales of Leqvio could affect our ability to meet the $1.00 billion repayment threshold in this timeframe, which in turn would have a negative impact on the percentage of the Leqvio royalty stream that we are entitled to retain.
While we believe that ONPATTRO and AMVUTTRA have and will continue to have a competitive product profile for the treatment of patients with hATTR amyloidosis with polyneuropathy, it is possible that ONPATTRO and/or AMVUTTRA may not compete favorably with these products and product candidates, or others, and, as a result, may not achieve commercial success.
While we believe that ONPATTRO and AMVUTTRA have and will 68 Table of Contents continue to have a competitive product profile for the treatment of patients with hATTR amyloidosis with polyneuropathy, it is possible that ONPATTRO and/or AMVUTTRA may not compete favorably with these products and product candidates, or others, and, as a result, may not achieve commercial success.
For example, for our clinical-stage candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical study or to report an alleged adverse event, or AE.
For example, for our clinical-stage candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical trial or to report an alleged adverse event, or AE.
Our dependence on collaborators for capabilities and funding means that our business could be adversely affected if any collaborator materially amends or terminates its collaboration agreement with us or fails to perform its obligations under that agreement. Our current or future collaborations, if any, may not be scientifically or commercially successful.
Our dependence on collaborators for capabilities and funding means that our business could be adversely affected if any collaborator materially amends or terminates its collaboration agreement with us, in whole or in part, or fails to perform its obligations under that agreement. Our current or future collaborations, if any, may not be scientifically or commercially successful.
We cannot assure you that upon inspection by a given regulatory authority in the future, such regulatory authority will determine that any of our clinical trials comply with GCP regulations.
We cannot assure you that upon inspection by a given regulatory authority in the future, such regulatory authority will determine that any of our clinical trials comply with GCP requirements.
It is possible that the product candidates we and our collaborators are developing will not obtain the regulatory approvals necessary for us or our collaborators to begin selling them, or, in the case of vutrisiran, will not obtain regulatory approval to be sold for a broader indication than the indication for which it is currently approved.
It is possible that the product candidates we and our collaborators are developing will not obtain the regulatory approvals necessary for us or our collaborators to begin selling them, or, in the case of vutrisiran, will not obtain regulatory approval to be sold for an additional, broader indication than the indication for which it is currently approved.
The Notes may become in the future convertible at the option of their holders under certain circumstances. If holders of the Notes elect to convert their notes, we may settle our conversion obligation by delivering to them a significant number of shares of our common stock, which would cause dilution to our existing stockholders.
The Notes may become in the future convertible at the option of their holders under certain circumstances. If holders of the Notes elect to 72 Table of Contents convert their notes, we may settle our conversion obligation by delivering to them a significant number of shares of our common stock, which would cause dilution to our existing stockholders.
While we believe our current cash, cash equivalents and marketable equity and debt securities, as well as the revenue we expect to generate from product sales and under our existing collaborations, including milestones and royalties on Leqvio sales, should enable us to achieve a self-sustainable profile without the need for future equity financing, we will depend on our ability to generate product, collaboration and royalty revenues to achieve this goal.
While we believe our current cash, cash equivalents and marketable equity and debt securities, as well as the revenue we expect to generate from product sales and under our existing collaborations, including milestones and royalties on Leqvio sales, should enable us to achieve a self-sustainable profile by the end of 2025 without the need for future equity financing, we will depend on our ability to generate product, collaboration and royalty revenues to achieve this goal.
These developments could, directly or indirectly, affect our ability to sell ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or future products, if approved, at a favorable price. At the federal level, for example, the IRA includes several provisions that will impact our business to varying degrees.
These developments could, directly or indirectly, affect our ability to sell ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or future products, if approved, at a favorable price. At the federal level, for example, the Inflation Reduction Act, or IRA, includes several provisions that will impact our business to varying degrees.
We have used substantial funds to develop our RNAi technologies and will require substantial funds to conduct further research and development activities, including pre-clinical testing and clinical trials of our product candidates, and to manufacture, market and sell our four approved products and any other products that are approved for commercial sale.
We have used substantial funds to develop our RNAi technologies and will require substantial funds to conduct further research and development activities, including preclinical testing and clinical trials of our product candidates, and to manufacture, market and sell our approved products and any other products that are approved for commercial sale.
If our third-party service providers cannot adequately and timely fulfill their obligations to us for any reason, or if the quality and accuracy of our clinical trial data is compromised due to failure by such third party service provider to adhere to our protocols or regulatory requirements or if such third party service providers otherwise fail to meet deadlines, our development plans and/or regulatory reviews for marketing approvals may be delayed or terminated.
If our third-party service providers cannot adequately and timely fulfill their obligations to us for any reason, or if the quality and accuracy of our clinical trial data is compromised due to failure by a third party service provider to adhere to our protocols or regulatory requirements or if a third party service provider otherwise fails to meet deadlines, our development plans and/or regulatory reviews for marketing approvals may be delayed or terminated.
Complying with these programs and future changes to these programs can be cost-and resource-intensive and could have a material adverse effect on our business, prospects, operating results and financial condition. There is a substantial risk of product liability claims in our business.
Complying with federal and state programs and future changes to these programs can be complex and cost-and resource-intensive, and could have a material adverse effect on our business, prospects, operating results and financial condition. There is a substantial risk of product liability claims in our business.
In particular, we have obtained licenses from, among others, Ionis, Arbutus, and Dicerna. We also intend to enter into additional licenses to third-party intellectual property in the future.
In particular, we have obtained licenses from, among others, Ionis, Arbutus, and Dicerna. We may also enter into additional licenses to third-party intellectual property in the future.
For example, ONPATTRO utilizes an intravenous mode of administration with pre-medication that physicians and/or patients may not readily adopt, and which may not compete favorably with other available options for the treatment of hATTR amyloidosis with polyneuropathy in adults, including inotersen, marketed by Ionis in several countries, which is administered subcutaneously, or tafamidis, marketed by Pfizer in several countries, which is in pill form.
For example, ONPATTRO utilizes an intravenous mode of administration with pre-medication that physicians and/or patients may not readily adopt, and which may not compete favorably with other available options for the treatment of hATTR amyloidosis with polyneuropathy in adults, including WAINUA (eplontersen), which is marketed by AstraZeneca and Ionis, and administered subcutaneously, or tafamidis, which is marketed by Pfizer in several countries and administered in pill form.
If one or more holders elect to convert their Notes, unless we elect to 77 Table of Con tents satisfy our conversion obligation by delivering solely shares of our common stock (other than paying cash in lieu of delivering any fractional share), we would be required to settle a portion or all of our conversion obligation through the payment of cash, which could adversely affect our liquidity.
If one or more holders elect to convert their Notes, unless we elect to satisfy our conversion obligation by delivering solely shares of our common stock (other than paying cash in lieu of delivering any fractional share), we would be required to settle a portion or all of our conversion obligation through the payment of cash, which could adversely affect our liquidity.
If we or our collaborators, CMOs or service providers fail to comply with applicable continuing regulatory requirements in the U.S. or foreign jurisdictions in which we seek to market our products, we or they may be subject to, among other things, fines, warning letters, holds on clinical trials, refusal by the FDA or foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, civil penalties and criminal prosecution.
If we or our collaborators, CMOs or service providers fail to comply with applicable continuing regulatory requirements in the U.S. or a foreign jurisdiction in which we seek to market our products, we or they may be subject to, among other things, fines, warning or untitled letters, holds on clinical trials, refusal by the FDA or foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, fines, injunctions, civil penalties and criminal prosecution.
In 71 Table of Con tents March 2022, we announced that we separately filed suit in United States District Court for the District of Delaware against Pfizer and Moderna seeking damages for infringement of U.S. Patent No. 11,246,933, or the ’933 patent in the parties’ manufacture and sale of their messenger RNA, or mRNA, COVID-19 vaccines.
In March 2022, we announced that we separately filed suit in United States District Court for the District of Delaware against Pfizer and Moderna seeking damages for infringement of U.S. Patent No. 11,246,933, or the ’933 patent in the parties’ manufacture and sale of their messenger RNA, or mRNA, COVID-19 vaccines.
In addition, we granted licenses or options for licenses to Ionis, Benitec Biopharma Ltd., Arrowhead, Arbutus, 74 Table of Con tents Quark, Sylentis and other companies under which these companies may independently develop RNAi therapeutics against a limited number of targets. Any one of these companies may develop its RNAi technology more rapidly and more effectively than we do.
In addition, we granted licenses or options for licenses to Ionis, Benitec Biopharma Ltd., Arrowhead, Arbutus, Quark, Sylentis and other companies under which these companies may independently develop RNAi therapeutics against a limited number of targets. Any one of these companies may develop its RNAi technology more rapidly and more effectively than we do.
In the U.S., we have entered into over 40 value-based agreements, or VBAs, and are negotiating additional VBAs with commercial health insurers.
In the U.S., we have entered into value-based agreements, or VBAs, and are negotiating additional VBAs with commercial health insurers.
While the ultimate impact of COVID-19, or any future pandemic or public health emergency, on our business is uncertain, any negative impacts of such pandemic or public health emergency, alone or in combination with others, could exacerbate other risk factors discussed herein.
While the ultimate impact of any pandemic or public health emergency on our business is uncertain, any negative impacts of such pandemic or public health emergency, alone or in combination with others, could exacerbate other risk factors discussed herein.
However, a number of our product candidates are currently in the earlier stages of development, and we will not be able to assess the impact of such regulations or any changes to such development programs for a number of years.
However, a number of our product candidates 56 Table of Contents are currently in the earlier stages of development, and we will not be able to assess the impact of such regulations or any changes to such development programs for a number of years.
Risks Related to Our Convertible Notes • We may not have sufficient cash flow from our business to pay our indebtedness. • We may not have the ability to raise the funds necessary to settle for cash conversions of the Notes or to repurchase the Notes for cash upon a fundamental change. • The conditional conversion feature of the Notes, if triggered, may adversely affect our liquidity.
Risks Related to Our Convertible Notes • We may not have sufficient cash flow from our business to pay our indebtedness. • We may not have the ability to raise the funds necessary to settle for cash conversions of our 1% Convertible Senior Notes due 2027, or the Notes, or to repurchase the Notes for cash upon a fundamental change. • The conditional conversion feature of the Notes, if triggered, may adversely affect our liquidity.
Specifically, we currently have active collaborations with, among others, Sanofi, Novartis, Regeneron, Vir, Novo Nordisk and Roche covering various products and product candidates in our pipeline. In such collaborations, we expect our current, and may expect our future, collaborators to provide substantial capabilities in clinical development, regulatory affairs, and/or marketing, sales and distribution.
Specifically, we currently have active collaborations with, among others, Roche, Regeneron, Sanofi and Novartis covering various products and product candidates in our pipeline. In such collaborations, we expect our current, and may expect any future, collaborators to provide substantial capabilities in clinical development, regulatory affairs, and/or marketing, sales and distribution.
For instance, the FDA may request additional clinical or other data or information in connection with the regulatory review of our or our collaborators’ product candidates, including by issuing a complete response letter which may require that we or our collaborators submit additional clinical or other data or impose other conditions that must be met in order to secure final approval of our or our collaborators’ NDA applications, including potentially requiring a facility inspection.
The FDA or foreign regulatory authorities may request additional clinical or other data or information in connection with the regulatory review of our or our collaborators’ product candidates, including by issuing a complete response letter that may require that we or our collaborators submit additional clinical or other data or impose other conditions that must be met in order to secure final approval of our or our collaborators’ NDA applications, including potentially requiring a facility inspection.
Our revenue from outside of the U.S. is expected to increase as our products, whether commercialized by us or our collaborators, gain marketing approval in such jurisdictions. Our primary foreign currency exposure relates to movements in the 48 Table of Con tents Japanese yen, Euro and British pound.
Our revenue from outside of the U.S. is expected to increase as our products, whether commercialized by us or our collaborators, gain marketing approval in such jurisdictions. Our primary foreign currency exposure relates to movements in the Japanese yen, Euro and British pound.
If we are not able to continue to develop and scale these capabilities, we may not be able to successfully commercialize our current and any future products. We received our first product approval in August 2018 and have established capabilities for marketing, sales, market access and distribution over the last several years.
If we are not able to continue to develop and scale these capabilities, we may not be able to successfully commercialize our products and product candidates. We received our first product approval in August 2018 and have established capabilities for marketing, sales, market access and distribution over the last several years.
Subsequently, we and Moderna jointly agreed to final judgment of non-infringement of two of our patents, and that judgment was entered by the court on August 30, 2023, and on September 7, 2023, we appealed the claim construction ruling to the Court of Appeals for the Federal Circuit in the 2022 lawsuit against Moderna.
Following the August 21, 2023 order, we and Moderna jointly agreed to final judgment of non-infringement of two of our patents, and that judgment was entered by the court on August 30, 2023, and on September 7, 2023, we appealed the claim construction ruling to the Court of Appeals for the Federal Circuit in the 2022 lawsuit against Moderna.
Additionally, timely completion of pre-clinical activities and initiation of planned clinical trials are dependent upon the availability of, for example, pre-clinical and clinical trial sites, researchers and investigators, patients or healthy volunteer subjects available for recruitment and enrollment, and regulatory agency personnel, which may be adversely affected by global health matters, such as the COVID-19 pandemic or any future pandemic or public health emergency.
Additionally, timely completion of preclinical activities and initiation of planned clinical trials are dependent upon the availability of, for example, preclinical and clinical trial sites, researchers and investigators, patients or healthy volunteer subjects available for recruitment and enrollment, and regulatory agency personnel, which may be adversely affected by global health matters, such as any pandemic or public health emergency.
We and our CROs are required to comply with applicable good clinical practice, or GCP, requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for our product candidates in clinical development, and to implement timely corrective action to address any non-compliance.
We and our CROs are required to comply with applicable GCP requirements, which are regulations and guidelines enforced by the FDA and foreign regulatory authorities for our product candidates in clinical development, and to implement timely corrective action to address any non-compliance.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeConsequently, costs related to incidents may not be covered by insurance. 79 Table of Con tents Impact of Cybersecurity Risks on Strategy and Results Our business operations and relationships with customers and suppliers are heavily reliant on technology, and any failure or disruption in our technological systems could have significant negative impacts on our business.
Biggest changeOur business operations and relationships with customers and suppliers are heavily reliant on technology, and any failure or disruption in our technological systems could have significant negative impacts on our business.
We categorize our third-party service providers by criticality, based on the criticality and sensitivity of our data each third-party service provider has access to, and, based on this, we employ a risk-based approach for review of the security measures implemented by each third-party service provider.
We categorize our third-party service providers by criticality, based on the criticality and sensitivity of our data each third-party service provider has access to, and, based on this, we employ a risk-based approach for review of the security measures implemented by our third-party service providers.
We have established a disclosure committee, which consists of our chief executive officer, chief financial officer, and senior leaders from finance, legal, accounting, corporate communications, and investor relations, including, but not limited to, our Chief Legal Officer, CIO, CISO, chief accounting officer, controller and senior vice president investor relations and corporate communications.
We have established a disclosure committee, which consists of our chief executive officer, chief financial officer, and senior leaders from finance, legal, accounting, corporate communications, and investor relations, including, but not limited to, our Chief Legal Officer, CIO, CISO, chief accounting officer, controller and Chief Corporate Communications Officer.
However, our management has determined that, during the period covered by this Annual Report on Form 10-K, no cybersecurity threats, including as a result of any previous cybersecurity incidents, have materially affected or are reasonably likely to materially affect our company, including our business strategy, operating results, or financial condition.
However, our management has determined that, during the period covered by this Annual Report on Form 10-K, no cybersecurity threats, including as a result of any previous cybersecurity incidents, 74 Table of Contents have materially affected or are reasonably likely to materially affect our company, including our business strategy, operating results, or financial condition.
The CISO briefs the disclosure committee, as necessary, on cybersecurity related matters, which includes information regarding our detection, prevention, mitigation, and remediation of cybersecurity incidents and monitoring of previously evaluated cybersecurity incidents for subsequent changes that might impact conclusions on materiality, and this information is presented to the nominating and corporate governance committee, as appropriate. 80 Table of Con tents
The CISO briefs the disclosure committee, as necessary, on cybersecurity related matters, which includes information regarding our detection, prevention, mitigation, and remediation of cybersecurity incidents and monitoring of previously evaluated cybersecurity incidents for subsequent changes that might impact conclusions on materiality, and this information is presented to the nominating and corporate governance committee, as appropriate. 75 Table of Contents
Such insurance is subject to several exclusions and may not cover the total loss or damage caused by an attack or a breach.
Such insurance is subject to several exclusions and may not cover the total loss or damage caused by an attack or a breach. Consequently, costs related to incidents may not be covered by insurance.
We believe that our current cybersecurity program provides adequate measures of protection against cybersecurity breaches and generally reduces our risks. However, cybersecurity threats are constantly evolving, becoming more frequent and more sophisticated and are being made by groups of individuals with a wide range of expertise and motives, which increases the difficulty of detecting and successfully defending against them.
While we have implemented measures to safeguard our operational and technology systems and have established a culture of monitoring and improvement, cybersecurity threats are constantly evolving, becoming more frequent and more sophisticated and are being made by groups of individuals with a wide range of expertise and motives, which increases the difficulty of detecting and successfully defending against them.
Removed
While we have implemented measures to safeguard our operational and technology systems and have established a culture of monitoring and improvement, the evolving nature of cybersecurity attacks and vulnerabilities means that these protections may not always be effective.

Item 2. Properties

Properties — owned and leased real estate

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Biggest changeTermeer Square Cambridge, Massachusetts Corporate headquarters and primary research facility 295,000 January 2034 Two five-year terms 300 Third Street Cambridge, Massachusetts Office space and additional research facility 129,000 January 2034 Two five-year terms 101 Main Street Cambridge, Massachusetts Office space* 61,000 March 2024 and June 2026 One five-year term on each lease 20 Commerce Way Norton, Massachusetts GMP manufacturing 200,000 Not applicable Not applicable 665 Concord Avenue Cambridge, Massachusetts GMP manufacturing** 15,000 September 2027 One five-year term Grafenauweg 4 6300 Zug, Switzerland International headquarters 14,500 March 2028 One five-year term Braywick Gate Braywick Road, Maidenhead Berkshire, United Kingdom Office space 21,500 May 2026 None Wisdom Cross Tower Antonio Vivaldistraat 150 Amsterdam, Netherlands Office space 12,500 April 2025 One five-year term Pacific Century Place 1-Chome-11-1 Marunouchi Chiyoda-ku Tokyo, Japan Office space 16,900 May 2025 None _________________________________________ * We lease office space located on the 12th and 13th floors at 101 Main Street, Cambridge, Massachusetts under a non-cancelable real property lease agreement by and between the Company and RREEF America REIT II CORP.
Biggest changeTermeer Square Cambridge, Massachusetts Corporate headquarters and primary research facility 295,000 January 2034 Two five-year terms 300 Third Street Cambridge, Massachusetts Office space and additional research facility 129,000 January 2034 Two five-year terms 101 Main Street Cambridge, Massachusetts Office space 37,000 June 2026 One five-year term 20 Commerce Way Norton, Massachusetts GMP manufacturing 200,000 Not applicable Not applicable 665 Concord Avenue Cambridge, Massachusetts GMP manufacturing 15,000 September 2027 One five-year term Grafenauweg 2 & 4 6300 Zug, Switzerland International headquarters 15,800 May 2029 One five-year term Braywick Gate Braywick Road, Maidenhead Berkshire, United Kingdom Office space 21,500 May 2026 None Wisdom Cross Tower Antonio Vivaldistraat 150 Amsterdam, Netherlands Office space 12,500 April 2030 One five-year term Pacific Century Place 1-Chome-11-1 Marunouchi Chiyoda-ku Tokyo, Japan Office space 12,700 May 2028 None _________________________________________ In addition to the locations above, we also occupy small offices in multiple locations in and outside of the U.S. to support our operations and growth.
ITEM 2. PROPERTIES Our operations are based primarily in Cambridge, Massachusetts; Zug, Switzerland; Maidenhead, United Kingdom; Amsterdam, Netherlands; and Tokyo, Japan. A description of certain of the facilities we lease or own as of January 31, 2024 is included in the table below. Location Primary Use Approximate Square Footage Lease Expiration Date Renewal Option 675 West Kendall Street Henri A.
ITEM 2. PROPERTIES Our operations are based primarily in Cambridge, Massachusetts; Zug, Switzerland; Maidenhead, United Kingdom; Amsterdam, Netherlands; and Tokyo, Japan. A description of certain of the facilities we lease or own as of January 31, 2025 is included in the table below. Location Primary Use Approximate Square Footage Lease Expiration Date Renewal Option 675 West Kendall Street Henri A.
In addition to the locations above, we also occupy small offices in multiple locations in and outside of the U.S. to support our operations and growth. In the future, we may lease, operate, purchase or construct additional facilities in which to conduct expanded research, development and manufacturing activities and support future commercial operations.
In the future, we may lease, operate, purchase or construct additional facilities in which to conduct expanded research, development and manufacturing activities and support future commercial operations.
Removed
PPP, dated as of April 15, 2015, or the Lease. On September 30, 2020, we entered into a First Amendment to the Lease, pursuant to which the term of the Lease with respect to the 12th and 13th floors was extended for an additional five years, through June 30, 2026.
Removed
In addition, we have a separate lease agreement for the 10th floor at 101 Main Street, which expires in March 2024 and will not be extended. ** We manufacture ONPATTRO (patisiran) formulated bulk drug product at this location.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeMINE SAFETY DISCLOSURES Not applicable. 81 Table of Con tents PART II
Biggest changeMINE SAFETY DISCLOSURES Not applicable. 76 Table of Contents PART II
ITEM 3. LEGAL PROCEEDINGS For a discussion of material pending legal proceedings, please read the section titled “Litigation” within Note 13, Commitments and Contingencies, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K, which is incorporated into this item by reference. ITEM 4.
ITEM 3. LEGAL PROCEEDINGS For a discussion of material pending legal proceedings, please read the section titled “Legal Matters” within Note 13, Commitments and Contingencies, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K, which is incorporated into this item by reference. ITEM 4.

Item 5. Market for Registrant's Common Equity

Market for Common Equity — stock, dividends, buybacks

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Biggest changeThe stock price performance reflected in the graph below is not necessarily indicative of future price performance. 82 Table of Con tents Comparison of Five-Year Cumulative Total Return Among Alnylam Pharmaceuticals, Inc., Nasdaq Composite Total Return and Nasdaq Biotechnology Total Return 12/31/2018 12/31/2019 12/31/2020 12/31/2021 12/30/2022 12/29/2023 Alnylam Pharmaceuticals, Inc. $ 100.00 $ 157.96 $ 178.26 $ 232.59 $ 325.95 $ 262.53 Nasdaq Composite Total Return $ 100.00 $ 136.69 $ 198.10 $ 242.03 $ 163.28 $ 236.17 Nasdaq Biotechnology Total Return $ 100.00 $ 125.11 $ 158.17 $ 158.20 $ 142.19 $ 148.72 ITEM 6.
Biggest changeThe stock price performance reflected in the graph below is not necessarily indicative of future price performance. 77 Table of Contents Comparison of Five-Year Cumulative Total Return Among Alnylam Pharmaceuticals, Inc., Nasdaq Composite Total Return and Nasdaq Biotechnology Total Return 12/31/2019 12/31/2020 12/31/2021 12/30/2022 12/29/2023 12/31/2024 Alnylam Pharmaceuticals, Inc. $ 100.00 $ 112.85 $ 147.24 $ 206.35 $ 166.20 $ 204.32 Nasdaq Composite Total Return $ 100.00 $ 144.92 $ 177.06 $ 119.45 $ 172.77 $ 223.87 Nasdaq Biotechnology Total Return $ 100.00 $ 126.42 $ 126.45 $ 113.65 $ 118.87 $ 118.20 ITEM 6.
ITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES Market Information Our common stock trades on The Nasdaq Global Select Market under the symbol “ALNY.” Holders of Record At January 31, 2024, there were 24 holders 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 Our common stock trades on The Nasdaq Global Select Market under the symbol “ALNY.” Holders of Record At January 31, 2025, there were 26 holders of record of our common stock.
The comparative stock performance graph below compares the five-year cumulative total stockholder return (assuming reinvestment of dividends, if any) from investing $100 on the last trading day of 2018, to the close of the last trading day of 2023, in each of our common stock and the selected indices.
The comparative stock performance graph below compares the five-year cumulative total stockholder return (assuming reinvestment of dividends, if any) from investing $100 on the last trading day of 2019, to the close of the last trading day of 2024, in each of our common stock and the selected indices.

Item 7. Management's Discussion & Analysis

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

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Biggest changeDiscussion of Results of Operations Revenues Total revenues consist of the following: Years Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Net product revenues $ 1,241,474 $ 894,329 $ 662,138 $ 347,145 39 % $ 232,191 35 % Net revenues from collaborations 546,185 134,912 180,953 411,273 305 % (46,041) (25) % Royalty revenue 40,633 8,177 1,196 32,456 397 % 6,981 * Total $ 1,828,292 $ 1,037,418 $ 844,287 $ 790,874 76 % $ 193,131 23 % * Indicates the percentage change period over period is greater than 500%. 84 Table of Con tents Net Product Revenues Net product revenues consist of the following, by product and region: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change ONPATTRO United States $ 97,739 $ 246,748 $ 213,210 $ (149,009) (60) % $ 33,538 16 % Europe 210,916 224,063 190,435 (13,147) (6) % 33,628 18 % Rest of World 45,891 86,797 71,092 (40,906) (47) % 15,705 22 % Total 354,546 557,608 474,737 (203,062) (36) % 82,871 17 % AMVUTTRA United States 411,169 82,521 — 328,648 398 % 82,521 N/A Europe 70,898 4,214 — 66,684 * 4,214 N/A Rest of World 75,771 7,060 — 68,711 * 7,060 N/A Total 557,838 93,795 — 464,043 495 % 93,795 N/A GIVLAARI United States 141,954 115,659 92,747 26,295 23 % 22,912 25 % Europe 57,498 48,670 30,895 8,828 18 % 17,775 58 % Rest of World 19,799 8,815 4,173 10,984 125 % 4,642 111 % Total 219,251 173,144 127,815 46,107 27 % 45,329 35 % OXLUMO United States 38,159 27,698 18,876 10,461 38 % 8,822 47 % Europe 60,025 37,915 38,949 22,110 58 % (1,034) (3) % Rest of World 11,655 4,169 1,761 7,486 180 % 2,408 137 % Total 109,839 69,782 59,586 40,057 57 % 10,196 17 % Total net product revenues $ 1,241,474 $ 894,329 $ 662,138 $ 347,145 39 % $ 232,191 35 % Net product revenues increased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to the launch of AMVUTTRA in the third quarter of 2022, partially offset by a decrease of demand for ONPATTRO due to patient switches to AMVUTTRA.
Biggest changeDiscussion of Results of Operations Revenues Total revenues consist of the following: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Net product revenues $ 1,646,228 $ 1,241,474 $ 894,329 $ 404,754 33 % $ 347,145 39 % Net revenues from collaborations 510,221 546,185 134,912 (35,964) (7) % 411,273 305 % Royalty revenue 91,794 40,633 8,177 51,161 126 % 32,456 397 % Total $ 2,248,243 $ 1,828,292 $ 1,037,418 $ 419,951 23 % $ 790,874 76 % 79 Table of Contents Net Product Revenues Net product revenues consist of the following, by product and region: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change ONPATTRO United States $ 74,787 $ 97,739 $ 246,748 $ (22,952) (23) % $ (149,009) (60) % Europe 134,197 210,916 224,063 (76,719) (36) % (13,147) (6) % Rest of World 43,873 45,891 86,797 (2,018) (4) % (40,906) (47) % Total 252,857 354,546 557,608 (101,689) (29) % (203,062) (36) % AMVUTTRA United States 630,613 411,169 82,521 219,444 53 % 328,648 398 % Europe 235,441 70,898 4,214 164,543 232 % 66,684 * Rest of World 104,396 75,771 7,060 28,625 38 % 68,711 * Total 970,450 557,838 93,795 412,612 74 % 464,043 495 % GIVLAARI United States 165,373 141,954 115,659 23,419 16 % 26,295 23 % Europe 65,906 57,498 48,670 8,408 15 % 8,828 18 % Rest of World 24,592 19,799 8,815 4,793 24 % 10,984 125 % Total 255,871 219,251 173,144 36,620 17 % 46,107 27 % OXLUMO United States 62,766 38,159 27,698 24,607 64 % 10,461 38 % Europe 80,753 60,025 37,915 20,728 35 % 22,110 58 % Rest of World 23,531 11,655 4,169 11,876 102 % 7,486 180 % Total 167,050 109,839 69,782 57,211 52 % 40,057 57 % Total net product revenues $ 1,646,228 $ 1,241,474 $ 894,329 $ 404,754 33 % $ 347,145 39 % * Indicates the percentage change period over period is greater than 500%.
During the years ended December 31, 2023 and 2022, in connection with advancing activities under our collaboration agreements, we incurred research and development expenses, primarily related to external development and clinical expenses, including the manufacture of clinical product.
During the years ended December 31, 2024, 2023 and 2022, in connection with advancing activities under our collaboration agreements, we incurred research and development expenses, primarily related to external development and clinical expenses, including the manufacture of clinical product.
We currently have programs focused on a number of therapeutic areas and, as of December 31, 2023, we generate worldwide product revenues from four commercialized products, ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, primarily in the U.S. and Europe.
We currently have programs focused on a number of therapeutic areas and, as of December 31, 2024, we generate worldwide product revenues from four commercialized products, ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, primarily in the U.S. and Europe.
Please see Note 3 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K for balances and activity in each product revenue allowance and reserve category for the years ended December 31, 2023 and 2022.
Please see Note 3, Net Product Revenues, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K for balances and activity in each product revenue allowance and reserve category for the years ended December 31, 2024 and 2023.
“Business” you can also find a summary of key events in 2023 and 2024 to-date related to our marketed products and our clinical development programs. We have incurred significant losses since we commenced operations in 2002 and as of December 31, 2023, we had an accumulated deficit of $7.01 billion.
“Business” you can also find a summary of key events in 2024 and 2025 to-date related to our marketed products and our clinical development programs. We have incurred significant losses since we commenced operations in 2002 and as of December 31, 2024, we had an accumulated deficit of $7.29 billion.
A substantial portion of our total revenues in recent years has been derived from collaboration revenues from collaborations with Roche, Regeneron and Novartis.
A meaningful portion of our total revenues in recent years has been derived from collaboration revenues from collaborations with Roche, Regeneron and Novartis.
However, we expect that certain expenses will be variable depending on the timing of manufacturing batches, clinical trial enrollment and results, regulatory review of our product candidates and programs, and stock-based compensation expenses due to our determination regarding the probability of vesting for performance-based awards.
However, we expect that certain expenses will be variable depending on the timing of manufacturing batches, clinical trial enrollment and results, regulatory review of our product candidates and programs, and stock-based compensation expenses based on our determinations regarding the probability of vesting for performance-based awards.
As a result of planned expenditures for research and development activities relating to our research platform, our drug development programs, including clinical trial and manufacturing costs, the establishment of late-stage clinical and commercial capabilities, including global commercial operations, continued management and growth of our patent portfolio, collaborations and general corporate activities, we expect to incur additional operating losses.
As a result of planned expenditures for research and development activities relating to our research platform, our drug development programs, including clinical trial and manufacturing costs, the continued build-out of late-stage clinical and commercial capabilities, including global commercial operations, continued management and growth of our patent portfolio, collaborations and general corporate activities, we may incur additional operating losses.
Actual results could vary materially from these estimates. 90 Table of Con tents Recent Accounting Pronouncements Please read Note 2 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K for a description of recent accounting pronouncements.
Actual results could vary materially from these estimates. Recent Accounting Pronouncements Please read Note 2, Summary of Significant Accounting Policies, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K for a description of recent accounting pronouncements.
An increase or decrease of 10% to the interest rate would result in an increase or decrease to our liability related to the sale of future royalties of approximately $33.9 million.
An increase or decrease of 10% to the interest rate would result in an increase or decrease to our liability related to the sale of future royalties of approximately $35.6 million.
Royalty revenue increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, due to increased royalties earned from global net sales of Leqvio by our collaborator, Novartis.
Royalty revenue increased during the year ended December 31, 2024, as compared to the year ended December 31, 2023, due to increased volume and rate of royalties earned from global net sales of Leqvio by our collaborator, Novartis.
Since we commenced operations in 2002, we have generated significant losses and as of December 31, 2023, we had an accumulated deficit of $7.01 billion. As of December 31, 2023, we had cash, cash equivalents and marketable securities of $2.44 billion, compared to $2.19 billion as of December 31, 2022.
Since we commenced operations in 2002, we have generated significant losses and as of December 31, 2024, we had an accumulated deficit of $7.29 billion. As of December 31, 2024, we had cash, cash equivalents and marketable securities of $2.69 billion, compared to $2.44 billion as of December 31, 2023.
ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS Overview We are a global commercial-stage biopharmaceutical company that discovers, develops, manufactures and commercializes novel therapeutics based on RNAi. Our commercial products and broad pipeline of investigational RNAi therapeutics are focused in rare, specialty and select prevalent indications. As described in Part I, Item 1.
ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS Overview We are a global commercial-stage biopharmaceutical company that discovers, develops, manufactures and commercializes novel therapeutics based on RNAi. Our commercial products and broad pipeline of investigational RNAi therapeutics are targeting a broad range of disease areas and indications. As described in Part I, Item 1.
Based on our current operating plan, we believe that our cash, cash equivalents and marketable securities as of December 31, 2023, together with the cash we expect to generate from product sales and under our current collaborations, will be sufficient to satisfy our near-term capital and operating needs for at least the next 12 months from the filing of this Annual Report on Form 10-K.
Based on our current operating plan, we believe that our cash, cash equivalents and marketable securities as of December 31, 2024 will be sufficient to satisfy our near-term capital and operating needs for at least 12 months from the filing of this Annual Report on Form 10-K.
In addition, we anticipate that we will continue to generate losses as a result of planned expenditures for research and development activities relating to our research platform, our drug development programs, including clinical trial and manufacturing costs, the establishment of late-stage clinical, manufacturing, commercial and compliance capabilities, including global operations, continued management and growth of our intellectual property including our patent portfolio, collaborations and general corporate activities.
In addition, we may incur additional operating losses as a result of planned expenditures for research and development activities relating to our research platform, our drug development programs, including clinical trial and manufacturing costs, the continued build-out of late-stage clinical, manufacturing, commercial and compliance capabilities, including global operations, continued management and growth of our intellectual property, including our patent portfolio, collaborations and general corporate activities.
However, our ongoing development efforts may not be successful and we may not be able to commence sales of any other products and/or successfully market and sell ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or any other approved products in the future.
However, our ongoing development and regulatory efforts may not be successful and we may not be able to commence sales of any other products and/or successfully expand the labels of or market and sell our existing commercialized products or any other approved products in the future.
We anticipate variability in our cost of goods sold as a percentage of net product revenues in 2024, as compared to 2023. We expect our cost of goods sold will increase during 2024, as compared to 2023, primarily as a result of an expected increase in net product sales as well as increased royalties.
We expect our cost of goods sold, including cost of goods sold as a percentage of net product revenues, will increase during 2025, as compared to 2024, primarily as a result of an expected increase in net product revenues and increased royalties on net sales of AMVUTTRA.
The liability related to the sale of future royalties and the related interest expense are based on our current estimates of future royalties and commercial milestones expected to be paid over the life of the arrangement, which we determine by using third-party forecasts of Leqvio’s global net revenue.
Interest on the liability related to the sale of future royalties is recognized using the effective interest rate method over the life of the related royalty stream. 85 Table of Contents The liability related to the sale of future royalties and the related interest expense are based on our current estimates of future royalties and commercial milestones expected to be paid over the life of the arrangement, which we determine by using third-party data to estimate Leqvio’s global net revenue.
We expect that research and development expenses combined with selling, general and administrative expenses will increase during 2024, as compared to 2023, as we continue to advance and develop our platform and pipeline, advance our product candidates, including collaborated programs, into later-stage development, prepare regulatory submissions and continue to build-out our global commercial and compliance infrastructure as well as launch our commercial products into additional 87 Table of Con tents markets, assuming regulatory approvals.
We expect that research and development expenses combined with selling, general and administrative expenses will increase during 2025, as compared to 2024, as we continue to build out our global commercial and compliance infrastructure, launch our current commercial products into new markets, prepare for future commercial product launches, including the launch of AMVUTTRA in cardiomyopathy, assuming regulatory approvals, advance our product candidates, including collaborated programs, into later-stage development, advance and develop our platform and preclinical pipeline, and prepare regulatory submissions.
We expect capital expenditures to increase in 2024 to support the increase in our manufacturing and production capacity needs. • Amounts related to future long-term debt total $1.02 billion, of which we do not expect to make payments on principal within the next 12 months. • Payments associated with the liability related to the sale of future royalties were approximately $21.6 million in 2023, with an estimated $58.2 million to be paid within the next 12 months. • Amount associated with the achievement of a development milestone payable to Blackstone was $84.5 million as of December 31, 2023, with $21.1 million to be paid within the next 12 months.
We expect capital expenditures to increase in 2025 to support the increase in our manufacturing and production capacity needs. • Amounts related to future long-term debt total $1.02 billion, of which we do not expect to make payments on principal within the next 12 months. • Payments to Blackstone associated with the liability related to the sale of future royalties were $57.0 million in 2024, with an estimated $131.8 million to be paid within the next 12 months. • Payments associated with an achieved development milestone due to Blackstone were $21.1 million in 2024, with the same amount to be paid within the next 12 months.
While we believe 2019 was our peak operating loss year, we expect to continue to incur annual operating losses, and will require substantial resources over the next several years as we expand our efforts to discover, develop and commercialize RNAi therapeutics, and aim to achieve financial self-sustainability by the end of 2025.
We will require substantial resources over the next several years as we expand our efforts to discover, develop and commercialize RNAi therapeutics, and aim to achieve financial self-sustainability by the end of 2025.
Recent and expected working and other capital requirements, in addition to the above matters, also include the items described below: • Amounts related to future lease payments for operating lease obligations at December 31, 2023 totaled $418.0 million, with $43.6 million expected to be paid within the next 12 months.
Recent and expected working and other capital requirements, in addition to the above matters, also include the items described below: • Amounts related to future lease payments for operating lease obligations as of December 31, 2024 totaled $384.5 million, with $43.4 million expected to be paid within the next 12 months. • Cash outflows for capital expenditures were $34.3 million in 2024 and $62.2 million in 2023.
Liability Related to the Sale of Future Royalties We account for the liability related to the sale of future royalties as a debt financing, as we have significant continuing involvement in the generation of the cash flows.
Liability Related to the Sale of Future Royalties We account for the liability related to the sale of future royalties as a debt financing.
We are also subject to potential rebates in connection with our value-based agreements, or VBAs, with certain commercial payors. 89 Table of Con tents We use the expected value method, which is the sum of probability-weighted amounts in a range of possible consideration amounts, or the most likely amount method, which is the single most likely amount in a range of possible considerations, to estimate variable consideration related to our product revenues.
We use the expected value method, which is the sum of probability-weighted amounts in a range of possible consideration amounts, or the most likely amount method, which is the single most likely amount in a range of possible considerations, to estimate variable consideration related to our product revenues.
Investing Activities Net cash used in investing activities increased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to net activities related to our marketable debt securities as a result of an increase of cash invested in marketable debt securities.
Investing Activities Net cash used in investing activities decreased during the year ended December 31, 2024, compared to the year ended December 31, 2023, primarily due to the timing of net investments of cash into our marketable debt securities.
These estimates reflect our historical experiences, current contractual requirements, and forecasted plans of development or manufacturing activities. We adjust these estimates for changes in actual costs incurred, contractual terms, and further forecasts. Such changes in estimates could have a significant impact on revenue and earnings in the period of the adjustment.
The amount of revenue from collaborations that we recognize is based, in part, on estimates of total costs to be incurred. These estimates reflect our historical experiences, current contractual requirements, and forecasted plans of development or manufacturing activities. We adjust these estimates for changes in actual costs incurred, contractual terms, and further forecasts.
Operating Costs and Expenses Operating costs and expenses consist of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Cost of goods sold $ 268,216 $ 140,174 $ 115,005 $ 128,042 91 % $ 25,169 22 % Cost of goods sold as a percentage of net product revenues 21.6 % 15.7 % 17.4 % Cost of collaborations and royalties 42,190 28,643 25,139 13,547 47 % 3,504 14 % Research and development 1,004,415 883,015 792,156 121,400 14 % 90,859 11 % Selling, general and administrative 795,646 770,658 620,639 24,988 3 % 150,019 24 % Total $ 2,110,467 $ 1,822,490 $ 1,552,939 $ 287,977 16 % $ 269,551 17 % Cost of Goods Sold Cost of goods sold as a percentage of net product revenues increased to 21.6% for the year ended December 31, 2023, as compared to 15.7% for the year ended December 31, 2022, primarily due to the following: • Increased volume and rate of royalties payable on net sales of AMVUTTRA.
Operating Costs and Expenses Operating costs and expenses consist of the following: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Cost of goods sold $ 306,513 $ 268,216 $ 140,174 $ 38,297 14 % $ 128,042 91 % Cost of goods sold as a percentage of net product revenues 18.6 % 21.6 % 15.7 % Cost of collaborations and royalties 16,857 42,190 28,643 (25,333) (60) % 13,547 47 % Research and development 1,126,232 1,004,415 883,015 121,817 12 % 121,400 14 % Selling, general and administrative 975,526 795,646 770,658 179,880 23 % 24,988 3 % Total $ 2,425,128 $ 2,110,467 $ 1,822,490 $ 314,661 15 % $ 287,977 16 % Cost of Goods Sold Cost of goods sold as a percentage of net product revenues decreased to 18.6% for the year ended December 31, 2024, as compared to 21.6% for the year ended December 31, 2023.
We expect our royalty revenues will increase in 2024, as compared to 2023, due to the continued growth of royalties earned from global net sales of Leqvio by our collaborator, Novartis. The amount of revenue from collaborations that we recognize, in part, is based on estimates of total costs to be incurred.
We expect net revenues from collaborations will increase in 2025, as compared to 2024, primarily driven by higher anticipated revenues under our Roche Collaboration and License Agreement. We expect our royalty revenue will increase in 2025, as compared to 2024, due to the continued growth of royalties earned from global net sales of Leqvio by our collaborator, Novartis.
Net Revenues from Collaborations We earn revenue in connection with collaboration agreements which allow our collaborators to utilize our technology platforms and develop product candidates.
We use the expected value method to estimate variable consideration for chargebacks, certain rebates, and other incentives and we use the most likely amount method for certain rebates and trade discounts and allowances. Net Revenues from Collaborations We earn revenue in connection with collaboration agreements which allow our collaborators to utilize our technology platforms and develop product candidates.
Net Revenues from Collaborations and Royalty Revenue Net revenues from collaborations and royalty revenue consist of the following: Years Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Roche $ 337,802 $ — $ — $ 337,802 N/A $ — N/A Regeneron Pharmaceuticals 100,468 87,844 113,226 12,624 14 % (25,382) (22) % Novartis AG 86,727 43,159 49,120 43,568 101 % (5,961) (12) % Other 21,188 3,909 18,607 17,279 442 % (14,698) (79) % Total net revenues from collaborations $ 546,185 $ 134,912 $ 180,953 $ 411,273 305 % $ (46,041) (25) % Royalty revenue $ 40,633 $ 8,177 $ 1,196 $ 32,456 397 % $ 6,981 * Net revenues from collaborations increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to revenue recognized under our agreements with Roche and Novartis.
Net Revenues from Collaborations and Royalty Revenue Net revenues from collaborations and royalty revenue consist of the following: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Roche $ 119,489 $ 337,802 $ — $ (218,313) (65) % $ 337,802 N/A Regeneron Pharmaceuticals 302,798 100,468 87,844 202,330 201 % 12,624 14 % Novartis AG 79,759 86,727 43,159 (6,968) (8) % 43,568 101 % Other 8,175 21,188 3,909 (13,013) (61) % 17,279 442 % Total net revenues from collaborations $ 510,221 $ 546,185 $ 134,912 $ (35,964) (7) % $ 411,273 305 % Royalty revenue $ 91,794 $ 40,633 $ 8,177 $ 51,161 126 % $ 32,456 397 % 80 Table of Contents Net revenues from collaborations decreased during the year ended December 31, 2024, as compared to the year ended December 31, 2023, primarily driven by: • a decrease in revenue recognized under our Roche Collaboration in 2024 due to the recognition of $310.0 million of revenue upon the transfer of licenses to Roche during the third quarter of 2023.
The following table summarizes research and development expenses incurred, for which we recognize revenue, that are directly attributable to our collaboration agreements, by collaborator: Year Ended December 31, (In thousands) 2023 2022 2021 Roche $ 44,620 $ — $ — Regeneron Pharmaceuticals 77,444 43,002 73,411 Other 4,951 1,172 15,575 Total $ 127,015 $ 44,174 $ 88,986 Selling, General and Administrative Selling, general and administrative expenses consist of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Compensation and related $ 298,888 $ 273,262 $ 224,237 $ 25,626 9 % $ 49,025 22 % Consulting and professional services 226,664 226,941 201,841 (277) — % 25,100 12 % Occupancy and all other costs 145,687 131,967 97,259 13,720 10 % 34,708 36 % Stock-based compensation 124,407 138,488 97,302 (14,081) (10) % 41,186 42 % Total $ 795,646 $ 770,658 $ 620,639 $ 24,988 3 % $ 150,019 24 % Selling, general and administrative expenses increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to increased headcount and other investments supporting our strategic growth including the global launch of AMVUTTRA.
The following table summarizes research and development expenses incurred, for which we recognize revenue, that are directly attributable to our collaboration agreements, by collaborator: Years Ended December 31, (In thousands) 2024 2023 2022 Roche $ 92,725 $ 44,620 $ — Regeneron Pharmaceuticals 71,659 77,444 43,002 Other 8,525 4,951 1,172 Total $ 172,909 $ 127,015 $ 44,174 82 Table of Contents Selling, General and Administrative Selling, general and administrative expenses consist of the following: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Compensation and related $ 386,743 $ 298,888 $ 273,262 $ 87,855 29 % $ 25,626 9 % Consulting and professional services 274,539 226,664 226,941 47,875 21 % (277) — % Occupancy and all other costs (1) 169,909 145,687 131,967 24,222 17 % 13,720 10 % Stock-based compensation 144,335 124,407 138,488 19,928 16 % (14,081) (10) % Total $ 975,526 $ 795,646 $ 770,658 $ 179,880 23 % $ 24,988 3 % (1) Occupancy and all other costs includes facilities, information technology, depreciation and certain departmental expenses.
Other (Expense) Income Other (expense) income consists of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Interest expense $ (121,221) $ (155,968) $ (143,021) $ 34,747 (22) % $ (12,947) 9 % Other expense, net Interest income 95,561 24,808 1,579 70,753 285 % 23,229 * Realized and unrealized (losses) gains on marketable equity securities (16,944) (33,312) 55,695 16,368 (49) % (89,007) (160) % Change in fair value of development derivative liability (90,997) (94,659) (38,433) 3,662 (4) % (56,226) 146 % Other (17,741) (6,204) (19,312) (11,537) 186 % 13,108 (68) % Loss on the extinguishment of debt — (76,586) — 76,586 (100) % (76,586) N/A Total $ (151,342) $ (341,921) $ (143,492) $ 190,579 (56) % $ (198,429) 138 % * Indicates the percentage change period over period is greater than 500%.
Other (Expense) Income Other (expense) income consists of the following: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Interest expense $ (141,858) $ (121,221) $ (155,968) $ (20,637) 17 % $ 34,747 (22) % Interest income 121,992 95,561 24,808 26,431 28 % 70,753 285 % Other expense, net Realized and unrealized losses on marketable equity securities (3,022) (16,944) (33,312) 13,922 (82) % 16,368 (49) % Change in fair value of development derivative liability (170,770) (90,997) (94,659) (79,773) 88 % 3,662 (4) % Other (6,832) (17,741) (6,204) 10,909 (61) % (11,537) 186 % Loss on the extinguishment of debt — — (76,586) — N/A 76,586 (100) % Total $ (200,490) $ (151,342) $ (341,921) $ (49,148) 32 % $ 190,579 (56) % Total other expense, net increased during the year ended December 31, 2024, as compared to the year ended December 31, 2023, primarily due to increased loss associated with the change in fair value of the development derivative liability as a result of valuation updates driven by the positive topline results for the HELIOS-B clinical trial announced in June 2024, partially offset by increased interest income driven by higher market interest rates on our marketable debt securities.
Cost of collaborations and royalties Cost of collaborations and royalties increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to increased demand of GalNAc material supplied to our collaborators to support certain product manufacturing and ongoing clinical trials and increased royalties payable to third parties on the net sales of licensed products by Novartis.
Cost of Collaborations and Royalties Cost of collaborations and royalties decreased during the year ended December 31, 2024, as compared to the year ended December 31, 2023, primarily due to decreased demand for GalNAc material supplied to our collaborators in support of certain 81 Table of Contents product manufacturing as our collaborators transition to producing the material independently, as well as reduced royalties payable from the expiration of licenses of third-party intellectual property.
Liquidity and Capital Resources The following table summarizes our cash flow activities: Year Ended December 31, $ Change (In thousands) 2023 2022 2021 2023 vs 2022 2022 vs 2021 Net cash provided by (used in): Operating activities $ 104,156 $ (541,274) $ (641,693) $ 645,430 $ 100,419 Investing activities $ (336,350) $ 169,354 $ (273,300) $ (505,704) $ 442,654 Financing activities $ 172,131 $ 425,753 $ 1,247,118 $ (253,622) $ (821,365) Operating Activities Net cash provided by operating activities increased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to receipt of a $310.0 million up-front payment received in connection with the Roche Collaboration and License Agreement and $100.0 million payment from Regeneron in connection with achieving certain criteria during early clinical development for our CNS program, ALN-APP, in addition to cash receipts from increased product sales, offset by cash disbursements related to working capital payments.
Liquidity and Capital Resources The following table summarizes our cash flow activities: Years Ended December 31, $ Change (In thousands) 2024 2023 2022 2024 vs 2023 2023 vs 2022 Net cash (used in) provided by: Operating activities $ (8,312) $ 104,156 $ (541,274) $ (112,468) $ 645,430 Investing activities $ (116,840) $ (336,350) $ 169,354 $ 219,510 $ (505,704) Financing activities $ 294,159 $ 172,131 $ 425,753 $ 122,028 $ (253,622) Operating Activities Net cash used in operating activities increased during the year ended December 31, 2024, compared to the year ended December 31, 2023, primarily due to decreased cash received from our collaborators, partially offset by stronger cash receipts from increased product sales.
Such collaborations include, or may include in the future, license and other fees, funded research and development, milestone payments and royalties on product sales by our licensors, including royalties on sales of Leqvio made by our collaborator, Novartis, as well as proceeds from the sale of equity or debt. 83 Table of Con tents Results of Operations The following data summarizes the results of our operations: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Total revenues $ 1,828,292 $ 1,037,418 $ 844,287 $ 790,874 76 % $ 193,131 23 % Operating costs and expenses $ 2,110,467 $ 1,822,490 $ 1,552,939 $ 287,977 16 % $ 269,551 17 % Loss from operations $ (282,175) $ (785,072) $ (708,652) $ 502,897 (64) % $ (76,420) 11 % Net loss $ (440,242) $ (1,131,156) $ (852,824) $ 690,914 (61) % $ (278,332) 33 % For discussion of our 2022 results and a comparison with 2021 results please refer to “Management’s Discussion and Analysis of Financial Conditions and Results of Operations” in our Annual Report on Form 10-K for the fiscal year ended December 31, 2022 that was filed with the SEC on February 23, 2023.
Such collaborations include, or may include in the future, license and other fees, equity investments, funded research and development, milestone payments and royalties on product sales by our licensors, including royalties on sales of Leqvio made by our collaborator Novartis. 78 Table of Contents Results of Operations The following data summarizes the results of our operations: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Total revenues $ 2,248,243 $ 1,828,292 $ 1,037,418 $ 419,951 23 % $ 790,874 76 % Total operating costs and expenses $ 2,425,128 $ 2,110,467 $ 1,822,490 $ 314,661 15 % $ 287,977 16 % Loss from operations $ (176,885) $ (282,175) $ (785,072) $ 105,290 (37) % $ 502,897 (64) % Total other expense, net $ (200,490) $ (151,342) $ (341,921) $ (49,148) 32 % $ 190,579 (56) % Benefit from (provision for) income taxes $ 99,218 $ (6,725) $ (4,163) $ 105,943 * $ (2,562) 62 % Net loss $ (278,157) $ (440,242) $ (1,131,156) $ 162,085 (37) % $ 690,914 (61) % * Indicates the percentage change period over period is greater than 500%.
We expect our cost of collaborations and royalties will decrease during 2024, as compared to 2023, primarily due to a decrease in demand of GalNAc material supplied to our collaborators in support of certain product manufacturing as our collaborators begin to transition to producing the material independently. 86 Table of Con tents Research and Development Research and development expenses consist of the following: Year Ended December 31, 2023 vs 2022 2022 vs 2021 (In thousands, except percentages) 2023 2022 2021 $ Change % Change $ Change % Change Clinical research and outside services $ 485,732 $ 438,418 $ 418,985 $ 47,314 11 % $ 19,433 5 % Compensation and related 260,423 225,589 196,134 34,834 15 % 29,455 15 % Occupancy and all other costs 160,987 126,847 108,622 34,140 27 % 18,225 17 % Stock-based compensation 97,273 92,161 68,415 5,112 6 % 23,746 35 % Total $ 1,004,415 $ 883,015 $ 792,156 $ 121,400 14 % $ 90,859 11 % Research and development expenses increased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to the following: • Increased compensation and related expenses as a result of increased headcount to support our R&D pipeline and development expenses; • Increased clinical research and outside services primarily associated with zilebesiran as we reached full enrollment for our KARDIA-1 and KARDIA-2 clinical studies and additional costs associated with manufacturing batches associated with those clinical activities.
Research and Development Research and development expenses consist of the following: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Clinical research and outside services $ 509,129 $ 485,732 $ 438,418 $ 23,397 5 % $ 47,314 11 % Compensation and related 327,929 260,423 225,589 67,506 26 % 34,834 15 % Occupancy and all other costs (1) 161,425 160,987 126,847 438 — % 34,140 27 % Stock-based compensation 127,749 97,273 92,161 30,476 31 % 5,112 6 % Total $ 1,126,232 $ 1,004,415 $ 883,015 $ 121,817 12 % $ 121,400 14 % (1) Occupancy and all other costs includes facilities, information technology, depreciation and certain departmental expenses.
Our collaborator is eligible to receive tiered royalties of 15% to 30% based on global annual net sales and therefore the growth in AMVUTTRA net sales during 2023 resulted in more net sales and a higher tier rate for the applicable royalties payable; and • Increased excess and obsolete charges primarily due to cancelling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the use of patisiran for the treatment of patients with ATTR amyloidosis with cardiomyopathy for which we did not receive regulatory approval in the U.S.
Approximately 5.0% of the 21.6% of cost of goods sold as a percentage of net product revenues for the year ended December 31, 2023 was attributable to cancelled manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the use of ONPATTRO for the treatment of patients with ATTR amyloidosis with cardiomyopathy, for which we did not receive regulatory approval in the U.S.
Removed
Additional growth was related to an increase in patients on GIVLAARI and OXLUMO.
Added
For a discussion of our 2023 results and a comparison with 2022 results please refer to “Management’s Discussion and Analysis of Financial Conditions and Results of Operations” in our Annual Report on Form 10-K for the fiscal year ended December 31, 2023, which was filed with the SEC on February 15, 2024.
Removed
During 2023, we recognized $337.8 million of revenue under our Collaboration and License Agreement with Roche, which was executed in July 85 Table of Con tents 2023, and under our Novartis Collaboration Agreement we recognized an additional $30.0 million of revenue, compared to 2022, associated with the achievement of specified commercialization and regulatory milestones.
Added
Net product revenues increased during the year ended December 31, 2024, compared to the year ended December 31, 2023, primarily due to growth from sales of AMVUTTRA driven by increased patient demand, partially offset by a decrease in sales of ONPATTRO due to patient switches to AMVUTTRA, as well as increased patients on GIVLAARI and OXLUMO therapies.
Removed
We expect net revenues from collaboration will decrease in 2024, as compared to 2023, primarily driven by a reduction in the revenues recognized under our Roche Collaboration and License Agreement.
Added
Partially offset by: • revenue of $185.0 million recognized under our Regeneron Collaboration as we modified the collaboration in June 2024 and provided Regeneron with an exclusive license to develop, manufacture and commercialize cemdisiran as a monotherapy; and • recognition of $65.0 million in revenue under our Roche Collaboration associated with dosing the first patient in the zilebesiran KARDIA-3 clinical trial during 2024.
Removed
Costs associated with clinical trials of other programs such as ALN-TTRsc04 and our ongoing early development studies also were higher when compared to 2022; and • Increased occupancy and all other costs as a result of higher costs related to infrastructure and other professional services to support our growing clinical footprint.
Added
Such changes in estimates could have a significant impact on revenue and earnings in the period of the adjustment.
Removed
Total other expense decreased during the year ended December 31, 2023, as compared to the year ended December 31, 2022, primarily due to increased interest income driven by higher market interest rates on our marketable debt securities, decreased interest expense as a result of a more favorable interest rate under the Convertible Senior Notes compared with the interest rate under the credit facility previously held with Blackstone and a $76.6 million loss on the extinguishment of the Blackstone credit agreement recognized in 2022.
Added
These one-time charges in 2023 did not recur in 2024, resulting in the decrease in cost of goods sold as a percentage of net product revenues in 2024, which was partially offset by higher volume and royalty rates payable on net sales of AMVUTTRA in 2024.
Removed
Financing Activities Net cash provided by financing activities decreased during the year ended December 31, 2023, compared to the year ended December 31, 2022, primarily due to greater cash received in 2022, including $136.2 million received from the issuance of convertible debt, net of repayment of the credit facility held with Blackstone and purchase of capped call transactions in September 2022, and greater net proceeds from the issuance of common stock in connection with stock option exercises and other types of equity. 88 Table of Con tents Additional Capital Requirements We currently have programs focused on a number of therapeutic areas and, as of December 31, 2023, have received regulatory approval and commercially launched four products.
Added
We expect our cost of collaborations and royalties will decrease during 2025, as compared to 2024, primarily as a result of our collaborators transitioning to produce GalNAc material independently.
Removed
Cash outflows for capital expenditures were $62.2 million in 2023 and $72.1 million in 2022.
Added
Research and development expenses increased during the year ended December 31, 2024, as compared to the year ended December 31, 2023, primarily due to the following: • increased clinical trial expenses mainly related to the advancement of our KARDIA-3 and cAPPRicorn-1 clinical programs; • increased costs associated with our preclinical activities as we develop our clinical pipeline of RNAi therapeutics targeting multiple tissue types; • increased employee compensation and related expenses to support our research and development pipeline and development expenses; and • increased stock-based compensation expenses primarily due to the accounting for certain performance-based awards.
Removed
We use the expected value method to estimate variable consideration for chargebacks, certain rebates, and other incentives and we use the most likely amount method for certain rebates and trade discounts and allowances. A 10% increase or decrease in these estimates impacts net sales by a corresponding increase or decrease of approximately $13.0 million.
Added
Partially offset by: • decreased expenses within other clinical programs, specifically the APOLLO-B Phase 3 clinical trial of patisiran due to the wind down of clinical activities during the open label extension period; and • decreased costs due to the timing of manufacturing of zilebesiran for clinical activities.
Removed
A 10% increase or decrease in the transaction price impacts net revenues from collaborators by a corresponding increase or decrease of approximately $43.0 million.
Added
Selling, general and administrative expenses increased during the year ended December 31, 2024, as compared to the year ended December 31, 2023, primarily due to higher costs associated with marketing investments to promote our TTR therapies and prepare for the potential launch of AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy and increased employee compensation expenses.
Removed
A 10% increase or decrease in the total forecasted costs to be incurred over the period the transfer of goods or services occurs impacts net revenues from collaborators by a corresponding decrease or increase of approximately $39.0 million.
Added
Benefit from (Provision for) Income Taxes Benefit from (provision for) income taxes was a follows: Years Ended December 31, 2024 vs 2023 2023 vs 2022 (In thousands, except percentages) 2024 2023 2022 $ Change % Change $ Change % Change Benefit from (provision for) income taxes $ 99,218 $ (6,725) $ (4,163) $ 105,943 * $ (2,562) 62 % * Indicates the percentage change period over period is greater than 500%. 83 Table of Contents We recorded a benefit from income taxes of $99.2 million for the year ended December 31, 2024 and a provision for income taxes of $6.7 million for the year ended December 31, 2023.
Removed
Interest on the liability related to the sale of future royalties will be recognized using the effective interest rate method over the life of the related royalty stream.
Added
The benefit from income taxes for the year ended December 31, 2024 primarily relates to the release of the valuation allowance on our certain Switzerland deferred tax assets, which mainly consist of the tax basis of the intangible assets that were transferred to our wholly-owned Switzerland subsidiary in 2020, 2021 and 2023 and net operating loss carryforwards.
Removed
Third-party forecasts are updated periodically as new data is obtained with respect to Leqvio’s global launch progress or as sales information becomes available. Increases, decreases or a shift in timing of estimated revenues affects the interest rate utilized in the calculation of the liability related to the sale of future royalties.
Added
We maintained a full valuation allowance on our U.S. deferred tax assets as of December 31, 2024.
Added
Financing Activities Net cash provided by financing activities increased during the year ended December 31, 2024, compared to the year ended December 31, 2023, primarily due to increased net proceeds from exercise of stock options.
Added
Additional Capital Requirements We currently have programs focused in many therapeutic areas and, as of December 31, 2024, have five marketed products, including one product commercialized by a collaborator.
Added
Further, we anticipate making an additional $76.5 million of fixed and royalty payments upon regulatory approval of AMVUTTRA for the treatment of ATTR amyloidosis with 84 Table of Contents cardiomyopathy and the first commercial sale of AMVUTTRA following regulatory approval of AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy, respectively, within the next 12 months.
Added
We are also subject to potential rebates in connection with our value-based agreements, or VBAs, with certain commercial payors.
Added
We periodically assess the expected payments and to the extent the amount or timing of our future estimated payments is materially different than our previous estimates, we account for any such change by prospectively adjusting the effective interest rate and related non-cash interest expense.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

3 edited+0 added−0 removed3 unchanged
Biggest changeAs of December 31, 2023 and December 31, 2022, a hypothetical increase in interest rates of 100 basis points across the entire yield curve on our holdings would have resulted in an immaterial decrease to the fair value of our holdings. Foreign Currency Exchange Risk.
Biggest changeAs of December 31, 2024 and 2023, a hypothetical increase in interest rates of 100 basis points across the entire yield curve on our holdings would have resulted in an immaterial decrease to the fair value of our holdings. Foreign Currency Exchange Risk.
As sales outside the United States continue to grow, and as we expand our international operations, we will continue to assess potential steps, including foreign currency hedging and other strategies, to mitigate our foreign exchange risk. 91 Table of Contents
As sales outside the United States continue to grow, and as we expand our international operations, we will continue to assess potential steps, including foreign currency hedging and other strategies, to mitigate our foreign exchange risk. 86 Table of Contents
As a result of our foreign operations, we face exposure to movements in foreign currency exchange rates, primarily the Euro and Yen against the U.S. Dollar. Fluctuations in the global markets may have a positive or negative effect on our foreign exchange rate exposure.
As a result of our foreign operations, we face exposure to movements in foreign currency exchange rates, primarily the Japanese yen, Euro and British pound against the U.S. Dollar. Fluctuations in the global markets may have a positive or negative effect on our foreign exchange rate exposure.

Other ALNY 10-K year-over-year comparisons