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What changed in ALNYLAM PHARMACEUTICALS, INC.'s 10-K — 2024 vs 2025

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

+744 added−722 removedSource: 10-K (2026-02-12) vs 10-K (2025-02-13)

Top changes in ALNYLAM PHARMACEUTICALS, INC.'s 2025 10-K

744 paragraphs added · 722 removed · 502 edited across 8 sections

Item 1. Business

Business — how the company describes what it does

215 edited+123 added−101 removed215 unchanged
Biggest changeWe have additional late-stage investigational programs advancing toward potential commercialization, including fitusiran for the treatment of hemophilia, which is being advanced by our collaborator Genzyme Corporation, a Sanofi Company, or Sanofi, and for which a New Drug Application, or NDA, has been filed with the FDA with a target action date of March 28, 2025, and cemdisiran for the treatment of complement-mediated diseases, which our collaborator, Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing in combination with pozelimab in Phase 3 clinical trials in myasthenia gravis and geographic atrophy and as a monotherapy in a Phase 3 clinical trial in paroxysmal nocturnal hemoglobinuria.
Biggest changeOur collaborator, Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing cemdisiran in combination with its anti-C5 monoclonal antibody, pozelimab, in a Phase 3 clinical trial 6 Table of Contents in paroxysmal nocturnal hemoglobinuria, and as a monotherapy and in combination with pozelimab in Phase 3 clinical trials in myasthenia gravis and geographic atrophy.
Results from our Enhanced Stabilization Chemistry, or ESC, GalNAc-conjugate delivery platform have demonstrated a durability of effect that provides increased potency and durability, as well as a wide therapeutic index, and has the potential to support once-monthly, once-quarterly, and bi-annual subcutaneous dose regimens. Our more recently approved medicines, GIVLAARI, OXLUMO, Leqvio, and AMVUTTRA, utilize this conjugate platform.
Results from our Enhanced Stabilization Chemistry, or ESC, GalNAc-conjugate delivery platform have demonstrated a durability of effect that provides increased potency and durability, as well as a wide therapeutic index, and has the potential to support once-monthly, once-quarterly, and bi-annual subcutaneous dose regimens. Our more recently approved medicines, AMVUTTRA, GIVLAARI, OXLUMO and Leqvio utilize this conjugate platform.
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.
Reducing APP protein production is expected to reduce the secretion of Aβ peptides that aggregate into extracellular amyloid deposits in CAA and AD and reduce the intraneuronal APP cleavage products that may trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in AD.
In addition to multiple pending trademark applications in the U.S. and other major countries, we have registered trademarks in the U.S., including but not limited to Alnylam ® and the Alnylam logo, as well as ONPATTRO ® and the ONPATTRO logo, AMVUTTRA ® and the AMVUTTRA logo, GIVLAARI ® and the GIVLAARI logo and OXLUMO ® and the OXLUMO logo.
In addition to multiple pending trademark applications in the U.S. and other major countries, we have registered trademarks in the U.S., including but not limited to Alnylam ® and the Alnylam logo, as well as AMVUTTRA ® and the AMVUTTRA logo, ONPATTRO ® and the ONPATTRO logo, GIVLAARI ® and the GIVLAARI logo and OXLUMO ® and the OXLUMO logo.
Within 20 days of FDA’s acceptance of an ANDA or 505(b)(2) application containing a Paragraph IV certification, the applicant must notify the NDA holder and patent owner that the application has been submitted, and provide the factual and legal basis for the applicant’s opinion that the patent is invalid, unenforceable, or not infringed.
Within 20 days of the FDA’s acceptance of an ANDA or 505(b)(2) application containing a Paragraph IV certification, the applicant must notify the NDA holder and patent owner that the application has been submitted, and provide the factual and legal basis for the applicant’s opinion that the patent is invalid, unenforceable, or not infringed.
Pediatric Study Plans The FDCA requires that a sponsor planning to submit an NDA for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit a pediatric study plan to FDA outlining the proposed pediatric study or studies they plan to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation.
Pediatric Study Plans The FDCA requires that a sponsor planning to submit an NDA for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must submit a pediatric study plan to the FDA outlining the proposed pediatric study or studies they plan to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation.
For fast track products, sponsors may have greater interactions with the FDA, and the FDA may initiate review of sections of a fast track product’s application before the application is complete in some circumstances. Fast track designation may be rescinded if FDA believes that the product no longer meets the qualifying criteria.
For fast track products, sponsors may have greater interactions with the FDA, and the FDA may initiate review of sections of a fast track product’s application before the application is complete in some circumstances. Fast track designation may be rescinded if the FDA believes that the product no longer meets the qualifying criteria.
Breakthrough designation may be rescinded if a product no longer meets the qualifying criteria. FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness of the treatment, prevention, or diagnosis of such condition.
Breakthrough designation may be rescinded if a product no longer meets the qualifying criteria. The FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness of the treatment, prevention, or diagnosis of such condition.
For products granted accelerated approval, FDA generally requires sponsors to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the product’s clinical benefit. The Food and Drug Omnibus Reform Act of 2022 gave FDA the authority to require, as appropriate, a post-approval study to be underway prior to granting accelerated approval.
For products granted accelerated approval, the FDA generally requires sponsors to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the product’s clinical benefit. The Food and Drug Omnibus Reform Act of 2022 gave the FDA the authority to require, as appropriate, a post-approval study to be underway prior to granting accelerated approval.
All promotional materials for products approved under accelerated approval are subject to prior review by the FDA unless FDA informs the sponsor otherwise.
All promotional materials for products approved under accelerated approval are subject to prior review by the FDA unless the FDA informs the sponsor otherwise.
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 expect to continue to rely on third-party CMOs for the supply of drug substance and drug product, including for AMVUTTRA, ONPATTRO, 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.
ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as the other programs we are advancing to commercialization are focused on a broad range of disease areas and indications, and we have been executing on our strategy to make ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO and any future products successful, including through efforts to increase awareness and diagnosis.
AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO, as well as the other programs we are advancing to commercialization are focused on a broad range of disease areas and indications, and we have been executing on our strategy to make AMVUTTRA, ONPATTRO, GIVLAARI, OXLUMO and any future products successful, including through efforts to increase awareness and diagnosis.
In 2015, we amended our manufacturing services agreement with Agilent Technologies, Inc., or Agilent, to provide for Agilent to supply, subject to any conflicting obligations under our third-party agreements, a specified percentage of the active pharmaceutical ingredients required for certain of our products in clinical development, as well as other products the parties may agree upon in the future.
In 2015, we amended our manufacturing services agreement with Agilent Technologies, Inc., or Agilent, to provide for Agilent to supply, subject to any conflicting obligations under our third-party agreements, a specified percentage of the active pharmaceutical ingredients, or API, required for certain of our products in clinical development, as well as other products the parties may agree upon in the future.
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.
As of October 2016, the EMA began proactively 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.
Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. hATTR Amyloidosis with Polyneuropathy (hATTR-PN). In addition to ONPATTRO and AMVUTTRA, currently approved therapies to treat hATTR-PN include TEGSEDI (inotersen, not available in the U.S.) marketed by Ionis and WAINUA (eplontersen) marketed by Ionis and AstraZeneca plc.
Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. hATTR Amyloidosis with Polyneuropathy (hATTR-PN). In addition to ONPATTRO and AMVUTTRA, currently approved therapies to treat hATTR-PN include WAINUA (eplontersen) marketed by Ionis and AstraZeneca, and TEGSEDI (inotersen, not available in the U.S.) marketed by Ionis.
For those medicinal products for which the centralized procedure is not available, the applicant must submit MAAs to the national medicines regulators through one of three procedures: (1) a national procedure, which results in a marketing authorization in a single EU member state; (2) the decentralized procedure, in which applications are submitted simultaneously in two or more EU member states and a reference member state is appointed to lead the scientific assessment; and (3) the mutual recognition procedure, which must be used if the product has already been nationally authorized in at least one EU member state which assumes the role as the reference member state, and the marketing authorization holder wishes to obtain a marketing authorization for the same product in at least one other member state.
For those medicinal products for which the centralized procedure is not mandatory, the applicant must submit MAAs to the national medicines regulators through one of three procedures: (1) a national procedure, which results in a marketing authorization in a single EU member state; (2) the decentralized procedure, in which applications are submitted simultaneously in two or more EU member states and a reference member state is appointed to lead the scientific assessment; and (3) the mutual recognition procedure, which must be used if the product has already been nationally authorized in at least one EU member state which assumes the role as the reference member state, and the marketing authorization holder wishes to obtain a marketing authorization for the same product in at least one other member state.
Under the Exclusive TTR License, Sanofi is eligible to receive (i) royalties up to 25% 17 Table of Contents increasing over time, based on annual net sales of ONPATTRO in territories excluding the U.S., Canada and Western Europe, provided royalties on annual net sales of ONPATTRO in Japan were set at 25% beginning at the effective date of the Exclusive TTR License and (ii) tiered royalties on global annual net sales of AMVUTTRA across all indications in the following tiers: 15% of global annual net sales of $0 to $150.0 million; 17.5% of global annual net sales greater than $150.0 million to $300.0 million; 20% of global annual net sales greater than $300.0 million to $500.0 million; 25% of global annual net sales greater than $500.0 million to $1.50 billion; and 30% of global annual net sales in excess of $1.50 billion.
Under the Exclusive TTR License, Sanofi is eligible to receive (i) royalties up to 25% increasing over time, based on annual net sales of ONPATTRO in territories excluding the U.S., Canada and Western Europe, provided royalties on annual net sales of ONPATTRO in Japan were set at 25% beginning at the effective date of the Exclusive TTR License and (ii) tiered royalties on global annual net sales of AMVUTTRA across all indications in the following tiers: 15% of global annual net sales of $0 to $150.0 million; 17.5% of global annual net sales greater than $150.0 million to $300.0 million; 20% of global annual net sales greater than $300.0 million to $500.0 million; 25% of global annual net sales greater than $500.0 million to $1.50 billion; and 30% of global annual net sales in excess of $1.50 billion.
The rare pediatric disease PRV program was initially created in 2012, and Congress has extended the PRV program through September 30, 2024, with the potential for PRVs to be granted through September 30, 2026 for a drug that receives rare pediatric disease designation by September 30, 2024.
The rare pediatric disease PRV program was initially created in 2012, and Congress extended the PRV program through September 30, 2024, with the potential for PRVs to be granted through September 30, 2026 for a drug that receives rare pediatric disease designation by September 30, 2024.
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.
However, this timeline excludes clock stops, when additional written 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 indicated in the table above, to date we have received marketing approval for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and Novartis has received approval for Leqvio, in each case in certain territories for the specific indications approved in each such territory, with additional regulatory submissions pending. 10 Table of Contents Our TTR Franchise About Transthyretin Amyloidosis (ATTR) ATTR amyloidosis is an underdiagnosed, rapidly progressive and fatal disease that affects multiple parts of the body including the heart, nerves and digestive system.
As indicated in the table above, to date we have received marketing approval for AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO, Novartis has received approval for Leqvio, and Sanofi has received approval for Qfitlia, in each case in certain territories for the specific indications approved in each such territory, with additional regulatory submissions pending. 10 Table of Contents Our TTR Franchise About Transthyretin (ATTR) Amyloidosis ATTR amyloidosis is an underdiagnosed, rapidly progressive and fatal disease that affects multiple parts of the body including the heart, nerves and digestive system.
New Drug Development Process The steps ordinarily required before a new drug product may be marketed in the U.S. include: • completion of nonclinical laboratory tests, animal tests and formulation studies conducted according to good laboratory practices, or GLP, and applicable regulations; • the submission to the FDA of an IND, which must become effective prior to commencement of clinical testing in the U.S.; • approval by an institutional review board, or IRB, representing each clinical site before each trial may be initiated; • completion of adequate and well-controlled clinical trials in accordance with good clinical practices, or GCP, to establish that the drug product is safe and effective for the indication and other conditions of use for which FDA approval is sought; • submission to the FDA of an NDA (or supplemental NDA for approved products); 23 Table of Contents • satisfactory completion of a pre-approval FDA inspection of the manufacturing facility or facilities at which the product will be produced to assess compliance with current good manufacturing practices, or cGMP; and • FDA review and approval of the NDA (or supplemental NDA for approved products.
New Drug Development Process The steps ordinarily required before a new drug product may be marketed in the U.S. include: • completion of nonclinical laboratory tests, animal tests and formulation studies conducted according to good laboratory practices, or GLP, and applicable regulations; • the submission to the FDA of an IND, which must become effective prior to commencement of clinical testing in the U.S.; • approval by an institutional review board, or IRB, representing each clinical site before each trial may be initiated; • completion of adequate and well-controlled clinical trials in accordance with good clinical practices, or GCP, to establish that the drug product is safe and effective for the indication and other conditions of use for which FDA approval is sought; • submission to the FDA of an NDA (or supplemental NDA for approved products); • satisfactory completion of a pre-approval FDA inspection of the manufacturing facility or facilities at which the product will be produced to assess compliance with current good manufacturing practices, or cGMP; and • FDA review and approval of the NDA (or supplemental NDA for approved products).
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.
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 off-label promotion with customers that file claims.
We have established five major collaborations—including with the UK BioBank and Our Future Health—to support the sourcing of novel, genetically validated targets and to secure access to databases of genetic information. Our Product Pipeline Our broad pipeline includes five approved products and multiple late and early-stage investigational RNAi therapeutics across a broad range of disease areas and indications.
We have established six major collaborations—including with the UK BioBank and Our Future Health—to support the sourcing of novel, genetically validated targets and to secure access to databases of genetic information. Our Product Pipeline Our broad pipeline includes six approved products and multiple late and early-stage investigational RNAi therapeutics across a broad range of disease areas and indications.
By harnessing the RNAi pathway, we have developed a new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics are comprised of small interfering RNA, or siRNA, that function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in the cause or pathway of disease, thus preventing them from being made.
By harnessing the RNAi pathway, we have pioneered a new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics are comprised of small interfering RNA, or siRNA, that function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in the cause or pathway of disease, thus preventing them from being made.
Our next generation Enhanced Stabilization Chemistry-Plus, or ESC+ GalNAc-conjugates utilize advanced design features to further improve specificity, while maintaining potency and durability, further improving our therapeutic index by up to six-fold. Our first RNAi therapeutics based on this ESC+ design, zilebesiran and elebsiran, are currently in clinical development.
Our next generation Enhanced Stabilization Chemistry-Plus, or ESC+, GalNAc-conjugates utilize advanced design features to further improve specificity, while maintaining potency and durability, further improving our therapeutic index by up to six-fold. Our first RNAi therapeutics based on this ESC+ design, zilebesiran and elebsiran, are currently in late-stage clinical development.
These clinical-stage therapeutics have not been approved by the FDA, EMA, or any other health authority and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics. 9 Table of Contents The table below represents our commercial products and late- and early-stage development programs as of February 1, 2025.
These clinical-stage therapeutics have not been approved by the FDA, EMA, or any other health authority and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics. 9 Table of Contents The table below represents our commercial products and late- and early-stage development programs as of February 1, 2026.
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.
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 32 Table of Contents improper payments to non-U.S. officials for the purpose of obtaining or retaining business.
Consequently, patients with AHP can wait up to 15 years for a confirmed diagnosis. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease, or liver disease including hepatocellular carcinoma. Our RNAi therapeutic, GIVLAARI is the first GalNAc-conjugate RNA therapeutic to be approved.
Consequently, patients with AHP can wait up to 15 years for a confirmed diagnosis. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease, or liver disease including hepatocellular carcinoma. GIVLAARI is the first GalNAc-conjugate RNA therapeutic to be approved.
The NDA holder or patent holder may then initiate a patent infringement suit in response to the Paragraph IV notice. If this is done within 45 days of receiving notice of the Paragraph IV certification, a 30-month stay of the U.S. FDA’s ability to approve the ANDA or 505(b)(2) application is triggered.
The NDA holder or patent holder may then initiate a patent infringement suit in response to the Paragraph IV notice. If this is done within 45 days of receiving notice of the Paragraph IV certification, a 30-month stay of the FDA’s ability to approve the ANDA or 505(b)(2) application is triggered.
Below is a brief description of certain other collaboration and license agreements we have entered into. PeptiDream, Inc. In July 2021, we entered into a license and collaboration agreement with PeptiDream to discover and develop peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver.
Below is a brief description of certain of our other collaboration and license agreements. PeptiDream, Inc. In July 2021, we entered into a license and collaboration agreement with PeptiDream to discover and develop peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver.
For example, the federal False Claims Act, or FCA, imposes liability on any person or entity who, among other things, knowingly and willfully presents, or causes to be presented, a false or fraudulent claim for payment by a federal healthcare program, including Medicaid and Medicare.
For example, the FCA imposes liability on any person or entity who, among other things, knowingly and willfully presents, or causes to be presented, a false or fraudulent claim for payment by a federal healthcare program, including Medicaid and Medicare.
In addition to receiving rare pediatric disease designation, in order to receive a rare pediatric disease priority review voucher upon NDA approval, the application must be granted priority review, rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population, not seek approval for a different adult indication in the original rare pediatric disease product 28 Table of Contents application and be for a drug that does not include a previously approved active ingredient.
In addition to receiving rare pediatric disease designation, in order to receive a rare pediatric disease priority review voucher upon NDA approval, the application must be granted priority review, rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population, not seek approval for a different adult indication in the original rare pediatric disease product application and be for a drug that does not include a previously approved active ingredient.
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 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. 16 Table of Contents Regeneron.
The application is “abbreviated” because it need not include nonclinical or clinical data to demonstrate safety and effectiveness and may instead rely on the U.S. FDA’s previous finding that the brand drug, or reference drug, is safe and effective.
The application is “abbreviated” because it need not include nonclinical or clinical data to demonstrate safety and effectiveness and may instead rely on the FDA’s previous finding that the brand drug, or reference drug, is safe and effective.
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.
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.
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.
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. 38 Table of Contents Corporate Information Alnylam Pharmaceuticals, Inc. is a Delaware corporation that was formed in May 2003.
As part of this strategy, we have entered into, and expect to enter into additional, collaboration and licensing agreements as a means of obtaining resources, capabilities and funding to advance our investigational RNAi therapeutic programs. Our collaboration strategy is to form collaborations that create significant value for ourselves and our collaborators in the advancement of RNAi therapeutics.
As part of this strategy, we have entered into, and expect to enter into additional, collaboration and licensing agreements as a means of accessing resources and capabilities to advance our investigational RNAi therapeutic programs. Our collaboration strategy is to form collaborations that create significant value for ourselves and our collaborators in the advancement of RNAi therapeutics.
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.
Acute Hepatic Porphyria. 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.
OXLUMO has also been approved in several other countries and regulatory filings for lumasiran (the generic name of OXLUMO) in additional territories are pending or planned during 2025 and beyond.
OXLUMO has also been approved in several other countries and regulatory filings for lumasiran (the generic name of OXLUMO) in additional territories are pending or planned during 2026 and beyond.
In 2023, we announced positive interim results from the Phase 1 clinical trial of mivelsiran, the first investigational RNAi therapeutic that leverages our C16 conjugate technology, in 8 Table of Contents early onset AD. Mivelsiran targets amyloid precursor protein and is currently in development for the treatment of AD and CAA.
In 2023, we announced positive interim results from the Phase 1 clinical trial of mivelsiran, the first investigational RNAi therapeutic that leverages our C16 conjugate technology, in early onset AD. Mivelsiran targets amyloid precursor protein and is currently in development for the treatment of AD and CAA.
In December 2023 and November 2024, we announced positive initial results in the Phase 1 study of nucresiran in healthy volunteers. Single doses of 300 mg or higher of nucresiran achieved rapid knockdown with a mean TTR reduction of greater than 90% at Day 15.
In December 2023 and November 2024, we announced positive initial results in the Phase 1 11 Table of Contents study of nucresiran in healthy volunteers. Single doses of 300 mg or higher of nucresiran achieved rapid knockdown with a mean TTR reduction of greater than 90% at Day 15.
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.
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 or supplement, failure of the sponsor to complete these agreed studies in a timely manner may result in a refusal to file.
A request for scientific advice can be made nationally by engaging the national competent authorities or 32 Table of Contents centrally which is coordinated by the EMA at different stages of product development in relation to questions concerning an assessment of the product quality, non-clinical testing and clinical development.
A request for scientific advice can be made nationally by engaging the national competent authorities or centrally which is coordinated by the EMA at different stages of product development in relation to questions concerning an assessment of the product quality, non-clinical testing and clinical development.
The new employees were hired to support a variety of functions and key initiatives, including extending our research, clinical and preclinical pipeline development, as well as our medical affairs and commercialization capabilities, with hires in commercial, compliance, legal, clinical development and operations, research, medical affairs and other general and administrative functions.
The new employees were hired to support a variety of functions and key initiatives, including extending our research, clinical and preclinical pipeline development, as well as our medical affairs and commercialization capabilities, with hires in commercial, compliance, legal, clinical development and operations, research, medical affairs, chemistry, manufacturing, and controls and other general and administrative functions.
ONPATTRO Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8168775 United States Compositions of Matter & Methods of Use 8/10/2032 Alnylam 8334373 United States Compositions of Matter & Methods of Use 5/27/2025 Alnylam 8741866 United States Compositions of Matter & Methods of Use 10/20/2029 Alnylam 9234196 United States Compositions of Matter & Methods of Use 10/20/2029 Alnylam 8802644 United States Compositions of Matter & Methods of Use 10/21/2030 Arbutus Biopharma 8158601 United States Compositions of Matter & Methods of Use 11/10/2030 Arbutus Biopharma 2937418 Europe Compositions of Matter & Methods of Use 8/28/2033 Alnylam 2344639 Europe Compositions of Matter & Methods of Use 10/20/2029 Alnylam 2440183 Europe Compositions of Matter 10/21/2030 Arbutus Biopharma _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
ONPATTRO Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor 8168775 United States Compositions of Matter & Methods of Use 8/10/2032 Alnylam 8741866 United States Compositions of Matter & Methods of Use 10/20/2029 Alnylam 9234196 United States Compositions of Matter & Methods of Use 10/20/2029 Alnylam 8802644 United States Compositions of Matter & Methods of Use 10/21/2030 Arbutus Biopharma 8158601 United States Compositions of Matter & Methods of Use 11/10/2030 Arbutus Biopharma 2937418 Europe Compositions of Matter & Methods of Use 8/28/2033 Alnylam 2344639 Europe Compositions of Matter & Methods of Use 10/20/2029 Alnylam 2440183 Europe Compositions of Matter 10/21/2030 Arbutus Biopharma _________________________________________ * Shown here are selected granted patents in the U.S. and Europe.
Fitusiran is an investigational, subcutaneously administered RNAi therapeutic targeting AT for the treatment of hemophilia A and B, with and without inhibitors, that is being advanced by our collaborator, Sanofi. Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to prevent bleeding.
Qfitlia is a subcutaneously administered RNAi therapeutic targeting AT for the treatment of hemophilia A and B, with and without inhibitors, that is being advanced by our collaborator, Sanofi. Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to prevent bleeding.
AMVUTTRA is approved in the U.S. for the treatment of hereditary transthyretin-mediated amyloidosis, or hATTR amyloidosis, with polyneuropathy in adults, in the EU, and the United Kingdom, or UK, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries.
AMVUTTRA is approved in the United States, or U.S., for the treatment of hereditary transthyretin-mediated amyloidosis, or hATTR amyloidosis, with polyneuropathy in adults, in the European Union, or EU, and the United Kingdom, or UK, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries.
ONPATTRO is approved in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults and has also been approved in the European Union, or EU, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, in Japan for the treatment of TTR-type familial amyloidosis with polyneuropathy, and in multiple additional countries.
ONPATTRO is approved in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults and has also been approved in the European Union, or EU, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 5 Table of Contents polyneuropathy, in Japan for the treatment of TTR-type familial amyloidosis with polyneuropathy, and in multiple additional countries.
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.
Leqvio (inclisiran) 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.
In addition to OXLUMO, Novo Nordisk’s RIFVLOZA (nedosiran) is approved in the U.S. for treatment of PH1 to lower urinary oxalate levels in children nine years of age and older and adults with relatively preserved kidney function. Other currently used treatments include hyper-hydration, vitamin B6, oral citrate, and dual liver/kidney transplantation.
Primary Hyperoxaluria. In addition to OXLUMO, Novo Nordisk’s RIVFLOZA (nedosiran) is approved in the U.S. for treatment of PH1 to lower urinary oxalate levels in children nine years of age and older and adults with relatively preserved kidney function. Other currently used treatments include hyper-hydration, vitamin B6, oral citrate, and dual liver/kidney transplantation.
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.
The Federal Food, Drug, and Cosmetic Act, or FDCA, and other 23 Table of Contents 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.
Please see Note 9, Liability Related to the Sale of Future Royalties, and Note 10, Development Derivative Liability, 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 additional details on our transaction with Blackstone, including its ongoing financial and accounting impact on our business.
Please see Note 9, Liabilities Related To The Sale Of Future Royalties And Development Funding, 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 additional details on our transaction with Blackstone, including its ongoing financial and accounting impact on our business.
While the manufacturing or quality information is currently generally protected against disclosure as it is treated as confidential information, there exists a presumptive public interest right to access the nonclinical and clinical information contained in marketing authorization dossiers, including the full clinical study reports, in response to freedom of information requests after the marketing authorization has been granted.
While the manufacturing or quality information is currently generally protected against disclosure as it is treated as commercially confidential information, there exists a presumptive public interest right to access the nonclinical and clinical information contained in marketing authorization dossiers, including the full clinical study reports, in response to freedom of information requests after the marketing 34 Table of Contents authorization has been granted.
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.
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 incorporate Ionis’ intellectual property.
Intellectual Property, Proprietary Rights and Exclusivities We have devoted considerable effort and resources through both in-licensing and filing patent applications on our own inventions, as well as protecting our trade secrets and know-how to establish what we believe to be a strong intellectual property position relevant to RNAi therapeutic products and delivery technologies.
Intellectual Property, Proprietary Rights and Exclusivities We have devoted considerable effort and resources through both in-licensing and filing patent applications on our own inventions, as well as protecting our trade secrets and know-how to establish what we believe to be a strong intellectual 18 Table of Contents property position relevant to RNAi therapeutic products and delivery technologies.
There is a special regime for biosimilars, or biological medicinal products that are similar to a reference medicinal product but that do not meet the definition of a generic medicinal product, for example, because of differences in raw materials or manufacturing processes.
There is a special regime for approval of biosimilars, or biological medicinal products that are considered to be similar to a reference medicinal product but that do not meet the definition of a generic medicinal product, for example, because of differences in raw materials or manufacturing processes.
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.
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.
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.
An IRB must operate in compliance with FDA regulations. 24 Table of Contents 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.
Outside of the U.S. we believe we have made strong progress with patient access and have established availability of ONPATTRO, AMVUTTRA, OXLUMO and GIVLAARI in more than 60 markets through direct reimbursement or in partnership with our distributors.
Outside of the U.S. we believe we have made strong progress with patient access and have established availability of AMVUTTRA, ONPATTRO, OXLUMO and GIVLAARI, collectively, in more than 70 markets through direct reimbursement or in partnership with our distributors.
Such applications often are submitted for changes to previously approved drug products. The acceptance and approval of ANDAs and 505(b)(2) applications can be delayed by patents and non-patent exclusivity covering the listed drug.
Such applications often are submitted for changes to previously approved drug products. 26 Table of Contents The acceptance and approval of ANDAs and 505(b)(2) applications can be delayed by patents and non-patent exclusivity covering the listed drug.
The PDUFA also imposes an annual program fee for each approved prescription drug product, which has been set at approximately $417,000 for fiscal year 2024. The FDA adjusts the PDUFA user fees on an annual basis. Fee waivers, reductions and exceptions are available in certain circumstances.
The PDUFA also imposes an annual program fee for each approved prescription drug product, which has been set at approximately $442,000 for fiscal year 2026. The FDA adjusts the PDUFA user fees on an annual basis. Fee waivers, reductions and exceptions are available in certain circumstances.
An ANDA or 505(b)(2) applicant may also certify that a listed patent is invalid, unenforceable, or will not be infringed by its proposed product, and thus that it is seeking approval prior to patent 26 Table of Contents expiration (i.e., a Paragraph IV certification).
An ANDA or 505(b)(2) applicant may also certify that a listed patent is invalid, unenforceable, or will not be infringed by its proposed product, and thus that it is seeking approval prior to patent expiration (i.e., a Paragraph IV certification).
During 2020, we completed construction and qualification of our GMP manufacturing facility in Norton, Massachusetts, where we currently manufacture drug substance for clinical programs and, eventually, intend to manufacture drug substance for commercial use.
During 2020, we completed construction and qualification of our GMP manufacturing facility in Norton, Massachusetts, where we currently manufacture drug substance for clinical programs and, eventually, intend to manufacture drug substance for 36 Table of Contents commercial use.
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.
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.
Regulations and administrative guidance often are revised or reinterpreted by the agencies in ways that may significantly affect our business and our products. It is impossible to predict whether legislative changes will be enacted or if FDA or comparable ex-U.S. regulations, guidance or interpretations will change.
Regulations and administrative guidance often are revised or reinterpreted by the agencies in ways that may significantly affect our business and our products. It is impossible to predict whether legislative changes will be enacted by the FDA or comparable foreign regulations, or if guidance or interpretations will change.
Factors payors may consider in determining reimbursement include, among others, the extent to which the product and/or the use of the product is: • a covered benefit under a health plan; • safe, effective and medically necessary; • appropriate for the specific patient; • clinically superior or therapeutically advantageous compared to other products; • cost-effective; and • neither experimental nor investigational.
Factors third party payors may consider in determining reimbursement include, among others, the extent to which the product and/or the use of the product is: • a covered benefit under a health plan; • safe, effective and medically necessary; • appropriate for the specific patient; • clinically superior or therapeutically advantageous compared to other products; • cost-effective; and 29 Table of Contents • neither experimental nor investigational.
Patisiran was also evaluated in a Phase 4 clinical trial in hATTR amyloidosis patients with polyneuropathy due to a T60A or V122I variant. ONPATTRO (patisiran) - ATTR Amyloidosis with Cardiomyopathy In February 2025, ONPATTRO received regulatory approval from the Brazilian Health Regulatory Agency, or ANVISA, for the treatment of ATTR amyloidosis with cardiomyopathy.
Patisiran was also evaluated in a Phase 4 clinical trial in hATTR amyloidosis patients with polyneuropathy due to a T60A or V122I variant. ONPATTRO — ATTR Amyloidosis with Cardiomyopathy In February 2025, ONPATTRO received regulatory approval from ANVISA in Brazil for the treatment of ATTR amyloidosis with cardiomyopathy.
The manufacturer or importer must have a qualified person who is responsible for certifying that each batch of product has been manufactured in accordance with EU standards of cGMP before releasing the product for commercial distribution in the EU or for use in a clinical trial.
The manufacturer or importer must have a qualified person who is responsible for certifying that each batch of product has been manufactured in accordance with EU standards of cGMP and the requirements of the marketing authorization before releasing the product for commercial distribution in the EU or for use in a clinical trial.
In the U.S. and Canada, ONPATTRO is indicated for the treatment of hATTR amyloidosis with polyneuropathy in adults. In the EU, Switzerland, Brazil and Israel, ONPATTRO is indicated for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy, and in Japan, ONPATTRO is indicated for the treatment of TTR type familial amyloidosis with polyneuropathy.
In the EU, Switzerland, Brazil and Israel, ONPATTRO is indicated for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy, and in Japan, ONPATTRO is indicated for the treatment of TTR type familial amyloidosis with polyneuropathy.
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 the treatment of individuals with inhibitors, there is an approved Factor VIIa replacement product, two anti-TFPI products, an activated prothrombin complex concentrate, as well as a bispecific antibody that mimics Factor VIII. In addition, new, innovative molecules have been approved or are currently in development for treatment of hemophilia A and B, both with and without inhibitors.
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.
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 2025, we enhanced our capabilities by adding approximately 270 new full-time employees.
In January 2018, we and Sanofi amended our 2014 collaboration and entered into the Exclusive License Agreement, referred to as the Exclusive TTR License, under which we were granted exclusive rights to pursue the further global development and commercialization of all TTR products, including ONPATTRO, AMVUTTRA and any back-up products, and the ALN-AT3 Global License Terms, referred to as the AT3 License Terms, under which Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.
In January 2018, we and Sanofi amended our 2014 collaboration and entered into the Exclusive License Agreement, referred to as the Exclusive TTR License, under which we were granted exclusive rights to pursue the further global development and commercialization of TTR products, including ONPATTRO, AMVUTTRA and certain back-up products, and the ALN-AT3 Global License Terms, referred to as the AT3 License Terms, under which Sanofi has the exclusive right to pursue the further global development and commercialization of Qfitlia and certain back-up products.
GIVLAARI has also received marketing authorizations for the treatment of AHP in adults in Brazil and Canada, and for the treatment of AHP in adults and adolescents in Japan, the UK, Argentina, Australia, Switzerland, Israel and Taiwan.
GIVLAARI has also received marketing authorizations for the treatment of AHP in adults in Brazil, Canada and Mexico and for the treatment of AHP in adults and adolescents in Japan, the UK, Argentina, Australia, Switzerland, Israel, Taiwan, UAE and Kuwait.
In February 2013, we and MDCO (acquired by Novartis in January 2020) entered into a license and collaboration agreement pursuant to which we granted to MDCO an exclusive, worldwide license to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases.
In February 2013, we and The Medicines Company (acquired by Novartis in January 2020), or MDCO, entered into a license and collaboration agreement pursuant to which we granted to MDCO an exclusive, worldwide license to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases, which we refer to as the MDCO agreement.
Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular product candidate to currently available therapies.
Some jurisdictions operate positive and negative list systems under which products may only be accessed in the respective national health systems once a reimbursement price has been agreed. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular product candidate to currently available therapies.
In April 2020, we entered into a strategic financing collaboration with certain affiliates of Blackstone to accelerate our advancement of RNAi therapeutics.
Strategic Financing Collaboration The Blackstone Group Inc. In April 2020, we entered into a strategic financing collaboration with certain affiliates of Blackstone to accelerate our advancement of RNAi therapeutics.
The FDA is not bound by the recommendation of an advisory committee, but it carefully considers and often follows such recommendations.
The FDA is not bound by the recommendation of an advisory committee, but it carefully considers and often 25 Table of Contents follows such recommendations.
Finally, our Medical Affairs organization generates real world evidence to address knowledge gaps. These capabilities ultimately enable patient diagnosis and improved patient care, including through support for independent third party genetic testing programs, including Alnylam Act.
Finally, our Medical Affairs organization generates real world evidence to address knowledge and data gaps. These capabilities are designed to enable increased patient diagnosis and improved patient care, including through support for independent third party genetic testing programs, including Alnylam Act.
We and Roche share equally (50/50) all costs incurred in connection with development activities that are conducted to support regulatory approval of zilebesiran in the U.S.
We and Roche share equally (50/50) all costs incurred in connection with development activities that are conducted primarily to support regulatory approval of zilebesiran in the U.S. if incremental development activities are needed.
From January 31, 2023, sponsors are required submit an on-line application through a single on-line platform known as Clinical Trials Information System, or CTIS, for approval.
From January 31, 2023, sponsors are required submit an on-line 33 Table of Contents application through a single on-line platform known as Clinical Trials Information System, or CTIS, for approval.

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Item 1A. Risk Factors

Risk Factors — what could go wrong, per management

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Biggest changeConduct regulated by the federal civil monetary penalties law often overlaps with other healthcare laws, including the federal Anti-Kickback Statute. • The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which in addition to privacy and security protections applicable to healthcare providers and other entities, prohibits executing, or attempting to execute, a scheme to defraud any healthcare benefit program and making false statements relating to healthcare matters. • Federal “sunshine” requirements imposed on drug, device, and medical supply manufacturers when payment is available under Medicare, Medicaid or the Children’s Health Insurance Program to report annually to HHS information regarding any “transfer of value” made or distributed to healthcare providers and organizations.
Biggest changeConduct regulated by the federal civil monetary penalties law often overlaps with other healthcare laws, including the federal Anti-Kickback Statute. • The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which in addition to privacy and security protections applicable to healthcare providers and other entities, prohibits executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private programs, and making false statements relating to healthcare matters. • Federal “sunshine” requirements imposed on drug, device, and medical supply manufacturers when payment is available under Medicare, Medicaid or the Children’s Health Insurance Program to report annually to HHS information regarding any “transfer of value” made or distributed to certain healthcare providers and organizations. • Federal laws that require pharmaceutical manufacturers to calculate, report, and certify certain complex product prices and other data to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under government healthcare programs, which data may be used in the calculation of reimbursement and/or discounts on approved products. • Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers. 62 Table of Contents • The Federal Food, Drug, and Cosmetic Act, which among other things, strictly regulates drug product and medical device marketing, prohibits manufacturers from marketing such products prior to approval or for unapproved indications and regulates the distribution of samples.
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.
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, under certain circumstances, our collaborators may have additional termination rights for convenience with respect to the collaboration as a whole or a particular program under the collaboration.
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.
Moreover, any adverse actions by Novartis with respect to, 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.
Our estimates regarding the potential market size for ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or any future products that we may commercialize, may be materially different from the actual market size, including as a result of the indication approved by regulatory authorities, which could result in significant changes in our business plan and may have a material adverse effect on our business, prospects, operating results and financial condition.
Our estimates regarding the potential market size for AMVUTTRA, ONPATTRO, GIVLAARI, OXLUMO or any future products that we may commercialize, may be materially different from the actual market size, including as a result of the indication approved by regulatory authorities, which could result in significant changes in our business plan and may have a material adverse effect on our business, prospects, operating results and financial condition.
Further, GDPR provides a broad right for EEA Member States to create supplemental national laws, such as laws relating to the processing of health, genetic and biometric data, which could further limit our ability to use and share such data or could cause our costs to increase, and harm our business and financial condition.
Further, the GDPR provides a broad right for EEA Member States to create supplemental national laws, such as laws relating to the processing of health, genetic and biometric data, which could further limit our ability to use and share such data or could cause our costs to increase, and harm our business and financial condition.
If those organizations refuse to grant us a license to such patent rights on reasonable terms or at all and/or a court rules that we need such patent rights that have been asserted against us, we may be unable to market our products, including ONPATTRO, AMVUTTRA, GIVLAARI or OXLUMO, or to perform research and development or other activities covered by such patents.
If those organizations refuse to grant us a license to such patent rights on reasonable terms or at all and/or a court rules that we need such patent rights that have been asserted against us, we may be unable to market our products, including AMVUTTRA, ONPATTRO, GIVLAARI or OXLUMO, or to perform research and development or other activities covered by such patents.
Risks Related to Our Common Stock Our stock price has been and may in the future be volatile, and an investment in our common stock could suffer a decline in value. Our stock price has been and may in the future be volatile.
Risks Related to Our Common Stock • Our stock price has been and may in the future be volatile, and an investment in our common stock could suffer a decline in value.
The subsequent discovery of previously unknown or underestimated problems with a product could result in: • sales of our approved products may be lower than originally anticipated; • regulatory approvals for our approved products may be restricted or withdrawn; • we may decide, or be required, to send product warning letters or field alerts to physicians, pharmacists and hospitals; • additional nonclinical studies or clinical trials, changes in labeling, adoption of a REMS plan, or changes to manufacturing processes, specifications and/or facilities may be required; and/or • government investigations or lawsuits, including class action suits, may be brought against us.
The subsequent discovery of previously unknown or underestimated problems with a product could result in: • sales of our approved products may be lower than originally anticipated; • regulatory approvals for our approved products may be restricted or withdrawn; • we may decide, or be required, to send product warning letters or field alerts to physicians, pharmacists and hospitals; • additional nonclinical studies or clinical trials, changes in labeling, adoption of a REMS plan, or changes to manufacturing processes, specifications and/or facilities may be required; and/or • government investigations or lawsuits, including class action and product liability suits, may be brought against us.
It is possible that changes in insurer policies regarding co-pay coupons (such as co-pay accumulator and maximizer programs) and patient assistance programs (such as alternative funding 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 our sales, business, and financial condition.
It is possible that changes in insurer policies regarding co-pay coupons (such as co-pay accumulator and maximizer programs) and patient assistance programs (such as alternative funding 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 assistance programs, which could result in fewer patients using affected products, and therefore could have a material adverse effect on our sales, business, and financial condition.
In these circumstances, we will not be able to generate revenues from these product candidates, and this will substantially harm our business, prospects, operating results and financial condition. If any collaborator materially amends, terminates or fails to perform its obligations under agreements with us, the development and commercialization of our product candidates could be delayed or terminated.
In these circumstances, we will not be able to generate revenues from these product candidates, and this will substantially harm our business, prospects, operating results and financial condition. If any collaborator materially amends, terminates or fails to perform its obligations under agreements with us, the development and commercialization of our products or product candidates could be delayed or terminated.
As a result of Regeneron’s opt-out, we have full development and commercialization rights to mivelsiran in all indications but we will be responsible for funding further development and commercialization of mivelsiran, including the ongoing Phase 2 development program, without funding from Regeneron. Regeneron will be eligible to receive low double-digit royalties on sales of mivelsiran, if approved.
As a result of Regeneron’s opt-out, we have full development and commercialization rights to mivelsiran in all indications but we are responsible for funding further development and commercialization of mivelsiran, including the ongoing Phase 2 development program, without funding from Regeneron. Regeneron will be eligible to receive low double-digit royalties on sales of mivelsiran, if approved.
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 addition, we granted licenses or options for licenses to Ionis, Benitec Biopharma Ltd., Arrowhead, Arbutus, 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.
Industry Related Risks – Risks Related to Development, Clinical Testing and Regulatory Approval of Our Product Candidates and the Commercialization of Our Approved Products • Any product candidate we or our collaborators develop may fail in development or experience significant delays. • If any of our current or future products or product candidates causes undesirable side effects or has other unexpected adverse properties, such side effects or properties could delay or prevent regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval. • We or our collaborators may be unable to obtain regulatory approval for our or our collaborated product candidates, and, as a result, we or our collaborators may be unable to commercialize such product candidates. • Even if we or our collaborators obtain regulatory approvals, our products will be subject to ongoing regulatory oversight. 38 Table of Contents • We may incur significant liability if enforcement authorities allege or determine that we are engaging in commercial activities with respect to our unapproved product candidates or promoting our commercially approved products in a way that violates applicable regulations. • Even if we or our collaborators receive regulatory approval to market our product candidates, the market may not be receptive to such product candidates upon their commercial introduction. • We are a multi-product commercial company and expect to continue to invest significant financial and management resources to continue to build our marketing, sales, market access and distribution capabilities and further establish our global infrastructure, and our efforts may not be successful. • Any products we currently market or may develop in the future may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives.
Industry Related Risks – Risks Related to Development, Clinical Testing and Regulatory Approval of Our Product Candidates and the Commercialization of Our Approved Products • Any product candidate we or our collaborators develop may fail in development or experience significant delays. • If any of our current or future products or product candidates causes undesirable side effects or has other unexpected adverse properties, such side effects or properties could delay or prevent regulatory approval, limit the commercial potential or result in significant negative consequences following any potential regulatory approval. • We or our collaborators may be unable to obtain regulatory approval for our or our collaborated product candidates, and, as a result, we or our collaborators may be unable to commercialize such product candidates. • Even if we or our collaborators obtain regulatory approvals, our products will be subject to ongoing regulatory oversight. • We may incur significant liability if enforcement authorities allege or determine that we are engaging in commercial activities with respect to our unapproved product candidates or promoting our commercially approved products in a way that violates applicable regulations. • Even if we or our collaborators receive regulatory approval to market our product candidates, the market may not be receptive to such product candidates upon their commercial introduction. • We are a multi-product commercial company and expect to continue to invest significant financial and management resources to continue to build our marketing, sales, market access and distribution capabilities and further establish our global infrastructure, and our efforts may not be successful. • Any products we currently market or may develop in the future may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives.
Raimondo overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes. The Loper decision could result in additional legal challenges to regulations and guidance issued by federal agencies, including the FDA, on which we rely.
Raimondo overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes. The Loper decision could result in additional legal challenges to regulations and guidance issued by federal agencies, including FDA and CMS, on which we rely.
The adequacy decision concluded that the U.S. ensures an adequate level of protection for personal data transferred from the EU to US companies under the new framework, and the EC stated that as a result personal data can flow safely from the EU to US companies participating in the framework, without having to put in place additional data protection safeguards.
The adequacy decision concluded that the U.S. ensures an adequate level of protection for personal data transferred from the EU to U.S. companies under the new framework, and the EC stated that as a result personal data can flow safely from the EU to U.S. companies participating in the framework, without having to put in place additional data protection safeguards.
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.
The manufacturing processes for our products and any other product candidates that we may develop is subject to FDA and foreign regulatory authority approval processes, and we will need to meet, and will need to contract with CMOs that can meet, all applicable FDA and foreign regulatory authority requirements on an ongoing basis.
In addition, government funding of other government agencies or of government programs that provide research funding on which our operations may rely directly or indirectly via third party research and development projects associated with our product development programs, is subject to the political process, which is inherently fluid and unpredictable.
In addition, government funding of agencies and programs that provide research funding on which our operations may rely directly or indirectly via third party research and development projects associated with our product development programs, is subject to the political process, which is inherently fluid and unpredictable.
Any of these occurrences may harm our ability to develop other product candidates, and may harm our business, financial condition and prospects significantly. We or our collaborators may be unable to obtain U.S. or foreign regulatory approval for our or our collaborated product candidates and, as a result, we or our collaborators may be unable to commercialize such product candidates.
Any of these occurrences may harm our ability to develop other product candidates, and may harm our business, financial condition and prospects significantly. We or our collaborators may be unable to obtain U.S. or foreign regulatory approval for our or our product candidates and, as a result, we or our collaborators may be unable to commercialize such product candidates.
Subsequent guidance published by the European Data Protection Board, or EDPB, in June 2021 described what such supplementary measures must be, and stated that businesses should avoid or cease transfers of personal data if, in the absence of supplementary measures, equivalent protections cannot be afforded.
Subsequent guidance published by the European Data Protection Board in June 2021 described what such supplementary measures must be, and stated that businesses should avoid or cease transfers of personal data if, in the absence of supplementary measures, equivalent protections cannot be afforded.
We expect to face competition from any of these and potentially other additional new drugs that enter the market to treat patients with ATTR amyloidosis with cardiomyopathy. ONPATTRO and AMVUTTRA are approved in certain jurisdictions for the treatment of certain patients with hATTR amyloidosis with polyneuropathy.
We expect to face competition from any of these and potentially other additional new drugs that enter the market to treat patients with ATTR amyloidosis with cardiomyopathy. AMVUTTRA and ONPATTRO are also approved in certain jurisdictions for the treatment of certain patients with hATTR amyloidosis with polyneuropathy.
If any of our current or future products or product candidates causes undesirable side effects or has other unexpected adverse properties, such side effects or properties could delay or prevent regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval.
If any of our current or future products or product candidates causes undesirable side effects or has other unexpected adverse properties, such side effects or properties could delay or prevent regulatory approval, limit the commercial potential or result in significant negative consequences following any potential regulatory approval.
This evolution creates uncertainty and risk of noncompliance with regulations applicable to our business, resulting in potential regulatory actions against us, along with the potential for litigation related to off-label marketing or other prohibited activities.
This evolution creates uncertainty and risk of noncompliance with regulations applicable to our business, resulting in potential regulatory actions against us, along with the potential for litigation related to off-label or deceptive marketing or other prohibited activities.
Generally, a “biotechnology company of concern” is a biotechnology company that is subject to the jurisdiction, direction, control, or operates on behalf of a foreign adversary’s government and poses a risk to the national security of the U.S.
Generally, a “biotechnology company of concern”, or BCOC, is a biotechnology company that is subject to the jurisdiction, direction, control, or operates on behalf of a foreign adversary’s government and poses a risk to the national security of the U.S.
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.
For example, for our clinical-stage product 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.
Inadequate funding for the FDA and other government agencies and/or potentially shifting priorities under the new administration could hinder the FDA’s and/or those other government agencies’ ability to hire and retain key leadership and other personnel, prevent new products and services from being developed and/or commercialized in a timely manner, or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.
Inadequate funding for the FDA and other government agencies and/or potentially shifting priorities under the current administration could hinder the agencies’ ability to hire and retain key leadership and other personnel, prevent new products and services from being developed and/or commercialized in a timely manner, or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.
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 Leqvio 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.
In addition, as a condition to providing additional funding to us, future investors may demand, and may be granted, rights superior to those of existing stockholders.
In addition, as a condition to providing additional funding to us, future investors may demand, and may be granted, rights superior to those of our existing stockholders.
It may be difficult for us to convince the medical community and third-party payors to accept and use our products, or to provide favorable reimbursement.
It may be difficult for us to convince patients, the medical community and third-party payors to accept and use our products, or to provide favorable reimbursement.
In addition, several companies have investigational drugs in clinical development for the treatment of PH1, including Biocodex, Inc. in collaboration with M8 Pharmaceuticals, Inc., and YolTech Therapeutics.
In addition, several companies have investigational drugs in clinical development for the treatment of PH1, including Biocodex, Inc. in collaboration with M8 Pharmaceuticals, Inc., and YolTech.
We do not currently have adequate capacity or capabilities to advance all opportunities arising from our growing pipeline of RNAi therapeutics. Accordingly, we have entered into collaborations with third party collaborators we believe can provide such capacity and capabilities in certain territories and/or for certain product candidates, and we intend to enter into additional such collaborations in the future.
We do not currently have adequate capacity or capabilities to advance all opportunities arising from our growing pipeline of RNAi therapeutics. Accordingly, we have entered into collaborations with third party collaborators we believe can provide such capacity and capabilities in certain territories and/or for certain product candidates, and we may enter into additional such collaborations in the future.
If we or our collaborators continue to successfully develop product candidates, and obtain approval for them, we and our collaborators will face competition based on many different factors, including: • the safety and effectiveness of our or our collaborators’ products relative to alternative therapies, if any; • the ease with which our or our collaborators’ products can be administered and the extent to which patients accept relatively new routes of administration; • the timing and scope of regulatory approvals for these products; • the availability and cost of manufacturing, marketing and sales capabilities; • the price of our or our collaborators’ products relative to alternative approved therapies; • reimbursement coverage; and • patent position.
If we or our collaborators continue to successfully develop product candidates, and obtain approval for them, we and our collaborators will face competition based on many different factors, including: • the safety and effectiveness of our or our collaborators’ products relative to alternative therapies, if any; 71 Table of Contents • the ease with which our or our collaborators’ products can be administered and the extent to which patients accept relatively new routes of administration; • the timing and scope of regulatory approvals for these products; • the availability and cost of manufacturing, marketing and sales capabilities; • the price of our or our collaborators’ products relative to alternative approved therapies; • reimbursement coverage; and • patent position.
The loss of the service of any members of our senior management could significantly delay or prevent the achievement of product development and commercialization, and other business objectives, and adversely impact our stock price. Our employment arrangements with our key personnel are terminable without notice. We do not carry key person life insurance on any of our employees.
The loss of the services of any members of our senior management could significantly delay or prevent the achievement of product development and commercialization, and other business objectives, and adversely impact our stock price. Our employment arrangements with our key personnel are terminable without notice. We do not carry key person life insurance on any of our employees.
In particular, governments in certain markets such as in EU, the U.K., Japan, and China, provide healthcare at low (or zero) direct costs to consumers at the point of care, and thus have significant power as large single payers to regulate prices or impose other cost control mechanisms.
In particular, governments in certain markets such as in EU, the U.K., Japan, and China, provide healthcare at low (or zero) direct costs to consumers at the point of care, and thus have significant power as large single payors to regulate prices or impose other cost control mechanisms.
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.
RNAi is a 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.
If we were to lose a commercialization collaborator, we would have to attract a new collaborator (potentially on less favorable terms for us than we have with our existing collaborator) or develop expanded sales, distribution and marketing capabilities internally, which would require us to invest significant amounts of financial and management resources.
If we were to lose a commercialization collaborator, we would have to attract a new collaborator (potentially on less favorable terms for us than we have with our existing collaborator) or develop expanded sales, distribution and marketing capabilities internally, which would require us to invest significant financial and management resources.
Our competitors may develop or commercialize products with significant advantages over any products we or our collaborators develop based on any of the factors listed above or on other factors. In addition, our competitors may develop collaborations with or receive funding from larger pharmaceutical or biotechnology companies, providing them with an advantage over us and our collaborators.
Our competitors may develop or commercialize products with significant advantages over any products we or our collaborators develop based on any of the factors listed above or on other factors. In addition, our competitors may enter into collaborations with or receive funding from larger pharmaceutical or biotechnology companies, providing them with an advantage over us and our collaborators.
For example, it could: • make us more vulnerable to adverse changes in general U.S. and worldwide economic, industry and competitive conditions and adverse changes in government regulation; • limit our flexibility in planning for, or reacting to, changes in our business and our industry; • place us at a disadvantage compared to our competitors who have less debt; • limit our ability to borrow additional amounts to fund acquisitions, for working capital and for other general corporate purposes; and • make an acquisition of our company less attractive or more difficult.
For example, it could: • make us more vulnerable to adverse changes in general U.S. and worldwide economic, industry and competitive conditions and adverse changes in government regulation; • limit our flexibility in planning for, or reacting to, changes in our business and our industry; • place us at a disadvantage compared to our competitors who have less debt; 74 Table of Contents • limit our ability to borrow additional amounts to fund acquisitions, for working capital and for other general corporate purposes; and • make an acquisition of our company less attractive or more difficult.
For example, on December 12, 2024, the Board of Regents of the University of Texas System, or the University of Texas, filed a lawsuit in the United States District Court for the Western District of Texas, alleging that we infringe one of the University of Texas’ patents by making, using and commercializing ONPATTRO in the U.S.
For example, in December 2024, the Board of Regents of the University of Texas System, or the University of Texas, filed a lawsuit in the United States District Court for the Western District of Texas, alleging that we infringe one of the University of Texas’ patents by making, using and commercializing ONPATTRO in the U.S.
The failure of any CMO to perform its obligations as expected, or, to the extent we manufacture all or a portion of our product candidates ourselves, our failure to execute on our manufacturing requirements, could adversely affect our business in a number of ways, including: • we or our current or future collaborators may not be able to initiate or continue clinical trials of product candidates that are under development; • we or our current or future collaborators may be delayed in submitting regulatory applications, or receiving regulatory approvals, for our product candidates; • we may lose the cooperation of our collaborators; • our facilities and those of our CMOs, and our products could be the subject of inspections by regulatory authorities that could have a negative outcome and result in supply delays; • we may be required to cease distribution or recall some or all batches, of our products or take action to recover clinical trial material from clinical trial sites; and • ultimately, we may not be able to meet the clinical and commercial demands for our product candidates and products.
The failure of any CMO to perform its obligations as expected, or, to the extent we manufacture all or a portion of our product candidates ourselves, our failure to execute on our manufacturing requirements, could adversely affect our business in a number of ways, including: • we or our collaborators may not be able to initiate or continue clinical trials of product candidates that are under development; • we or our collaborators may be delayed in submitting regulatory applications, or receiving regulatory approvals, for our product candidates; • we may lose the cooperation of our collaborators; 48 Table of Contents • our facilities and those of our CMOs, and our products could be the subject of inspections by regulatory authorities that could have a negative outcome and result in supply delays; • we may be required to cease distribution or recall some or all batches, of our products or take action to recover clinical trial material from clinical trial sites; and • ultimately, we may not be able to meet the clinical and commercial demands for our products and product candidates.
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.
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 currently expect to rely on third parties to launch and market certain of our product candidates in certain geographies, if approved. However, we are commercializing ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and intend to commercialize other product candidates, if approved, on our own globally in major markets.
We currently expect to rely on third parties to launch and market certain of our product candidates in certain geographies, if approved. However, we are commercializing AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO, and intend to commercialize additional product candidates, if approved, on our own in major markets globally.
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.
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.
Additional countries may adopt similar approaches to the pricing of prescription drugs. In such countries, pricing negotiations with governmental authorities can take considerable time after receipt of regulatory approval for a product. In addition, governments and other stakeholders can put considerable pressure on prices and reimbursement levels, including as part of cost containment measures.
Additional countries may adopt similar approaches to the pricing of prescription drugs. In such countries, 61 Table of Contents pricing negotiations with governmental authorities can take considerable time after receipt of regulatory approval for a product. In addition, governments and other stakeholders can put considerable pressure on prices and reimbursement levels, including as part of cost containment measures.
Factors that could have an adverse impact on Leqvio sales include: • competitors may develop new therapies or alternative formulations of products for HeFH and ASCVD; • lack of acceptance of Leqvio by patients, the medical community or third party payors; • any negative developments relating to Leqvio, such as safety, efficacy, or reimbursement issues; • any disputes concerning patents or proprietary rights, or under license and collaboration agreements; • foreign currency exchange rate fluctuations; and • adverse regulatory or legislative developments that limit or prohibit the sale of Leqvio, such as restrictions on the use of Leqvio or safety-related label changes, including enhanced risk management programs.
Factors that could have an adverse impact on Leqvio sales include: • competitors may develop new therapies or alternative formulations of products for HeFH and ASCVD; • lack of acceptance of Leqvio by patients, the medical community or third party payors; • any negative developments relating to Leqvio, such as safety, efficacy, or pricing or reimbursement issues; • any disputes concerning patents or proprietary rights (including any emergence of potential generic competition), or under license and collaboration agreements; • foreign currency exchange rate fluctuations; and • adverse regulatory or legislative developments that limit or prohibit the sale of Leqvio, such as restrictions on the use of Leqvio or safety-related label changes, including enhanced risk management programs.
During 2020, we completed construction and qualification of our manufacturing facility in Norton, Massachusetts where we manufacture drug substances for early-stage clinical development and have the possibility to manufacture drug substances for late-stage clinical development and commercial use, in the future.
During 2020, we completed construction and qualification of our manufacturing facility in Norton, Massachusetts where we manufacture drug substances for early-stage clinical development and have the potential to manufacture drug substances for late-stage clinical development and commercial use, in the future.
I f a regulatory agency determines that our promotional materials, or other activities constitute off-label promotion, it could request that we modify our promotional materials or other activities, conduct corrective advertising, or subject us to regulatory enforcement actions, such as the issuance of a warning or untitled letter, injunction, seizure, civil fines and criminal penalties.
I f a regulatory agency determines that our promotional materials, or other activities constitute off-label promotion, it 56 Table of Contents could request that we modify our promotional materials or other activities, conduct corrective advertising, or subject us to regulatory enforcement actions, such as the issuance of a warning or untitled letter, injunction, seizure, civil fines and criminal penalties.
Any products we currently market or may develop in the future may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, thereby harming our business, prospects, operating results and financial condition. The regulations that govern marketing approvals, coverage, pricing and reimbursement for new drugs vary widely from country to country and are subject to change.
Any products we currently market or may develop in the future may become subject to unfavorable pricing regulations or healthcare reform initiatives, thereby harming our business, prospects, operating results and financial condition. The regulations that govern marketing approvals, coverage, pricing and reimbursement for new drugs vary widely from country to country and are subject to change.
These could include changes to the level of scrutiny applied by the Health Resources and Services Administration to enforce non-compliance with the 340B Drug Pricing Program, new price restrictions on products we sell to Medicaid, Medicare or other government purchasers, or other regulatory changes impacting reimbursement or competitive dynamics in multisource markets.
These could include changes to the level of scrutiny applied by the Health Resources and Services Administration to enforce non-compliance with the 340B Drug Pricing Program, new price restrictions on products we sell to Medicaid, Medicare or other government purchasers, or other regulatory changes impacting reimbursement or competitive dynamics in multi-source markets.
If such owners do not properly or successfully obtain, maintain or enforce the patents underlying such licenses, our competitive position and business, prospects, operating results and financial condition may be harmed. • Other companies or organizations may challenge our patent rights or may assert patent rights that prevent us from developing and commercializing our products. • If we become involved in intellectual property litigation or other proceedings related to a determination of rights, including our ongoing patent infringement litigation against Pfizer, Inc., or Pfizer, and Moderna, Inc., or Moderna, we could incur substantial costs and expenses, and in the case of such litigation or proceedings against us, substantial liability for damages or be required to stop our product development and commercialization efforts. • 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 current and future products and product candidates.
If such owners do not properly or successfully obtain, maintain or enforce the patents underlying such licenses, our competitive position and business, prospects, operating results and financial condition may be harmed. • Other companies or organizations may challenge our patent rights or may assert patent rights that prevent us from developing and commercializing our products. • If we become involved in intellectual property litigation or other proceedings related to a determination of rights, we could incur substantial costs and expenses, and in the case of such litigation or proceedings against us, substantial liability for damages or be required to stop our product development and commercialization efforts. • 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 current and future products and product candidates.
We may incur substantial costs to comply with, and substantial fines or penalties if we violate, any of these laws or regulations. Risks Related to Patents, Licenses and Trade Secrets If we are not able to obtain and enforce patent protection for our discoveries, our ability to develop and commercialize our product candidates will be harmed.
We may incur substantial costs to comply with, and substantial fines or penalties if we violate, any of these laws or regulations. 66 Table of Contents Risks Related to Patents, Licenses and Trade Secrets If we are not able to obtain and enforce patent protection for our discoveries, our ability to develop and commercialize our product candidates will be harmed.
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.
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 46 Table of Contents 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 the impacted product candidate(s), 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.
If we are unable to manufacture sufficient quantities of material or if we encounter problems with our facilities in the future, we may also need to secure alternative suppliers, and such alternative suppliers may not be available, or we may be unable to enter into agreements with them on reasonable terms and in a timely manner, or at all.
If we are unable to manufacture sufficient quantities of material or if we encounter problems with our facilities in the future, we may also need to secure alternative suppliers, and such alternative suppliers may not be available, or we may be unable to enter into agreements with them on 47 Table of Contents reasonable terms and in a timely manner, or at all.
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.
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.
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.
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.
We will also be required to effectively and efficiently govern, manage and ensure timely enhancements to our systems, including in their design, architecture and interconnections as well as their organizational and technical protections. The pervasiveness of cybersecurity incidents in general and the risks of cyber-crime are complex and continue to evolve.
We will also be required to effectively and efficiently govern, manage and ensure timely enhancements to our systems, including in their design, architecture and interconnections as well as their organizational and technical protections. 50 Table of Contents The pervasiveness of cybersecurity incidents in general and the risks of cyber-crime are complex and continue to evolve.
Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights, and failure to obtain or maintain trade secret protection could adversely affect our business, prospects, operating results and financial condition. Risks Related to Competition The pharmaceutical market is intensely competitive.
Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights, and failure to obtain or maintain trade secret protection could adversely affect our business, prospects, operating results and financial condition. 70 Table of Contents Risks Related to Competition The pharmaceutical market is intensely competitive.
We could encounter delays if a clinical trial is suspended or terminated by us, by the FDA or any other regulatory authority, or if the IRBs of the institutions in which such trials are being conducted suspend or terminate the participation of their clinical investigators and sites subject to their review.
We could encounter delays if a clinical trial is suspended or terminated by us, by the FDA or any other regulatory authority, or if the institutional review boards of the institutions in which such trials are being conducted suspend or terminate the participation of their clinical investigators and sites subject to their review.
For example, although we reported positive results from the APOLLO-B Phase 3 clinical trial of patisiran in patients with ATTR amyloidosis with cardiomyopathy, in October 2023, the FDA issued a CRL in response to our sNDA for patisiran, indicating the sNDA could not be approved in its present form.
For example, although we reported positive results from the APOLLO-B Phase 3 clinical trial of patisiran in patients with ATTR-CM, in October 2023, the FDA issued a CRL in response to our sNDA for patisiran, indicating the sNDA could not be approved in its present form.
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.
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. 65 Table of Contents There is a substantial risk of product liability claims in our business.
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.
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.
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.
Under our agreement with Blackstone Royalties, if Blackstone Royalties 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.
Related to this action, certain foreign governments, including China, have instituted or are considering imposing tariffs on certain U.S. goods. It remains unclear what the new administration or foreign governments will or will not do with respect to tariffs or other international trade agreements and policies.
Related to this action, certain foreign governments, including China, have instituted or are considering imposing reciprocal tariffs on certain U.S. goods. It remains unclear what the current administration or foreign governments will or will not do with respect to tariffs or other international trade agreements and policies.
Any such legal challenges, if successful, could have a material impact on our business. Additionally, the Loper decision may result in increased regulatory uncertainty, inconsistent judicial interpretations, and other impacts to the agency rule-making process, any of which could adversely impact our business and operations.
Any such legal challenges, if successful, could have a material impact on our business. Additionally, the Loper decision may result in increased regulatory uncertainty, inconsistent judicial interpretations, and other impacts to the agency rulemaking process, any of which could adversely impact our business and operations.
We are also aware of other product candidates in clinical development for the treatment of ATTR amyloidosis with cardiomyopathy, including WAINUA (eplontersen), which is being developed by Ionis and AstraZeneca plc, or AstraZeneca, and is in Phase 3 clinical development; nexiguran ziclumeran (formerly NTLA-2001), which is being developed by Intellia Therapeutics, Inc. and Regeneron and is in Phase 3 clinical development; ALN-2220 (formerly NI006), which is being developed by Neurimmune AG and Alexion Pharmaceuticals, Inc.
We are also aware of other product candidates in clinical development for the treatment of ATTR amyloidosis with cardiomyopathy, including WAINUA (eplontersen), which is being developed by Ionis and AstraZeneca plc, or AstraZeneca, and is in Phase 3 clinical development; nexiguran ziclumeran (formerly NTLA-2001), which is being developed by Intellia Therapeutics, Inc. and Regeneron and is in Phase 3 clinical development; cliramitug (formerly ALXN220/NI006), which is being developed by Neurimmune AG and Alexion Pharmaceuticals, Inc.
Moreover, if we elect, or are required, to delay, suspend or terminate any clinical trial of any product candidate, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated.
Moreover, if we elect, or are required, to delay, suspend or terminate any clinical trial of any product candidate, the commercial prospects of such product candidates may be 53 Table of Contents harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated.
While issued patents are presumed valid, this does not guarantee that the patent will survive a validity challenge or be held enforceable. Any patents we have obtained, or obtain in the future, may be challenged, invalidated, adjudged unenforceable or circumvented by parties attempting to design 64 Table of Contents around our intellectual property.
While issued patents are presumed valid, this does not guarantee that the patent will survive a validity challenge or be held enforceable. Any patents we have obtained, or obtain in the future, may be challenged, invalidated, adjudged unenforceable or circumvented by parties attempting to design around our intellectual property.
Without protection for the intellectual property we license, other companies might be able to offer substantially identical products for sale, which could adversely affect our competitive business position and harm our business, prospects, operating results and financial condition. In addition, we sublicense our rights under various third-party licenses to our collaborators.
Without protection for the intellectual property we license, other companies might be able to offer substantially identical products for sale, which could adversely affect our 67 Table of Contents competitive business position and harm our business, prospects, operating results and financial condition. In addition, we sublicense our rights under various third-party licenses to our collaborators.
We have based our expectations on a number of factors, many of which are difficult to predict or are outside of our control, including: • progress in our research and development programs, including programs across a broad range of disease areas and indications, as well as what may be required by regulatory authorities to advance these programs; • the timing, receipt and amount of milestone, royalty, research and development funding and other payments, if any, from present and future collaborators, if any, including milestone, royalty and research and development funding payments from Roche with respect to the development and commercialization of zilebesiran, as well as milestone and royalty payments from Novartis related to the commercialization of Leqvio; • our ability to establish and maintain existing and additional collaborations and/or new business initiatives; • the potential for improved product profiles to emerge from our new technologies and our ability to successfully advance our delivery efforts in extrahepatic tissues; • the resources, time and costs required to successfully initiate and complete our preclinical studies and clinical trials, obtain regulatory approvals, prepare for global commercialization of our product candidates and obtain and maintain licenses to third-party intellectual property; • our ability to establish, maintain and operate our own manufacturing facilities in a timely and cost-effective manner; • our ability to manufacture, or contract with third parties for the manufacture of, our product candidates for clinical testing and our approved products for commercial sale; • the impact of any future pandemics or public health emergencies or the ongoing conflicts in the Middle East and Ukraine on the initiation or completion of preclinical studies or clinical trials and the supply of our products or product candidates; • the resources, time and cost required for the preparation, filing, prosecution, maintenance and enforcement of patent claims; • the costs associated with legal activities, including litigation and government investigations, arising in the course of our business activities and our ability to prevail or reach a satisfactory result in any such legal disputes and investigations; • the timing, receipt and amount of sales milestones and royalties, if any, from our approved products and our product candidates, if and when approved; and • the outcome of the regulatory review process and commercial success of our products, including AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy, and products for which we are entitled to receive royalties, including Leqvio and fitusiran, assuming regulatory approval.
We have based our expectations on a number of factors, many of which are difficult to predict or are outside of our control, including: • progress in our research and development programs, including programs across a broad range of disease areas and indications, as well as what may be required by regulatory authorities to advance these programs; • the timing, receipt and amount of milestone, royalty, research and development funding and other payments, if any, from present and future collaborators, if any, including milestone, royalty and research and development funding payments from Roche with respect to the development and commercialization of zilebesiran, as well as royalty payments from Novartis and Sanofi related to the commercialization of Leqvio and Qfitlia, respectively; • our ability to establish and maintain existing and additional collaborations and/or new business initiatives; • the potential for improved product profiles to emerge from our new technologies and our ability to successfully advance our delivery efforts in extrahepatic tissues; • the resources, time and costs required to successfully initiate and complete our preclinical studies and clinical trials, obtain regulatory approvals, prepare for global commercialization of our product candidates and obtain and maintain licenses to third-party intellectual property; • our ability to establish, maintain, operate and expand our own manufacturing facilities in a timely and cost-effective manner; • our ability to manufacture, or contract with third parties for the manufacture of, our product candidates for clinical testing and our approved products for commercial sale; • the impact of any future pandemics or public health emergencies on the initiation or completion of preclinical studies or clinical trials and the supply of our products or product candidates; • the resources, time and cost required for the preparation, filing, prosecution, maintenance and enforcement of patent claims; • the costs associated with legal activities, including litigation and government investigations, arising in the course of our business activities and our ability to prevail or reach a satisfactory result in any such legal disputes and investigations; and • the outcome of the global regulatory review process and commercial success of our products, including AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy, and products for which we are entitled to receive royalties, including Leqvio and Qfitlia.
Cyber-attacks can be designed to collect sensitive or proprietary information, manipulate, destroy or corrupt data, systems or applications, or accounts, to steal money or extort money through the use of so-called “ransomware”, and to disable the functioning or use of applications or technology assets.
Cyber-attacks can be designed to collect sensitive or proprietary information, manipulate, destroy or corrupt data, systems or applications, or accounts, to steal money or extort money through the use of so-called “ransomware,” and to disable the functioning or use of applications or technology assets.
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.
In some cases, the delivery technology we utilize is 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.
Some of this information could be subject to information breaches, unauthorized access, human error, computer viruses, denial-of-service attacks, malicious code, spam attacks, phishing, ransomware or other forms of social engineering and other events that could impact the security, reliability, confidentiality, integrity and availability of our systems, including by third parties with a wide range of motives and expertise, including organized criminal groups, nation-states, “hacktivists,” patient groups, rogue current or former employees and others.
Some of this information could be subject to information breaches, unauthorized access, human error, computer viruses, denial-of-service attacks, malicious code, spam attacks, phishing, ransomware or other forms of social engineering, third-party or employee theft or misuse, negligent actions and other events that could impact the security, reliability, confidentiality, integrity and availability of our systems, including by third parties with a wide range of motives and expertise, including organized criminal groups, nation-states, “hacktivists,” patient groups, rogue current or former employees and others.
Despite the implementation of security measures, our internal computer systems and those of our contractors, consultants and collaborators are vulnerable to damage or interruption from computer viruses, unauthorized or inappropriate access or use, natural disasters, pandemics or public health emergencies, terrorism, war (including the ongoing conflicts in Ukraine and the Middle East), and telecommunication and electrical failures.
Despite the implementation of security measures, our internal computer systems and those of our contractors, consultants and collaborators are vulnerable to damage or interruption from computer viruses, unauthorized or inappropriate access or use, natural disasters, pandemics or public health emergencies, terrorism, war (including the ongoing conflict in Ukraine), and telecommunication and electrical failures.
We may experience numerous unforeseen events during, or as a result of, nonclinical testing and the clinical trial process that could extend our clinical development timelines and delay or prevent regulatory approval or our ability to commercialize our product candidates, including: • our nonclinical tests or clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional nonclinical testing or clinical trials, or we may abandon projects that have the potential to be promising; • delays in filing IND applications or comparable foreign applications or delays or failure in obtaining the necessary approvals from regulators or IRBs/ethics committees in order to commence a clinical trial at a prospective trial site, or their suspension or termination of a clinical trial once commenced; • conditions imposed on us by an IRB or ethics committee, or the FDA or comparable foreign regulatory authorities regarding the scope or design of our clinical trials; • problems in engaging IRBs or ethics committees to oversee clinical trials or problems in obtaining or maintaining IRB or ethics committee approval of clinical trials; • delays in enrolling patients and volunteers into clinical trials, and variability in the number and types of patients and volunteers available for clinical trials, including as a result of a pandemic or public health emergency or the ongoing conflicts in Ukraine and the Middle East; • disruptions caused by man-made or natural disasters or pandemics, epidemics or public health emergencies or other business interruptions; • high drop-out rates for patients and volunteers in clinical trials; • negative or inconclusive results from our clinical trials or the clinical trials of others for product candidates similar to ours; • inadequate supply or quality of product candidate materials or other materials necessary for the conduct of our clinical trials or disruption or delays in clinical supply due to a future pandemic or public health emergency; • serious and unexpected drug-related side effects experienced by patients taking our approved products, participants in our clinical trials or individuals using drugs similar to our products or product candidates; 50 Table of Contents • poor or disappointing effectiveness of our product candidates during clinical trials; • the imposition of a clinical hold by regulatory authorities as a result of a serious adverse event or manufacturing concerns or after an inspection of our clinical trial operations or trial sites; • unfavorable FDA or other regulatory agency inspection and review of a clinical trial site or records of any clinical or nonclinical investigation; • failure of our third-party contractors or investigators to comply with regulatory requirements, including GLP, GCP and cGMP, or otherwise meet their contractual obligations in a timely manner, or at all; • governmental or regulatory delays and changes in regulatory requirements, policy and guidelines, including the imposition of additional regulatory oversight around clinical testing generally or with respect to our technology in particular; • delays in reaching a consensus with regulatory agencies on trial design; • interpretations of data by the FDA and similar foreign regulatory agencies that differ from ours; • lack of adequate funding to continue the clinical trial; or • diminished revenue potential of the applicable program due to competition.
We may experience numerous unforeseen events during, or as a result of, nonclinical testing and the clinical trial process that could extend our clinical development timelines and delay or prevent regulatory approval or our ability to commercialize our product candidates, including: • our nonclinical tests or clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional nonclinical testing or clinical trials, or we may abandon projects that have the potential to be promising; • delays in filing IND applications or comparable foreign applications or delays or failure in obtaining the necessary approvals from regulators or institutional review boards/ethics committees in order to commence a clinical trial at a prospective trial site, or their suspension or termination of a clinical trial once commenced; • conditions imposed on us by an institutional review board or ethics committee, or the FDA or comparable foreign regulatory authorities regarding the scope or design of our clinical trials; • problems in engaging institutional review boards or ethics committees to oversee clinical trials or problems in obtaining or maintaining institutional review board or ethics committee approval of clinical trials; • delays in enrolling patients and volunteers into clinical trials, and variability in the number and types of patients and volunteers available for clinical trials, including as a result of the availability of existing approved therapies for the indication for which the clinical trial is testing our product candidate; • disruptions caused by man-made or natural disasters or pandemics, epidemics or public health emergencies or other business interruptions; • high drop-out rates for patients and volunteers in clinical trials; • negative or inconclusive results from our clinical trials or the clinical trials of others for product candidates similar to ours; • inadequate supply or quality of product candidate materials or other materials necessary for the conduct of our clinical trials or disruption or delays in clinical supply due to a future pandemic or public health emergency; • serious and unexpected drug-related side effects experienced by patients taking our approved products, participants in our clinical trials or individuals using drugs similar to our products or product candidates; • poor or disappointing effectiveness of our product candidates during clinical trials; • the imposition of a clinical hold by regulatory authorities as a result of a serious adverse event or manufacturing concerns or after an inspection of our clinical trial operations or trial sites; • unfavorable FDA or other regulatory agency inspection and review of a clinical trial site or records of any clinical or nonclinical investigation; • failure of our third-party contractors or investigators to comply with regulatory requirements, including GLP, GCP and cGMP, or otherwise meet their contractual obligations in a timely manner, or at all; • governmental or regulatory delays, including as a result of a government shutdown, and changes in regulatory requirements, policy and guidelines, including the imposition of additional regulatory oversight around clinical testing generally or with respect to our technology in particular; • delays in reaching a consensus with regulatory agencies on trial design; 52 Table of Contents • interpretations of data by the FDA or foreign regulatory authorities that differ from ours; • lack of adequate funding to continue the clinical trial; or • diminished revenue potential of the applicable program due to competition.
For example, in August 2017, Dicerna successfully added counterclaims against us in the above-referenced trade secret lawsuit alleging that our lawsuit represented abuse of process and claiming tortious interference with its business.
For example, in August 2017, Dicerna successfully added counterclaims against us in the above-referenced trade secret lawsuit alleging that our lawsuit represented abuse of process and claiming tortious 69 Table of Contents interference with its business.
Following arbitration proceedings, the panel ruled in 67 Table of Contents favor of each party on certain TAF associated claims and awarded Ionis compensation of $41.2 million for a TAF on certain rights we received in the Sanofi restructuring.
Following arbitration proceedings, the panel ruled in favor of each party on certain TAF associated claims and awarded Ionis compensation of $41.2 million for a TAF on certain rights we received in the Sanofi restructuring.
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.
Specifically, we currently have active collaborations with, among other companies, Roche, Regeneron, Sanofi and Novartis, covering various products and product candidates in our pipeline. In such collaborations, we expect our current, and any future, collaborators to provide substantial capabilities in clinical development, regulatory affairs, and/or marketing, sales and distribution.
Most typically, open-label clinical trials test only the investigational product candidate and sometimes may do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment.
Most typically, open-label clinical trials test only the investigational product candidate and sometimes may do so at different dose levels. Open-label clinical trials are subject to 51 Table of Contents various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment.
As we continue the commercialization of our approved products, and as the product candidates we develop enter and advance through clinical trials, we will need to continue to expand our global development, regulatory, manufacturing, quality, compliance, and marketing and sales capabilities, or contract with other organizations to provide these capabilities for us.
As we continue the commercialization of our approved products, and as the product candidates we develop enter and advance through clinical trials, we will need to continue to expand our global development, regulatory, manufacturing, quality, compliance, and marketing and sales capabilities, or contract with third parties to provide these capabilities for us.
Any of these 53 Table of Contents restrictions or commitment could limit an approved product’s market opportunity and have a negative impact on our business, prospects, operating results and financial condition and our stock price.
Any of these restrictions or commitment could limit an approved product’s market opportunity and have a negative impact on our business, prospects, operating results and financial condition and our stock price.
We believe that the efforts of governments and third-party payors to contain or reduce the cost of healthcare and legislative and regulatory proposals to broaden the availability of healthcare will continue to affect the business and financial condition of pharmaceutical and biopharmaceutical companies.
We believe that the efforts of governments and third-party payors to contain or reduce the cost of healthcare and broaden the availability of healthcare will continue to affect the business and financial condition of pharmaceutical and biopharmaceutical companies.

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Item 1C. Cybersecurity

Cybersecurity — threats and controls disclosure

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Biggest changeThis risk assessment process considers the nature of our business, requirements from our internal and external stakeholders, and industry trends and risks, including new and emerging risks. By continuously assessing the cybersecurity landscape, we develop targeted strategies that identify and address the risks most likely to impact our company.
Biggest changeBy continuously assessing the cybersecurity landscape, we develop targeted 76 Table of Contents strategies that identify and address the risks most likely to impact our company. We also conduct at least one cybersecurity incident tabletop exercise each year to test and enhance our incident response plans.
Pursuant to our processes, when a cybersecurity incident occurs, we convene a cross-functional incident response team whose membership is dictated by the severity of the incident but in all instances includes representatives from our information technology, legal and accounting departments.
Pursuant to our processes, when a cybersecurity incident occurs, we convene a cross-functional incident response team whose membership is dictated by the severity of the incident but in all instances includes representatives from our information technology, legal and finance departments.
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.
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.
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
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.
Our CISO, together with our Chief Information Officer, or CIO, provides at least two presentations each year to our board of directors or nominating and corporate governance committee on cybersecurity incidents, security program updates and ongoing risks, with additional updates being provided on an as-needed basis.
Our CISO, together with our chief information officer, or CIO, provides at least two presentations each year to our board of directors or nominating and corporate governance committee on, security 77 Table of Contents program updates and ongoing risks, with additional updates being provided on an as-needed basis.
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.
Such insurance is subject to several exclusions and may not cover the total loss or damage caused by an incident. Consequently, costs related to incidents may not be covered by insurance.
ITEM 1C. CYBERSECURITY Risk Management and Strategy We have in place a cross-functional, enterprise-wide cybersecurity program that is integrated into our overall risk management process and strategy and has direct involvement from our senior management and board oversight. Our cybersecurity program is based on industry standard CIS critical security controls.
ITEM 1C. CYBERSECURITY Risk Management and Strategy We have in place a cross-functional, enterprise-wide cybersecurity program that is integrated into our overall enterprise risk management process and strategy and has direct involvement from our senior management and board oversight. Our cybersecurity program is based on industry standards.
Our CISO has over 25 years of information security and information technology risk expertise in multiple industries, including financial, manufacturing, healthcare and life sciences, and holds industry standard certifications, including CISSP, CRISC and CISM.
Our CISO has over 25 years of information security and information technology risk expertise in multiple industries, including defense, manufacturing, financial and life sciences, and holds industry standard certifications.
By equipping our employees with the necessary knowledge and skills, we intend to cultivate a cybersecurity-conscious culture within our organization. We maintain insurance to provide coverage for a portion of the losses and damages that may result from a physical attack, cybersecurity attack or a security breach.
By equipping our employees with the necessary knowledge and skills, we intend to cultivate a cybersecurity-conscious culture within our organization. We maintain insurance to provide coverage for a portion of the losses and damages that may result from a range of cybersecurity incidents.
These third-party service providers may have access to our systems and/or sensitive information. To address cybersecurity risks arising from our third-party service providers, we assess and monitor risks relating to potential compromises of sensitive information at our third-party service providers and reevaluate these risks periodically.
We also utilize third-party service providers as a normal part of our business operations. These third-party service providers may have access to our systems and/or sensitive information. To address cybersecurity risks arising from our third-party service providers, we assess and monitor risks relating to potential compromises of sensitive information at our third-party service providers and reevaluate these risks periodically.
To assess, identify, and manage material risks from cybersecurity threats to our information systems and the associated costs, our cybersecurity program prioritizes vulnerability management and risk reduction, detection and prevention. As part of this program, we conduct continuous monitoring for anomalous behavior using a third-party security operations center.
To assess, identify, and manage material risks from cybersecurity threats to our information systems and the associated costs, our cybersecurity program prioritizes using a risk-based approach that prevents and detects threats. As part of this program, we conduct continuous monitoring for anomalous behavior using a third-party security operations center.
This incident response framework further enables us to quickly assess the severity of cybersecurity incidents and the materiality of incidents based on pre-defined criteria that considers both quantitative and qualitative factors to determine the appropriate response.
This incident response framework further enables us to quickly assess the severity of cybersecurity incidents and support materiality determination of incidents based on pre-defined criteria that considers both quantitative and qualitative factors to determine the appropriate response. If we determine that an incident is not material, we continue to monitor it for subsequent developments.
We also conduct at least one cybersecurity incident tabletop exercise each year to test and enhance our incident response plans. Our cybersecurity program is designed to detect and prevent disruption to critical information systems, minimize the loss or manipulation of sensitive information, efficiently remediate and recover from cybersecurity incidents and ensure compliance with regulations and disclosure requirements.
Our cybersecurity program is designed to detect and prevent disruption to critical information systems, minimize the loss or manipulation of sensitive information, efficiently remediate and recover from cybersecurity incidents and ensure compliance with regulations and disclosure requirements.
In addition, we conduct an annual cybersecurity risk assessment in conjunction with our third-party consultant that specializes in information security, and we incorporate recommendations from the risk assessment into our cybersecurity strategy, as appropriate.
In addition, we conduct an annual cybersecurity assessment in conjunction with our third-party consultant that specializes in information security, and we incorporate recommendations from the assessment into our cybersecurity strategy, as appropriate. This assessment process considers the nature of our business, requirements from our internal and external stakeholders, and industry trends and risks, including new and emerging risks.
Governance Our board of directors is responsible for cybersecurity risk management and oversight of our cybersecurity program.
Governance Our board of directors is responsible for cybersecurity risk management and oversight of our cybersecurity program. The nominating and corporate governance committee of the board of directors provides oversight of the program to identify, assess, manage and monitor cybersecurity risks.
Removed
The top risks facing our Company, including those related to cybersecurity, are included in our overall enterprise risk management program that is managed by a cross-functional group chaired by our compliance and internal audit functions.
Removed
Identified incidents are then escalated to the relevant management teams based on their severity, allowing for a swift determination of materiality and an effective mitigation process. If we determine that an incident is not material, we continue to monitor it for subsequent developments. We also utilize third-party service providers as a normal part of our business operations.
Removed
The nominating and corporate governance committee of the board of directors assists in the oversight of management’s implementation of our information technology policies and monitoring of the risks associated with our information systems, including reviewing and discussing with management our program to identify, assess, manage and monitor cybersecurity risks.

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 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.
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 23,350 June 2029 Two two-year terms 20 Commerce Way Norton, Massachusetts GMP manufacturing 200,000 Owned Owned 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 27 Market Street, Maidenhead Berkshire, United Kingdom Office space 15,600 October 2035 One five-year term 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, 2025 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, 2026 is included in the table below. Location Primary Use Approximate Square Footage Lease Expiration Date Renewal Option 675 West Kendall Street Henri A.

Item 3. Legal Proceedings

Legal Proceedings — active lawsuits and investigations

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Biggest changeITEM 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.
Biggest changeLEGAL 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. 78 Table of Contents ITEM 4.
MINE SAFETY DISCLOSURES Not applicable. 76 Table of Contents PART II
MINE SAFETY DISCLOSURES Not applicable. 79 Table of Contents PART II

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. 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.
Biggest changeThe stock price performance reflected in the graph below is not necessarily indicative of future price performance. 80 Table of Contents Comparison of Five-Year Cumulative Total Return Among Alnylam Pharmaceuticals, Inc., Nasdaq Composite Total Return and Nasdaq Biotechnology Total Return 12/31/2020 12/31/2021 12/30/2022 12/29/2023 12/31/2024 12/31/2025 Alnylam Pharmaceuticals, Inc. $ 100.00 $ 130.48 $ 182.85 $ 147.27 $ 181.05 $ 305.96 Nasdaq Composite Total Return $ 100.00 $ 122.18 $ 82.43 $ 119.22 $ 154.48 $ 187.14 Nasdaq Biotechnology Total Return $ 100.00 $ 100.02 $ 89.90 $ 94.03 $ 93.49 $ 124.75 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, 2025, there were 26 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, 2026, there were 23 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 2019, to the close of the last trading day of 2024, 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 2020, to the close of the last trading day of 2025, 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, 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%.
Biggest changeDiscussion of Results of Operations Revenues Total revenues consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Net product revenues $ 2,986,549 $ 1,646,228 $ 1,241,474 $ 1,340,321 81 % $ 404,754 33 % Net revenues from collaborations 553,366 510,221 546,185 43,145 8 % (35,964) (7) % Royalty revenue 174,022 91,794 40,633 82,228 90 % 51,161 126 % Total revenues $ 3,713,937 $ 2,248,243 $ 1,828,292 $ 1,465,694 65 % $ 419,951 23 % 82 Table of Contents Net Product Revenues Net product revenues, classified based on the geographic region in which the product is sold and by franchise (“TTR,” which includes AMVUTTRA and ONPATTRO, and “Rare,” which includes GIVLAARI and OXLUMO) consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change AMVUTTRA United States $ 1,731,222 $ 630,613 $ 411,169 $ 1,100,609 175 % $ 219,444 53 % Europe 405,899 235,441 70,898 170,458 72 % 164,543 232 % Rest of World 176,715 104,396 75,771 72,319 69 % 28,625 38 % Total 2,313,836 970,450 557,838 1,343,386 138 % 412,612 74 % ONPATTRO United States 62,126 74,787 97,739 (12,661) (17) % (22,952) (23) % Europe 79,429 134,197 210,916 (54,768) (41) % (76,719) (36) % Rest of World 31,234 43,873 45,891 (12,639) (29) % (2,018) (4) % Total 172,789 252,857 354,546 (80,068) (32) % (101,689) (29) % Total TTR 2,486,625 1,223,307 912,384 1,263,318 103 % 310,923 34 % GIVLAARI United States 205,715 165,373 141,954 40,342 24 % 23,419 16 % Europe 77,715 65,906 57,498 11,809 18 % 8,408 15 % Rest of World 25,057 24,592 19,799 465 2 % 4,793 24 % Total 308,487 255,871 219,251 52,616 21 % 36,620 17 % OXLUMO United States 68,467 62,766 38,159 5,701 9 % 24,607 64 % Europe 88,049 80,753 60,025 7,296 9 % 20,728 35 % Rest of World 34,921 23,531 11,655 11,390 48 % 11,876 102 % Total 191,437 167,050 109,839 24,387 15 % 57,211 52 % Total Rare 499,924 422,921 329,090 77,003 18 % 93,831 29 % Total net product revenues $ 2,986,549 $ 1,646,228 $ 1,241,474 $ 1,340,321 81 % $ 404,754 33 % Net product revenues increased during the year ended December 31, 2025, compared to the year ended December 31, 2024, primarily due to growth from AMVUTTRA revenues driven by increased patient demand, mainly in patients with ATTR-CM in the U.S., which was partially offset by a decreased number of patients on ONPATTRO, and due to growth from an increased number of patients on GIVLAARI and OXLUMO.
Due to numerous factors described in more detail under the caption Part I, Item 1A, “Risk Factors” of this Annual Report on Form 10-K, we may require significant additional funds earlier than we currently expect in order to continue to commercialize ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and to develop, conduct clinical trials for, manufacture and, if approved, commercialize additional product candidates.
Due to numerous factors described in more detail under the caption Part I, Item 1A, “Risk Factors” of this Annual Report on Form 10-K, we may require significant additional funds earlier than we currently expect in order to continue to commercialize AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO, and to develop, conduct clinical trials for, manufacture and, if approved, commercialize additional product candidates.
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.
However, we and our collaborators may not be able to successfully market and sell our existing commercialized products or any approved products in the future. Moreover, our ongoing development and regulatory efforts may not be successful, and we and our collaborators may not be able to commence sales of any other products in the future.
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.
Royalty revenue increased during the year ended December 31, 2025, as compared to the year ended December 31, 2024, due to increased volume and rate of royalties earned from global net sales of Leqvio by Novartis.
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.
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.
The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to the customer who directly purchases from us, and rebates that represent discount obligations under government programs, including Medicaid in the U.S. and similar programs in certain other countries, including countries in which we are accruing for estimated rebates because final pricing has not yet been negotiated.
The estimates for our product revenue allowances and accruals are most significantly affected by chargebacks, which are contractual commitments with the government and other entities to sell products to qualified healthcare providers at prices lower than the list prices charged to the customer who directly purchases from us, and rebates that represent discount obligations under government programs, including Medicare and Medicaid in the U.S. and similar programs in certain other countries, including countries in which we are accruing for estimated rebates because final pricing has not yet been negotiated. 88 Table of Contents We are also subject to potential rebates in connection with our value-based agreements, or VBAs, with certain commercial payors.
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.
Partially offset by: • recognition of $185.0 million of revenue under our collaboration with Regeneron during the year ended December 31, 2024, as we modified the collaboration agreement in June 2024 and provided Regeneron with an exclusive license to develop, manufacture and commercialize cemdisiran as a monotherapy; • recognition of $65.0 million of milestone revenue under our collaboration with Roche during the year ended December 31, 2024 associated with the dosing of the first patient in the KARDIA-3 Phase 2 clinical trial of zilebesiran; and • revenue recognized under our license agreement with Novartis associated with the achievement of a specified Leqvio commercialization milestone during the year ended December 31, 2024.
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.
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, 2025 totaled $366.3 million, with $48.1 million expected to be paid within the next 12 months. • Cash outflows for capital expenditures were $58.7 million in 2025 and $34.3 million in 2024.
Historically, we have generated losses principally from costs associated with research and development activities, acquiring, filing and expanding intellectual property rights, and selling, general and administrative costs.
Historically, we generated losses primarily from costs associated with research and development activities; acquiring, filing and protecting our intellectual property rights; and selling, general and administrative activities.
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 that research and development expenses combined with selling, general and administrative expenses will increase during 2026, as compared to 2025, as we continue to launch our current commercial products into new markets, prepare for future commercial product launches, including the continued launch of AMVUTTRA for the treatment of ATTR-CM, 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 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.
We expect our cost of goods sold, including cost of goods sold as a percentage of net product revenues, will increase during 2026, as compared to 2025, primarily as a result of an expected increase in sales of AMVUTTRA and an associated increase in the royalty rate payable on net sales of AMVUTTRA.
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.
We expect our cost of collaborations and royalties will decrease during 2026, as compared to 2025, primarily as a result of our collaborators having transitioned to producing GalNAc material independently.
However, our ongoing development efforts may not be successful and we may not be able to commence sales of any other products or successfully expand the approved indications for our approved products, including AMVUTTRA, in the future.
However, our ongoing development efforts may not be successful and we may not be able to commence sales of any other products in the future.
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.
Cost of Collaborations and Royalties Cost of collaborations and royalties decreased during the year ended December 31, 2025, as compared to the year ended December 31, 2024, primarily due to decreased demand for GalNAc material supplied to our collaborators in support of certain product manufacturing as our collaborators transition to producing the material independently.
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.
We expect capital expenditures to increase in 2026 to support the increase in our manufacturing and production capacity needs. • As of December 31, 2025, the carrying value of our convertible debt was $1.01 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 Leqvio royalties were $118.0 million in 2025, with an estimated $126.7 million to be paid within the next 12 months. • Payments associated with an achieved development milestone for the zilebesiran development funding liability due to Blackstone were $21.1 million in 2025, with the same amount expected to be paid within the next 12 months.
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.
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.
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.
Based on our current operating plan, we believe that our cash, cash equivalents, marketable securities, as well as the revenue we expect to generate from product sales and under our existing collaborations, including royalties on sales of Leqvio and Qfitlia, and available borrowing capacity under the revolving credit agreement as of December 31, 2025 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.
“Business” of this Annual Report on Form 10-K, we currently have five products that have received marketing approval, including one collaborated product, and multiple late-stage investigational programs advancing towards potential commercialization. In Part I, Item 1.
“Business” of this Annual Report on Form 10-K, we currently have six products that have received marketing approval, including two products marketed by our collaborators, and multiple late-stage investigational programs advancing towards potential commercialization.
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.
The liabilities related to the sale of future royalties and development funding and the related interest expense are based on our current estimates of future royalties and milestones expected to be paid and received over the life of the arrangement, which we determine by using third-party data to estimate Leqvio’s and AMVUTTRA’s global net revenues.
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.
Research and Development Research and development expenses consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Clinical research and outside services $ 640,672 $ 509,129 $ 485,732 $ 131,543 26 % $ 23,397 5 % Compensation and related 362,813 327,929 260,423 34,884 11 % 67,506 26 % Occupancy and all other costs (1) 162,895 161,425 160,987 1,470 1 % 438 — % Stock-based compensation 153,395 127,749 97,273 25,646 20 % 30,476 31 % Total research and development $ 1,319,775 $ 1,126,232 $ 1,004,415 $ 193,543 17 % $ 121,817 12 % (1) Occupancy and all other costs includes facilities, information technology, depreciation and certain departmental expenses.
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.
(Provision for) Benefit from Income Taxes (Provision for) benefit from income taxes was as follows: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change (Provision for) benefit from income taxes $ (9,405) $ 99,218 $ (6,725) $ (108,623) * $ 105,943 * * Not meaningful We recorded a provision for income taxes of $9.4 million for the year ended December 31, 2025 and a benefit from income taxes of $99.2 million for the year ended December 31, 2024.
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.
Selling, general and administrative expenses increased during the year ended December 31, 2025, as compared to the year ended December 31, 2024, primarily due to higher employee compensation costs, including stock-based compensation, mainly driven by higher headcount, and increased marketing investment associated with the commercial launch of AMVUTTRA in ATTR-CM.
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.
Liquidity and Capital Resources The following table summarizes our cash flow activities: Years Ended December 31, $ Change (In thousands) 2025 2024 2023 2025 vs 2024 2024 vs 2023 Net cash provided by (used in): Operating activities $ 524,080 $ (8,312) $ 104,156 $ 532,392 $ (112,468) Investing activities $ 436,329 $ (116,840) $ (336,350) $ 553,169 $ 219,510 Financing activities $ (305,190) $ 294,159 $ 172,131 $ (599,349) $ 122,028 Operating Activities During the year ended December 31, 2025, net cash provided by operating activities was $524.1 million, whereas during the year ended December 31, 2024 net cash used in operating activities was $8.3 million.
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.
Such changes in estimates could have a significant impact on revenue and earnings in the period of the adjustment. 84 Table of Contents Operating Costs and Expenses Operating costs and expenses consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Cost of goods sold $ 677,166 $ 306,513 $ 268,216 $ 370,653 121 % $ 38,297 14 % Cost of goods sold as a percentage of net product revenues 22.7 % 18.6 % 21.6 % Cost of collaborations and royalties 4,705 16,857 42,190 (12,152) (72) % (25,333) (60) % Research and development 1,319,775 1,126,232 1,004,415 193,543 17 % 121,817 12 % Selling, general and administrative 1,210,713 975,526 795,646 235,187 24 % 179,880 23 % Total $ 3,212,359 $ 2,425,128 $ 2,110,467 $ 787,231 32 % $ 314,661 15 % Cost of Goods Sold Cost of goods sold as a percentage of net product revenues increased to 22.7% for the year ended December 31, 2025, as compared to 18.6% for the year ended December 31, 2024, primarily as a result of increased sales of AMVUTTRA and an associated increase in the blended royalty rate payable on net sales of AMVUTTRA.
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.
We expect our royalty revenue will increase in 2026, as compared to 2025, primarily due to the continued growth of royalties earned from global net sales of Leqvio by Novartis. The amount of revenue from collaborations that we recognize is based, in part, on estimates of total costs to be incurred.
In addition to revenues from the commercial sales of our approved products and potentially from sales of future products, we expect our sources of potential funding for the next several years to continue to be derived in part from existing and new strategic collaborations.
We expect our sources of potential funding for the next several years to be derived primarily from sales of our commercialized products, with contributions from our existing collaborations, including royalties on sales of Leqvio by Novartis and on sales of Qfitlia by Sanofi, and any new strategic collaborations that we may enter in the future.
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.
As of December 31, 2025, we generate worldwide product revenues from our four commercialized products, AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO, primarily in the U.S. and Europe. Collaboration revenues, in particular from our collaborations with Roche, Regeneron and Novartis, have also represented a meaningful portion of our total revenues in recent years.
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.
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 and development funding of approximately $42.1 million as of December 31, 2025. If realized, the change in value would affect interest expense over the remaining life of the agreements.
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.
As of December 31, 2025, we had cash, cash equivalents and marketable securities of $2.91 billion, compared to $2.69 billion as of December 31, 2024.
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.
Research and development expenses increased during the year ended December 31, 2025, as compared to the year ended December 31, 2024, primarily due to the following: • increased clinical trial expenses for the ZENITH Phase 3 clinical trial of zilebesiran, the TRITON-CM Phase 3 clinical trial of nucresiran in patients with ATTR-CM and the TRITON-PN Phase 3 clinical trial of nucresiran in patients with hATTR-PN; • increased employee compensation and related expenses to support our research and development pipeline and development expenses; and • increased stock-based compensation expense.
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.
Partially offset by: 85 Table of Contents • decreased expenses within other clinical programs, in particular for the KARDIA-1 and KARDIA-2 Phase 2 clinical trials of zilebesiran and the HELIOS-B Phase 3 clinical trial of vutrisiran in patients with ATTR-CM due to the wind-down of clinical activities.
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.
Selling, General and Administrative Selling, general and administrative expenses consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Compensation and related $ 473,462 $ 386,743 $ 298,888 $ 86,719 22 % $ 87,855 29 % Consulting and professional services 348,976 274,539 226,664 74,437 27 % 47,875 21 % Occupancy and all other costs (1) 193,435 169,909 145,687 23,526 14 % 24,222 17 % Stock-based compensation 194,840 144,335 124,407 50,505 35 % 19,928 16 % Total selling, general and administrative $ 1,210,713 $ 975,526 $ 795,646 $ 235,187 24 % $ 179,880 23 % (1) Occupancy and all other costs includes facilities, information technology, depreciation and certain departmental expenses.
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.
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, 2025 and 2024. 83 Table of Contents Net Revenues from Collaborations and Royalty Revenue Net revenues from collaborations and royalty revenue consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Roche $ 394,881 $ 119,489 $ 337,802 $ 275,392 230 % $ (218,313) (65) % Regeneron Pharmaceuticals 113,957 302,798 100,468 (188,841) (62) % 202,330 201 % Novartis AG — 79,759 86,727 (79,759) (100) % (6,968) (8) % Other 44,528 8,175 21,188 36,353 445 % (13,013) (61) % Total net revenues from collaborations $ 553,366 $ 510,221 $ 546,185 $ 43,145 8 % $ (35,964) (7) % Royalty revenue $ 174,022 $ 91,794 $ 40,633 $ 82,228 90 % $ 51,161 126 % Net revenues from collaborations increased during the year ended December 31, 2025, as compared to the year ended December 31, 2024, primarily driven by: • recognition of $300.0 million of milestone revenue under our collaboration with Roche in September 2025 associated with the dosing of the first patient in the ZENITH Phase 3 clinical trial of zilebesiran; and • recognition of a $30.0 million payment in connection with the amendment to our agreement with Vir Biotechnology in March 2025.
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.
Other (Expense) Income Other (expense) income consisted of the following: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Interest expense $ (252,627) $ (141,858) $ (121,221) $ (110,769) 78 % $ (20,637) 17 % Interest income 111,470 121,992 95,561 (10,522) (9) % 26,431 28 % Loss related to convertible debt (42,473) — — (42,473) N/A — N/A Other income (expense), net Realized and unrealized losses on marketable equity securities (2,306) (3,022) (16,944) 716 (24) % 13,922 (82) % Change in fair value of development derivative liability — (170,770) (90,997) 170,770 (100) % (79,773) 88 % Other 7,510 (6,832) (17,741) 14,342 * 10,909 (61) % Total other expense, net $ (178,426) $ (200,490) $ (151,342) $ 22,064 (11) % $ (49,148) 32 % * Not meaningful Total other expense, net decreased during the year ended December 31, 2025, as compared to the year ended December 31, 2024, primarily due to: • decreased loss associated with the change in fair value of the development derivative liability as a result of the adoption of Accounting Standards Update 2025-07, or ASU 2025-07, as discussed in Note 2, Summary of Significant Accounting Policies and Note 9, Liabilities Related To The Sale Of Future Royalties And Development Funding, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data” of this Annual Report on Form 10-K. 86 Table of Contents Partially offset by: • increased interest expense associated with the vutrisiran and zilebesiran development funding liabilities as a result of the adoption of ASU 2025-07; and • loss related to convertible debt representing an inducement expense in connection with the partial repurchases of our 1.00% Convertible Senior Notes due 2027, or the 2027 Notes, in September and December 2025.
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.
Additionally, we collected lower net proceeds from the issuance of common stock in connection with stock option exercises during the year ended December 31, 2025, as compared to the year ended December 31, 2024. 87 Table of Contents Additional Capital Requirements We currently have programs focused in many therapeutic areas and, as of December 31, 2025, have six marketed products, including two products commercialized by collaborators.
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.
This was primarily attributed to the timing of sales, maturities, and purchases of our marketable securities during the year ended December 31, 2025, as compared to the year ended December 31, 2024.
We anticipate that our operating results will continue to fluctuate for the foreseeable future, therefore, period-to-period comparisons should not be relied upon as predictive of the results in future periods.
We anticipate that our operating results will continue to fluctuate for the foreseeable future and, therefore, period-to-period comparisons should not be relied upon as predictive of the results in future periods. 81 Table of Contents Given the significant and growing contribution of AMVUTTRA to our total product revenues following regulatory approvals of AMVUTTRA for the treatment of ATTR-CM, our cost of goods sold, operating income and operating margin in 2025 were significantly impacted by the royalties we pay to Sanofi on global sales of AMVUTTRA under our TTR license agreements, and we expect this will continue in future years.
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%.
Results of Operations The following table summarizes the results of our operations: Years Ended December 31, 2025 vs 2024 2024 vs 2023 (In thousands, except percentages) 2025 2024 2023 $ Change % Change $ Change % Change Total revenues $ 3,713,937 $ 2,248,243 $ 1,828,292 $ 1,465,694 65 % $ 419,951 23 % Total operating costs and expenses $ 3,212,359 $ 2,425,128 $ 2,110,467 $ 787,231 32 % $ 314,661 15 % Income (loss) from operations $ 501,578 $ (176,885) $ (282,175) $ 678,463 * $ 105,290 (37) % Total other expense, net $ (178,426) $ (200,490) $ (151,342) $ 22,064 (11) % $ (49,148) 32 % (Provision for) benefit from income taxes $ (9,405) $ 99,218 $ (6,725) $ (108,623) * $ 105,943 * Net income (loss) $ 313,747 $ (278,157) $ (440,242) $ 591,904 * $ 162,085 (37) % * Not meaningful For a discussion of our 2024 results and a comparison with 2023 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, 2024, which was filed with the SEC on February 13, 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.
Through these investments, we plan to expand our efforts to discover, develop and commercialize the next wave of RNAi therapeutics and aim to achieve the goals associated with our Alnylam 2030 strategy.
We maintained a full valuation allowance on our U.S. deferred tax assets as of December 31, 2024.
For the year ended December 31, 2025, we maintained a full valuation allowance against our net deferred tax assets in the U.S. Based on our recent financial performance and our future projections, we could record a reversal of all or a portion of the U.S. valuation allowance within the foreseeable future.
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.
This was primarily driven by stronger cash receipts from increased product sales during the year ended December 31, 2025, as compared to the year ended December 31, 2024, partially offset by increased employee compensation costs and higher interest payments.
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.
Financing Activities During the year ended December 31, 2025, net cash used in financing activities was $305.2 million, whereas during the year ended December 31, 2024 net cash provided by financing activities was $294.2 million.
Liability Related to the Sale of Future Royalties We account for the liability related to the sale of future royalties as a debt financing.
Liabilities Related to the Sale of Future Royalties and Development Funding We account for the liabilities related to the sale of future royalties and development funding as debt financings. Interest on these liabilities is recognized using the effective interest rate method over the life of the related repayment period.
Removed
“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.
Added
We achieved profitability for the first time in 2025, with full-year net product revenues of approximately $3.0 billion, driven primarily by strong growth in our TTR franchise. Nevertheless, we have incurred significant losses since inception and, as of December 31, 2025, we had an accumulated deficit of $6.70 billion.
Removed
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.
Added
With the achievement of profitability in 2025, going forward we expect to be able to fund our operations primarily from product revenues, which we expect will be supplemented by collaboration revenue and royalty revenue from products commercialized by our collaborators. We expect to continue investing significantly in research and development to advance our RNAi platform and clinical pipeline.
Removed
A meaningful portion of our total revenues in recent years has been derived from collaboration revenues from collaborations with Roche, Regeneron and Novartis.
Added
These planned expenditures include costs associated with our activities as we (i) progress our late-stage programs, including the Phase 3 TRITON-PN and TRITON-CM clinical trials of nucresiran (our next generation TTR silencer) in patients with hATTR-PN and ATTR-CM, respectively, and the Phase 3 ZENITH cardiovascular outcomes trial of zilebesiran in patients with uncontrolled hypertension, all three of which we initiated in 2025; (ii) progress our early stage clinical pipeline, including CNS and metabolic programs; (iii) continue our efforts to deliver RNAi therapeutics to additional tissues and to treat new disease areas; and (iv) selectively pursue complementary modalities through business development.
Removed
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.
Added
These goals include expanding to 10 tissue types and more than 40 clinical programs, delivering at least two new transformative medicines beyond TTR with blockbuster potential, investing approximately 30% of our revenues in non-GAAP R&D (including select external innovation), achieving 25%+ total revenue compound annual growth rate, and delivering approximately 30% non-GAAP operating margin through year-end 2030.
Removed
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.
Added
Sanofi is eligible to receive tiered royalties on global annual net sales of AMVUTTRA across all indications in the following tiers: 15% of global annual net sales of $0 to $150.0 million; 17.5% of global annual net sales greater than $150.0 million to $300.0 million; 20% of global annual net sales greater than $300.0 million to $500.0 million; 25% of global annual net sales greater than $500.0 million to $1.50 billion; and 30% of global annual net sales in excess of $1.50 billion.
Removed
Such changes in estimates could have a significant impact on revenue and earnings in the period of the adjustment.
Added
There are no royalties owed on nucresiran, our next-generation investigational RNAi therapeutic, which is currently in development for the treatment of ATTR amyloidosis.
Removed
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.
Added
Assuming successful development and regulatory approval, we believe that with its anticipated product profile, nucresiran has the potential to become a leading therapy for ATTR amyloidosis and to significantly improve our gross margins on product sales and our non-GAAP operating income margin.
Removed
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.
Added
We expect net revenues from collaborations will decrease in 2026, as compared to 2025, due to the $300.0 million of milestone revenue that we recognized under our Roche Collaboration and License Agreement in the year ended December 31, 2025.
Removed
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.
Added
The provision for income taxes for the year ended December 31, 2025 primarily related to U.S. state income taxes, utilization of Switzerland net deferred tax assets, as well as taxable income from jurisdictions in which we are subject to tax.
Removed
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.
Added
However, any such change is subject to actual performance and other considerations that may present positive or negative evidence at the time of the assessment.
Removed
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
Investing Activities During the year ended December 31, 2025, net cash provided by investing activities was $436.3 million, whereas during the year ended December 31, 2024 net cash used in investing activities was $116.8 million.
Removed
We are also subject to potential rebates in connection with our value-based agreements, or VBAs, with certain commercial payors.
Added
This was primarily due to $1.15 billion paid for the repurchase of $672.2 million aggregate principal amount of our 2027 Notes during the year ended December 31, 2025, partially offset by $645.7 million of net proceeds from our offering of the 0.00% Convertible Senior Notes due 2028 in the aggregate principal amount of $661.3 million, $35.3 million of which was used to pay the cost of the related capped call transactions.
Removed
Development Derivative Liability In August 2020, we entered into a co-development agreement, referred to as the Funding Agreement, with BXLS V Bodyguard – PCP L.P. and BXLS Family Investment Partnership V – ESC L.P., collectively referred to as Blackstone Life Sciences, pursuant to which Blackstone Life Sciences will provide up to $150.0 million in funding for the clinical development of vutrisiran and zilebesiran, two of our cardiometabolic programs.
Added
Payments associated with an achieved development milestone for the vutrisiran development funding liability due to Blackstone were $65.6 million in 2025, and we expect to pay $87.5 million within the next 12 months. Since we commenced operations in 2002, we have generated significant losses and as of December 31, 2025, we had an accumulated deficit of $6.70 billion.
Removed
As consideration for Blackstone Life Sciences’ funding for certain vutrisiran and zilebesiran clinical development costs, we have agreed to pay Blackstone Life Sciences fixed success-based payments upon achievement of specific milestones for vutrisiran and zilebesiran as well as a 1% royalty on net sales of vutrisiran for ten years.
Removed
The development derivative liability is recorded at fair value and represents our current estimate of the expected future payments to Blackstone Life Sciences. The development derivative liability is based on the probability weighted present value of the estimated cash flows pursuant to contractual terms of the Funding Agreement.
Removed
The most significant assumptions in determining the development derivative liability are the probability of success for the clinical development and regulatory approval of vutrisiran and zilebesiran and our current cost of borrowing. Estimates of the probability of success and our cost of borrowing are based on what we believe to be reasonable and supportable assumptions and require management’s judgment.

Item 7A. Quantitative and Qualitative Disclosures About Market Risk

Market Risk — interest-rate, FX, commodity exposure

2 edited+0 added−0 removed4 unchanged
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.
Biggest changeAs of December 31, 2025 and 2024, 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. 86 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. 89 Table of Contents

Other ALNY 10-K year-over-year comparisons