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Item 1. Business

2026-02-12 compared with 2025-02-13 · 473 added, 439 removed, 626 unchanged (59% of the section changed)

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RNAi is a naturally occurring biological pathway within cells for sequence-specific silencing and regulation of gene expression.

By harnessing the RNAi pathway, we have developed a new class of innovative medicines, known as RNAi therapeutics.

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.

We believe this is a revolutionary approach with the potential to transform the care of patients across a broad range of disease areas and indications.

To date, our efforts to advance this revolutionary approach have yielded the approval of five first-in-class RNAi-based medicines, ONPATTRO ® (patisiran), AMVUTTRA ® (vutrisiran), GIVLAARI ® (givosiran), OXLUMO ® (lumasiran) and Leqvio ® (inclisiran).

To date, our efforts to advance this revolutionary approach have yielded the approval of six first-in-class RNAi-based medicines:

AMVUTTRA ® (vutrisiran), ONPATTRO ® (patisiran), GIVLAARI ® (givosiran), OXLUMO ® (lumasiran), Leqvio ® (inclisiran) and Qfitlia ® (fitusiran).

Our research and development strategy is to target genetically validated genes that have been implicated in the cause or pathway of human disease.

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Our focus is on clinical indications where there is a high unmet need, a genetically validated target, early biomarkers for the assessment of clinical activity in Phase 1 clinical trials, and a definable path for drug development, regulatory approval, patient access and commercialization.

In early 2021, we launched our Alnylam P 5 x25 strategy, which focuses on our planned transition to a top-tier biotech company by the end of 2025.

With Alnylam P 5 x25 , we aim to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile.

We ended 2024 making considerable progress on these goals, and currently have five marketed products and more than 20 clinical programs, including several in late-stage development, across a broad range of disease areas and indications.

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.

In February 2025, ONPATTRO received regulatory approval from the Brazilian Health Regulatory Agency, or ANVISA, for the treatment of ATTR amyloidosis with cardiomyopathy.

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.

In early 2026, we launched our Alnylam 2030 strategy to drive the Company’s next era of growth and patient impact.

Specifically, we aspire to achieve the following by the end of 2030:

• Global TTR Leadership:

Build a Durable TTR Franchise

• Lead the market in TTR revenue by 2030 and cumulatively across the five-year period

• Launch best-in-class, next-generation silencer nucresiran in ATTR amyloidosis with polyneuropathy by 2028 and cardiomyopathy by 2030

• Growth Through Sustainable Innovation:

Deliver Therapies that Prevent, Halt, or Reverse Disease

• Deliver 2+ new transformative medicines beyond TTR with blockbuster potential

• Expand to 10 tissue types and >40 clinical programs

• Accelerate organic innovation and access select external innovation by reinvesting ~30% of revenues in non-GAAP R&D

• Scale with Discipline & Agility:

Deliver Exceptional Financial Results

• Achieve 25%+ total revenue growth compound annual growth rate through year-end 2030

• Deliver sustained, profitable growth with ~30% non-GAAP operating margin

We currently have six marketed products, including two products that are commercialized by collaborators, and more than 20 clinical programs, including several in late-stage development.

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.

In March 2025, the United States Food and Drug Administration, or the FDA, approved our supplemental New Drug Application, or sNDA, for AMVUTTRA for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.

In June 2025, the European Commission, or EC, granted approval of AMVUTTRA for the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy, following a positive opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency, or EMA, AMVUTTRA has also been approved by the Brazilian Health Regulatory Agency, or ANVISA, the Japanese Health Authority, or PMDA, the UK’s Medicines and Healthcare Products Regulatory Agency, or MHRA, and Health Canada for the treatment of ATTR amyloidosis with cardiomyopathy.

Regulatory reviews continue in other territories.

In June 2024, we reported positive topline results from the HELIOS-B clinical trial of vutrisiran (the generic name of AMVUTTRA) in patients with ATTR amyloidosis with cardiomyopathy and announced that we planned to proceed with global regulatory filings seeking approval of AMVUTTRA as a potential treatment for ATTR amyloidosis with cardiomyopathy.

In August and September 2024, we reported detailed results from the HELIOS-B clinical trial.

On October 9, 2024, we announced that we had filed a supplemental New Drug Application, or sNDA, with the United States Food and Drug Administration, or the FDA, using a Priority Review Voucher.

In November 2024, the FDA accepted our sNDA submission for review for vutrisiran, with an action date set for March 23, 2025 under the Prescription Drug User Fee Act, or PDUFA.

Vutrisiran is also under regulatory review by the European Medicines Agency, or the EMA, ANVISA, the Japanese Health Authority, or PMDA, and the Colombian Health Authority, or INVIMA.

ONPATTRO is approved in the U.S.

polyneuropathy, in Japan for the treatment of TTR-type familial amyloidosis with polyneuropathy, and in multiple additional countries.

In February 2025, ONPATTRO received regulatory approval from ANVISA in Brazil for the treatment of ATTR amyloidosis with cardiomyopathy.

GIVLAARI is approved in the U.S.

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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.

Leqvio (inclisiran), our fifth product, is being developed and commercialized by our collaborator Novartis AG, or Novartis, and has received marketing authorization from the European Commission, or EC, for the treatment of adults with hypercholesterolemia or mixed dyslipidemia and from the FDA as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, or HeFH, or clinical atherosclerotic cardiovascular

disease, or ASCVD, who require additional lowering of low-density lipoprotein cholesterol, or LDL-C.

Leqvio (inclisiran) 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 July 2023, the FDA approved an expanded indication for Leqvio to include treatment of adults with high LDL-C and who are at increased risk of heart disease.

Leqvio has also been approved in China and Japan, and as of the end of January 2025, Leqvio had been registered in more than 100 countries.

In addition to our marketed products, as part of our Alnylam P 5 x25 strategy, we have multiple drivers of future growth, including the development of transformative medicines to treat prevalent disease.

In addition to Leqvio, we are advancing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen in development for the treatment of hypertension.

In July 2025, based on robust LDL-C lowering data for PCSK9-targeting therapies, the FDA approved a label update for Leqvio enabling its use as monotherapy along with diet and exercise to reduce LDL-C in adults with hypercholesterolemia.

Leqvio has also been approved in China and Japan, and as of the end of December 2025, Leqvio is registered in 108 countries worldwide and is commercially available in 89 countries.

Qfitlia (fitusiran) is being commercialized by our collaborator, Genzyme Corporation, a Sanofi Company, or Sanofi, and was approved by the FDA in March 2025 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A or B, with or without factor VIII or IX inhibitors (neutralizing antibodies), and by China’s National Medical Products Administration, or NMPA, in December 2025, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in pediatric patients 12 years of age and older and adults with severe hemophilia A or B with or without factor IX inhibitors.

Qfitlia is the first and only therapeutic designed to lower antithrombin, a protein that inhibits blood clotting, with the goal of promoting thrombin generation to rebalance hemostasis and prevent bleeds.

A regulatory submission for Qfitlia has also been completed in Brazil.

In addition to our marketed products, we have multiple potential drivers of future growth, including additional transformative medicines currently in development for TTR and both other rare and prevalent diseases.

We are advancing nucresiran, our next-generation investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis.

In November 2024, we announced positive results from the ongoing Phase 1 clinical trial of nucresiran in healthy volunteers.

These results demonstrated that twice annual dosing of 300 mg of nucresiran resulted in mean reductions of serum TTR of greater than 90% from baseline at day 15 that were maintained over six months.

In September 2025, we initiated the TRITON-PN Phase 3 clinical trial of nucresiran in patients with hATTR polyneuropathy, and in June 2025, we initiated the TRITON-CM Phase 3 clinical trial of nucresiran in patients with ATTR amyloidosis with cardiomyopathy.

We are also developing zilebesiran, an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, for the treatment of hypertension.

In 2023, we entered into a Collaboration and License Agreement, or the Roche Collaboration and License Agreement, with F.

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or, collectively, Roche, pursuant to which we established a worldwide, strategic collaboration for the joint development and commercialization of zilebesiran.

In March 2024, we reported positive topline results from our KARDIA-2 clinical trial, which is designed to evaluate the safety and efficacy of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by a standard of care antihypertensive medication.

In April 2024, we dosed the first patient in our KARDIA-3 Phase 2 clinical trial, which is designed to evaluate the efficacy and safety of zilebesiran as an add-on therapy in adult patients with high cardiovascular risk and uncontrolled hypertension despite treatment with two to four standard of care antihypertensive medications, and we expect to report results from the KARDIA-3 Phase 2 clinical trial in the second half of 2025.

In January 2025, we announced that we expect to initiate a Phase 3 cardiovascular outcomes trial in the second half of 2025.

We are advancing nucresiran (formerly ALN-TTRsc04), an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis.

In November 2024, we announced positive new results from the ongoing Phase 1 study of nucresiran in healthy volunteers.

These results demonstrated that a single dose of nucresiran at 300 mg or higher resulted in mean reductions of serum TTR of greater than 90% from baseline achieved at Day 15 and sustained through at least Day 180.

We expect to initiate a Phase 3 clinical trial of nucresiran in patients with ATTR amyloidosis with cardiomyopathy in the first half of 2025.

We are also advancing mivelsiran (formerly ALN-APP), an investigational RNAi therapeutic targeting amyloid precursor protein in development for the treatment of Alzheimer’s disease, or AD, and cerebral amyloid angiopathy, or CAA.

In October 2024, we announced positive initial results from the multiple dose portion of the Phase 1 clinical trial of mivelsiran in patients with early-onset AD.

We expect to initiate a Phase 2 clinical trial of mivelsiran in patients with AD in the second half of 2025.

In July 2024, we initiated dosing in the cAPPRicorn-1 Phase 2 clinical trial of mivelsiran in patients with CAA.

We 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.

In further support of our Alnylam P 5 x25 strategy and in view of our evolving risk profile, we remain focused on the continued evolution of our global infrastructure, including key objectives such as optimizing our global structure for execution in key markets, enhancing performance consistent with our values, and continuing to strengthen our culture.

We continue to build our global compliance program to drive its evolution and enhancement through the launch of new systems and leveraging data analytics to strengthen the efficiency and effectiveness of our program.

Building from our global Code of Business Conduct and Ethics, our compliance program is designed to empower our employees and those with whom we work to execute on our strategy consistent with our values and in compliance with applicable laws and regulations, and to mitigate risk.

Comprised of components such as risk assessment and monitoring;

policies, procedures, and guidance;

training and communications;

dedicated resources;

and systems and processes supporting activities such as third party engagements and investigations and remediation, and the Company’s enterprise risk management program;

our program and related controls are built to enhance our business processes, structures, and controls across our global operations, and to empower ethical decision making.

Based on our expertise in RNAi therapeutics and broad intellectual property estate, we have formed collaborations with leading pharmaceutical and life sciences companies to support our development and commercialization efforts, including Roche, Regeneron, Sanofi, and Novartis (which acquired our collaborator The Medicines Company, or MDCO, in 2020) .

Key 2024 and Recent Highlights

TTR Franchise

• ONPATTRO (patisiran) and AMVUTTRA (vutrisiran)– hATTR Amyloidosis with Polyneuropathy

◦ Achieved global net product revenues for ONPATTRO and AMVUTTRA for the full year 2024 of $252.9 million and $970.5 million, respectively

• Vutrisiran – ATTR Amyloidosis with Cardiomyopathy

◦ Submitted an sNDA to the FDA using a Priority Review Voucher for vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy.

Parallel filings for regulatory approval have also been submitted in all major regions, including Europe and Japan

▪ The FDA has accepted the sNDA and set an action goal date of March 23, 2025, under PDUFA

• Nucresiran (formerly ALN-TTRsc04) – ATTR Amyloidosis

◦ Received Orphan Drug Designation from the FDA and announced positive interim Phase 1 data of nucresiran in patients with ATTR amyloidosis

Commercial/Late-Stage Pipeline

• GIVLAARI (givosiran) – Acute Hepatic Porphyria

◦ Recognized GIVLAARI global net revenue of $255.9 million for the year ended December 31, 2024

• OXLUMO (lumasiran) – Primary Hyperoxaluria Type 1

◦ Recognized OXLUMO global net revenue of $167.1 million for the year ended December 31, 2024

• Leqvio (inclisiran) – Hypercholesterolemia (in collaboration with Novartis)

◦ Our collaborator, Novartis, continued the launch of Leqvio, with a focus on increasing account and patient adoption, and continuing medical education

• Fitusiran – Hemophilia (in collaboration with Sanofi)

◦ Our collaborator, Sanofi, continued to advance fitusiran, an investigational RNAi therapeutic in development for the treatment of hemophilia A and B, with or without inhibitors, and the FDA has set a PDUFA target action date of March 28, 2025

Early-Stage and Preclinical Pipeline

• Zilebesiran – Hypertension

◦ Initiated Phase 1 studies of zilebesiran + REVERSIR for hypertension

• Mivelsiran – Cerebral Amyloid Angiopathy and Alzheimer’s Disease

◦ Announced positive initial results from the multiple dose portion of the Phase 1 study of mivelsiran in patients with Alzheimer’s disease

• ALN-HTT02 – Huntington’s Disease

◦ Initiated a Phase 1 study of ALN-HTT02 in adult patients with Huntington’s disease

Corporate Highlights

◦ Ended 2024 with $2.69 billion in cash, cash equivalents and marketable securities

In August 2025, we reported that our KARDIA-3 Phase 2 clinical trial, which was designed to evaluate the efficacy and safety of zilebesiran as an add-on therapy in adult patients with high cardiovascular risk and uncontrolled hypertension despite treatment with two to four standard of care antihypertensive medications, met the objective of informing the design, patient population, and dose for a global Phase 3 cardiovascular outcomes trial.

In September 2025, we initiated a Phase 3 cardiovascular outcomes clinical trial, ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension), which is designed to evaluate the potential of zilebesiran to reduce the risk of major adverse cardiovascular events in patients with uncontrolled hypertension on two or more antihypertensives, one being a diuretic.

We are also advancing mivelsiran (formerly ALN-APP), an investigational RNAi therapeutic targeting amyloid precursor protein in development for the treatment of cerebral amyloid angiopathy, or CAA, and Alzheimer’s disease, or AD.

In July 2025, we presented single- and multiple-dose data from the Phase 1 clinical trial of mivelsiran in patients with early-onset AD.

These data demonstrated that single and multiple doses of mivelsiran were generally well tolerated and demonstrated robust, durable, dose-dependent reductions of soluble amyloid precursor protein beta, or sAPPβ, in cerebrospinal fluid.

In July 2024, we initiated the cAPPricorn-1 Phase 2 clinical trial of mivelsiran in patients with CAA.

We expect to initiate a Phase 2 clinical trial of mivelsiran in patients with AD in the first half of 2026.

We have additional late-stage investigational programs advancing toward potential commercialization with collaborators, including cemdisiran for the treatment of complement-mediated diseases.

Our collaborator, Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing cemdisiran in combination with its anti-C5 monoclonal antibody, pozelimab, in a Phase 3 clinical trial

in paroxysmal nocturnal hemoglobinuria, and as a monotherapy and in combination with pozelimab in Phase 3 clinical trials in myasthenia gravis and geographic atrophy.

In August 2025, Regeneron announced that cemdisiran monotherapy met the primary and key secondary endpoints in the Phase 3 NIMBLE clinical trial in generalized myasthenia gravis and that it is planning a U.S.

regulatory submission for cemdisiran monotherapy in the first quarter of 2026, pending discussions with the FDA.

Convertible Senior Notes and Repurchases

In September 2025, we issued $661.3 million aggregate principal amount of 0.00% Convertible Senior Notes due 2028, or the 2028 Notes.

The 2028 Notes will mature on September 15, 2028, unless earlier converted, redeemed or repurchased.

The 2028 Notes will not bear regular interest.

Before June 15, 2028, holders of 2028 Notes will have the right to convert their 2028 Notes in certain circumstances and during specified periods.

From and after June 15, 2028, the 2028 Notes will be convertible at the option of the holders of 2028 Notes at any time prior to the close of business on the trading day immediately preceding the maturity date.

We will settle any conversions of 2028 Notes by paying or delivering, as applicable, cash or shares of our common stock, par value $0.01 per share, or Common Stock, or a combination of cash and shares of Common Stock, at our election.

In connection with the issuance of the 2028 Notes, we paid $35.3 million, including expenses to enter into privately negotiated capped call transactions with certain initial purchasers of the 2028 Notes or their respective affiliates and certain other financial institutions, or capped call transactions.

The capped call transactions are expected generally to reduce the potential dilution upon conversion of the 2028 Notes in the event that the market price per share of our Common Stock, as measured under the terms of the capped call transactions, is greater than the strike price of the capped call transactions, which initially corresponds to the conversion price of the 2028 Notes, and is subject to anti-dilution adjustments generally similar to those applicable to the conversion rate of the 2028 Notes.

The initial cap price of the capped call transaction is approximately $837.61 per share, and is subject to certain adjustments under the terms of the capped call transactions.

Concurrently with the pricing of the 2028 Notes, we entered into privately negotiated transactions, or the September 2025 note repurchase transactions, with certain holders of our 1.00% Convertible Senior Notes due 2027, or the 2027 Notes, to repurchase for cash approximately $637.8 million aggregate principal amount of the 2027 Notes for a total repurchase cost (including accrued and unpaid interest) of approximately $1.11 billion.

In addition, in December 2025, we entered into additional privately negotiated transactions, or the December 2025 note purchase transactions, with certain holders of our 2027 Notes to repurchase for cash approximately $34.4 million aggregate principal amount of the 2027 Notes for a total repurchase cost (including accrued and unpaid interest) of approximately $52.3 million.

Following the closing of the December 2025 note purchase transactions, or, together with the September 2025 note purchase transactions, the note repurchase transactions, approximately $362.8 million aggregate principal amount of the 2027 Notes remain outstanding.

We had previously entered into capped call transactions with certain financial institutions in connection with the issuance 2027 Notes, which transactions remain in place following the note repurchase transactions.

Revolving Credit Facility

In September 2025, we entered into a revolving credit agreement, or the Revolving Credit Agreement, among the lenders party thereto, Bank of America, N.A., as Administrative Agent, or the Agent, and the other parties named therein.

The Revolving Credit Agreement provides for a $500.0 million revolving line of credit, or the Revolving Credit Facility, including a $150.0 million letter of credit sublimit.

The Revolving Credit Agreement provides that we have the right at any time and from time to time to incur one or more incremental revolving commitments and/or incremental term loans, subject to certain customary conditions and other requirements.

At our option, and subject to certain conditions, borrowings bear interest at a base rate, a term Secured Overnight Financing Rate, or SOFR, rate or an alternative currency term rate, plus, in each case, an applicable margin based upon our Total Leverage Ratio (as defined in the Revolving Credit Agreement).

For borrowings that bear interest at a term SOFR rate, the applicable margin is a per annum amount equal to an amount between 1.50% and 2.50% (depending on our Total Leverage Ratio).

Interest is payable quarterly in arrears with respect to borrowings bearing interest at the alternate base rate or on the last day of an interest period, but at least every three months, with respect to borrowings bearing interest at a term SOFR rate or an alternative currency term rate.

We are also required to pay on a quarterly basis a commitment fee in a per annum amount equal to an amount between 0.20% to 0.35% (depending on our Total Leverage Ratio) of unused available commitments under the Revolving Credit Facility.

We are also obligated to pay the Agent fees customary for revolving credit facilities of this size and type.

The obligations under the Revolving Credit Agreement are required to be guaranteed by certain of our material domestic subsidiaries and are secured by substantially all of our assets and the assets of such subsidiary guarantors, subject to customary exceptions.

The Revolving Credit Agreement contains customary affirmative and negative covenants and conditions to borrowing, as well as customary events of default.

Revolving loans under the Revolving Credit Agreement may be borrowed, repaid and reborrowed, without premium or penalty (subject to customary breakage costs), until their maturity date under the Revolving Credit Agreement, or the Maturity

Date, at which time all amounts borrowed must be repaid.

The Maturity Date is currently September 30, 2030, but may be adjusted to an earlier date upon the occurrence of certain events in accordance with the terms of the Revolving Credit Agreement.

As of December 31, 2025, we had no borrowings and $17.5 million of letters of credit outstanding under the Revolving Credit Agreement.

RNAi Therapeutics – A Class of Innovative Medicines

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One of the biggest scientific challenges with RNAi therapeutics has been delivering the therapeutic to its destination in the body.

In recent years, we have made tremendous progress on delivery of RNAi therapeutics, beginning with delivery to the liver and more recently with delivery to the CNS and other tissues.

We believe this success will enable us to sustainably and organically create and commercialize transformative medicines that benefit patients around the world across a broad range of disease areas and indications while also delivering strong financial performance, which will result in a leading biotech profile by the end of 2025.

We have made tremendous progress on delivery of RNAi therapeutics, beginning with delivery to the liver and more recently with delivery to the CNS and other tissues.

Early RNAi delivery efforts focused on delivery of RNAi therapeutics utilizing LNPs, which encapsulate siRNA molecules in specific lipid-based formulations.

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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.

Our more recently approved medicines, AMVUTTRA, GIVLAARI, OXLUMO and Leqvio utilize this conjugate platform.

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 first RNAi therapeutics based on this ESC+ design, zilebesiran and elebsiran, are currently in late-stage clinical development.

Additional advancements include our IKARIA™ platform harboring chemistry innovations that enable robust target knockdown with the potential for bi-annual or annual dosing regimens .

We believe that this platform could have potential applications in a wide range of diseases.

In November 2024, we announced positive interim results from the Phase 1 clinical trial of nucresiran, our investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis which utilizes our IKARIA technology, demonstrating rapid knockdown of TTR that was sustained for six months following a single dose.

In November 2024, we announced positive interim results from the Phase 1 clinical trial of nucresiran, our next generation investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis which utilizes our IKARIA technology, demonstrating rapid knockdown of TTR that was sustained for six months following a single dose.

Our platform enhancements have also provided a strong foundation for pursuing a conjugate-based approach to extrahepatic delivery, including delivery to the brain and spinal cord, as well as ocular delivery.

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C16 conjugates provide robust CNS knockdown with wide biodistribution and long duration of action.

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.

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.

We are also advancing our C16 technology as part of our collaboration with Regeneron, including work on ALN-HTT02, our investigational RNAi therapeutic in development for the treatment of Huntington’s disease, or HD, which is a devastating, fatal neurodegenerative disease for which there are currently no approved disease-modifying therapies.

We are continuing to advance other extrahepatic delivery approaches, including delivery to muscle and adipose cells.

In addition, we are exploring peptide and antibody-based approaches for targeted siRNA delivery to new tissues as part of our collaboration with PeptiDream, Inc., which aims to discover and develop novel conjugates for targeted delivery of RNAi therapeutics to a broader range of tissues.

We are continuing to advance other extrahepatic delivery approaches, including delivery to muscle and adipose cells, as well as to additional tissues in line with our Alnylam 2030 goal to expand to 10 tissue types by 2030.

In addition, we are exploring peptide and antibody-based approaches for targeted siRNA delivery to new tissues, including as part of our collaboration with PeptiDream, Inc., which aims to discover and develop novel conjugates for targeted delivery of RNAi therapeutics to a broader range of tissues.

As we seek to address more complex conditions with multiple comorbidities, we are also advancing our GEMINI technology, which combines conjugate siRNAs for the simultaneous silencing of two transcripts using a single chemical entity.

Finally, we continue to leverage human genetics to advance our efforts to bring innovative medicines to patients.

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.

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 five approved products and multiple late and early-stage investigational RNAi therapeutics across a broad range of disease areas and indications.

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.

We describe our commercial and clinical-stage pipeline in more detail below.

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The table below represents our commercial products and late- and early-stage development programs as of February 1, 2026.

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.

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.

Our TTR Franchise

About Transthyretin Amyloidosis (ATTR)

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.

There are two forms of ATTR – hATTR and wild-type ATTR, which can manifest in a variety of ways.

ATTR with cardiomyopathy – including hereditary and wild-type forms – affects greater than 300,000 people worldwide, while hATTR with polyneuropathy affects fewer than 30,000 people worldwide.

We estimate that ATTR amyloidosis with cardiomyopathy – including hereditary and wild-type forms – affects more than 300,000 people worldwide, while hATTR amyloidosis with polyneuropathy affects fewer than 30,000 people worldwide.

AMVUTTRA (vutrisiran)

AMVUTTRA (vutrisiran) is a subcutaneously administered RNAi therapeutic targeting TTR.

With its rapid knockdown, it targets and silences TTR mRNA, thereby reducing the production of TTR protein before it is made.

AMVUTTRA utilizes our ESC+ delivery platform, and is designed for increased potency and high metabolic stability to allow for quarterly subcutaneous administration.

Vutrisiran has received orphan drug designation in the U.S., EU and Japan;

specific orphan drug designations vary by country/region.

AMVUTTRA — hATTR Amyloidosis with Polyneuropathy

In June 2022, AMVUTTRA was approved by the FDA for the treatment of hATTR amyloidosis with polyneuropathy in adults.

AMVUTTRA was subsequently approved in the EU, UK, Argentina, Switzerland and Canada 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 Brazil for the treatment of hATTR amyloidosis in adults and in multiple other countries/regions globally.

AMVUTTRA has launched in several additional countries and regulatory filings in additional territories are currently under review and additional filings are planned for 2026.

AMVUTTRA — ATTR Amyloidosis with Cardiomyopathy

In March 2025, the FDA approved our sNDA for AMVUTTRA for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.

In June 2025, the EC approved AMVUTTRA for the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy, following a positive opinion from the Committee for Medicinal Products for Human Use of the EMA.

AMVUTTRA has also been approved by ANVISA, the PMDA, the MHRA, and Health Canada for the treatment of ATTR amyloidosis with cardiomyopathy.

We have also filed for regulatory approval for vutrisiran (the generic name for AMVUTTRA) in Colombia, Republic of South Korea, Hong Kong, Taiwan, Australia, Republic of Serbia, North Macedonia, and Kuwait and additional regulatory filings are pending or planned in 2026 and beyond.

ONPATTRO ( patisiran)

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specific orphan drug designations vary by country/region.

ONPATTRO ( patisiran) – hATTR Amyloidosis with Polyneuropathy

ONPATTRO — hATTR Amyloidosis with Polyneuropathy

ONPATTRO is the first ever FDA-approved RNAi therapeutic and was our first product to receive marketing approval.

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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.

ONPATTRO — ATTR Amyloidosis with Cardiomyopathy

In February 2025, ONPATTRO received regulatory approval from ANVISA in Brazil for the treatment of ATTR amyloidosis with cardiomyopathy.

We do not plan to pursue label expansions for ONPATTRO in other regions.

AMVUTTRA (vutrisiran)

AMVUTTRA (vutrisiran) is a subcutaneously administered RNAi therapeutic targeting TTR.

With its rapid knockdown, it targets and silences TTR mRNA, thereby reducing the production of TTR protein before it is made.

AMVUTTRA utilizes our ESC+ delivery platform, and designed for increased potency and high metabolic stability to allow for quarterly subcutaneous administration.

Vutrisiran has received orphan drug designation in the U.S., EU and Japan;

specific orphan drug designations vary by country/region.

AMVUTTRA (vutrisiran) – hATTR Amyloidosis with Polyneuropathy

In June 2022, AMVUTTRA was approved by the FDA for the treatment of hATTR amyloidosis with polyneuropathy in adults.

AMVUTTRA has launched in several additional countries and regulatory filings in additional territories are currently under review and additional filings are planned for 2025.

Vutrisiran – ATTR Amyloidosis with Cardiomyopathy

Vutrisiran is also in development as a potential treatment for patients with ATTR amyloidosis with cardiomyopathy in the ongoing HELIOS-B Phase 3 clinical trial.

In June 2024, we reported positive topline results from the HELIOS-B clinical trial of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy.

In August and September 2024, we reported detailed results from the HELIOS-B clinical trial, and on October 9, 2024, we announced that we had filed an sNDA with the FDA, using a Priority Review Voucher.

We later announced on October 16, 2024, that we had submitted a Type II Variation to the EMA.

In November 2024, the FDA accepted our sNDA submission for review for vutrisiran, with an action date set for March 23, 2025 under PDUFA.

Vutrisiran is also under regulatory review by the EMA, ANVISA, PMDA, and INVIMA.

Additional filings are planned for 2025 and beyond.

HELIOS-B Phase 3 Study

The HELIOS-B Phase 3 clinical trial, initiated in late 2019, was a randomized, double-blind, placebo-controlled, multicenter global study designed and powered to evaluate the efficacy and safety of vutrisiran on the reduction of all-cause mortality and recurrent cardiovascular events as a primary composite endpoint in patients with ATTR amyloidosis

with cardiomyopathy.

The secondary endpoints evaluated included change from baseline in 6-minute walk test, or 6-MWT, change from baseline in Kansas City Cardiomyopathy Questionnaire, or KCCQ-OS, all-cause mortality, and change from baseline in New York Heart Association, or NYHA, class, with additional exploratory endpoints evaluated.

The study randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy.

Patients were randomized 1:1 to receive vutrisiran 25mg or placebo subcutaneously once every three months during a double-blind treatment period of up to 36 months.

After the double-blind period, all eligible patients remaining on the study were able to receive vutrisiran in an open-label extension period of HELIOS-B.

Efficacy and Safety Results

In June 2024, we announced positive topline results, noting that study met the primary endpoint, demonstrating a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular events during the double-blind period in both the overall population and in the monotherapy population.

In the overall population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28%, with similar reductions in both the mortality and cardiovascular events components of the endpoint.

Mortality in the overall population was reduced by 31% during the double-blind period and by 36% up to 42 months.

In the monotherapy population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 33% and reduced the risk of mortality by 35% up to 42 months.

As a component of the primary endpoint, a non-significant reduction of 30% in mortality was observed in the monotherapy population during the double-blind period.

The study also demonstrated statistically significant improvements across all secondary endpoints in both the overall and monotherapy populations.

This includes key measures of disease progression:

6-MWT, KCCQ and NYHA Class at Month 30.

In the HELIOS-B clinical trial, the safety and tolerability profiles of vutrisiran were consistent with what had been established in the currently approved patient population, as well as earlier clinical studies.

Nucresiran (formerly ALN-TTRsc04) – ATTR Amyloidosis

Nucresiran is an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis that utilizes our IKARIA technology and provides the potential to achieve deeper and more durable rapid knockdown of TTR, allowing for less frequent dosing.

In December 2023 and November 2024, we announced positive initial results in the Phase 1 study of nucresiran in healthy volunteers.

Nucresiran — ATTR Amyloidosis

Nucresiran is our next generation investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis that utilizes our IKARIA technology and provides the potential to achieve deeper and more durable rapid knockdown of TTR, allowing for less frequent dosing.

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.

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There have been no safety signals identified, including no injection site reactions and no liver-related signals.

These Phase 1 results suggest nucresiran has the potential to offer over 90% max TTR reduction and to be administered once annually.

The Phase 1 study is ongoing, and in January 2025, we announced that we expect to initiate a Phase 3 study of nucresiran in ATTR amyloidosis with cardiomyopathy in the first half of 2025.

Nucresiran has received orphan drug designation in the U.S.

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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.

GIVLAARI is the first GalNAc-conjugate RNA therapeutic to be approved.

GIVLAARI works by specifically reducing induced liver aminolevulinic acid synthase 1 mRNA, leading to reduction of toxins associated with attacks and other disease manifestations of AHP and is administered by subcutaneous injection.

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for the treatment of adults with AHP and in the EU for the treatment of AHP in adults and adolescents aged 12 years and older.

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.

We have also filed for regulatory approval for givosiran (the non-branded drug name for

GIVLAARI) in Colombia, Mexico, South Korea and Kuwait, and additional regulatory filings are pending or planned in 2025 and beyond.

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.

We have also filed for regulatory approval for givosiran (the generic name for GIVLAARI) in Colombia, South Korea, Kingdom of Saudi Arabia, and Serbia, and additional regulatory filings are pending or planned in 2026 and beyond.

OXLUMO (lumasiran) — Primary Hyperoxaluria Type 1 ( PH1)

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for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients, and has received marketing authorization in the EU for the treatment of PH1 in all age groups.

OXLUMO has also received additional marketing authorizations in Argentina, Australia, Brazil, the UK, Switzerland, Canada, Israel, Taiwan, Oman and Qatar, and regulatory filings in other territories are pending and additional filings are planned for 2025 and beyond.

OXLUMO has also received additional marketing authorizations in Argentina, Australia,

Brazil, the UK, Switzerland, Canada, Israel, Oman, Qatar, Kingdom of Saudi Arabia, United Arab Emirates, Kuwait and South Korea, and regulatory filings in other territories are pending and additional filings are planned for 2026 and beyond.

Leqvio (inclisiran) — Hypercholesterolemia

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Our RNAi therapeutic Leqvio, developed and commercialized by our collaborator, Novartis, is the first and only siRNA therapy (or RNAi therapeutic) to lower LDL-C, and is the first RNAi therapeutic approved for a prevalent disease.

Leqvio is a subcutaneously administered RNAi therapeutic targeting proprotein convertase subtilisin/kexin type 9, or PCSK9, to reduce LDL-C levels via an RNAi mechanism of action and could help improve outcomes for patients with ASCVD, a deadly form of cardiovascular disease.

Leqvio is approved in the U.S.

as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including HeFH, to reduce LDL-C.

Leqvio is approved in the EU for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet:

in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximally tolerated dose of a statin, or alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

As of the end of January 2025, Leqvio had been approved in over 100 countries.

Leqvio is subcutaneously administered and targets proprotein convertase subtilisin/kexin type 9, or PCSK9, to reduce LDL-C levels and could help improve outcomes for patients with ASCVD, a deadly form of cardiovascular disease.

As of the end of December 2025, Leqvio had been approved in over 100 countries.

Multiple additional Phase 3 clinical trials of Leqvio are currently ongoing, including two cardiovascular outcomes trials in secondary prevention, ORION-4 co-sponsored by Novartis and Oxford University and the Novartis-sponsored VICTORION-2-PREVENT.

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.

Following its acquisition of MDCO, Novartis has all of the rights and obligations under the MDCO agreement.

A description of the MDCO agreement is included below under the heading “Our Collaboration and Licensing Strategy.”

Additional Late-Stage Clinical Development Programs

Fitusiran — Hemophilia

Qfitlia (fitusiran) — Hemophilia

Hemophilia is a hereditary bleeding disorder characterized by an underlying defect in the ability to generate adequate levels of thrombin needed for effective fibrin clot formation, thereby resulting in recurrent bleeds into joints, muscles, and major internal organs.

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People who develop inhibitors become refractory to replacement factor therapy and are twice as likely to be hospitalized for a bleeding episode.

Lowering antithrombin, or AT, may promote the generation of sufficient levels of thrombin needed to form an effective fibrin clot and prevent bleeding.

Antithrombin, or AT, acts by inactivating thrombin and other coagulation factors, and plays a key role in normal hemostasis by helping to limit the process of fibrin clot formation.

Lowering AT may promote the generation of sufficient levels of thrombin needed to form an effective fibrin clot and prevent bleeding.

This rationale is supported by human genetic data suggesting that co-inheritance of thrombophilic mutations, including AT deficiency, may ameliorate bleeding in hemophilia.

We believe this approach is a unique and innovative strategy for preventing bleeding in people with hemophilia.

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.

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.

AT acts by inactivating thrombin and other coagulation factors, and plays a key role in normal hemostasis by helping to limit the process of fibrin clot formation.

Fitusiran is currently being evaluated in the ATLAS Phase 3 program.

Sanofi presented positive results from the ATLAS-A/B and ATLAS-INH Phase 3 clinical trials of fitusiran in December 2021, and in July 2022, Sanofi presented positive results from the Phase 3 ATLAS-PPX study evaluating the efficacy and safety of once-monthly fitusiran (80 mg) in adults and adolescents with severe hemophilia A or B who were previously treated with prior factor or bypassing agent prophylaxis.

In 2023, Sanofi presented positive results from the ATLAS-OLE Phase 3 extension clinical trial of fitusiran, demonstrating a substantially improved safety profile and consistent bleed protection in people with hemophilia A or B, with or without inhibitors.

Specifically, the risk of thrombosis was reduced, with rates comparable to those reported in the general hemophilia population.

In June 2024, Sanofi presented new ATLAS Phase 3 clinical trial data that reinforce the potential of fitusiran to provide prophylaxis for people with hemophilia A or B, with or without inhibitors, and announced that their NDA for fitusiran had been accepted for review by the FDA with a PDUFA action date of March 28, 2025.

Regulatory submissions for fitusiran for the treatment of hemophilia A or B in adults and adolescents with or without inhibitors have been completed in China and Brazil.

The FDA granted fitusiran Breakthrough Therapy Designation for hemophilia B with inhibitors in December 2023.

Qfitlia was approved by the FDA in March 2025 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A or B, with or without factor VIII or IX inhibitors (neutralizing antibodies) and by China’s NMPA in December 2025 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in pediatric patients 12 years of age and older and adults with severe hemophilia A or B with or without factor IX inhibitors.

A regulatory submission for Qfitlia has also been completed in Brazil.

We have granted Sanofi global rights to develop and commercialize fitusiran and any back-up products.

A description of our Sanofi collaboration, as well as the amended and restated AT3 License Terms, is included under the heading “Our Collaboration and Licensing Strategy.”

Cemdisiran — Complement-Mediated Diseases

The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in a broad range of human diseases including myasthenia gravis, paroxysmal nocturnal hemoglobinuria, and geographic atrophy, among others.

Cemdisiran is a subcutaneously administered, investigational RNAi therapeutic targeting the C5 component of the complement pathway in development for the treatment of complement-mediated diseases.

In June 2024, we granted Regeneron global rights to develop, manufacture and commercialize cemdisiran as a monotherapy in addition to the license we previously granted Regeneron to investigate cemdisiran in combination with anti-C5 antibodies.

Regeneron is now solely responsible for development, manufacturing, and commercialization of cemdisiran as a monotherapy and in combination with anti-C5 antibodies.

Regeneron is evaluating cemdisiran in combination with its anti-C5 monoclonal antibody, pozelimab, in a Phase 3 clinical trial in paroxysmal nocturnal hemoglobinuria and as a monotherapy and in combination with pozelimab in Phase 3 clinical trials in myasthenia gravis and geographic atrophy.

Early-Stage Clinical Development Programs

Additional Late-Stage Clinical Development Programs

Zilebesiran — Hypertension

Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure of above 140 mm Hg and/or a diastolic blood pressure greater than 90 mm Hg, although the American College of Cardiology/American Heart Association guidelines define hypertension as a systolic blood pressure above 130 mm Hg and/or a diastolic blood pressure greater than 80 mm Hg.

American Heart Association guidelines define hypertension as a systolic blood pressure above 130 mm Hg and/or a diastolic blood pressure greater than 80 mm Hg.

More than one billion people worldwide live with hypertension.

alone, approximately 47 percent of adults live with hypertension, with more than half of patients on medication remaining above the blood pressure target level.

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.

In particular, there are a number of high unmet need settings where novel approaches to hypertension warrant additional development focus, including patients with poor medication adherence and in patients with high cardiovascular risk.

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Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.

The KARDIA-1 Phase 2 clinical trial is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually.

In September 2023, we reported positive topline results from the KARDIA-1 clinical trial, with zilebesiran meeting the primary endpoint and demonstrating greater than 15mmHg reduction of systolic blood pressure at three months of treatment compared to placebo at the two highest single doses evaluated.

The KARDIA-2 Phase 2 clinical trial is evaluating the safety and efficacy of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by a standard of care antihypertensive medication.

In April 2024, we reported positive topline results from the KARDIA-2 clinical trial, with zilebesiran meeting the primary endpoint and demonstrating additive, placebo-adjusted reductions of up to 12.1 mmHg in 24-hour mean systolic blood pressure at Month 3 when zilebesiran was added to a thiazide-like diuretic, calcium channel blocker or angiotensin receptor blocker.

At Month 6, zilebesiran demonstrated clinically significant and placebo-adjusted, time-adjusted reductions in office systolic blood pressure when added to indapamide, amlodipine and olmesartan, despite the addition of rescue antihypertensives at Month 3.

In addition, zilebesiran resulted in clinically significant placebo-adjusted, time-adjusted reductions in 24-hour mean systolic blood when added to indapamide and amlodipine, sustained to Month 6.

A non-statistically significant result was observed when zilebesiran was added to the maximum dose of olmesartan when evaluated by time-adjusted change from baseline in 24-hour mean systolic blood pressure at Month 6.

In April 2024, we initiated the KARDIA-3 Phase 2 clinical trial, which is evaluating zilebesiran as an add-on therapy in high cardiovascular risk patients with uncontrolled hypertension despite receiving two or more antihypertensives.

We plan to announce topline results from KARDIA-3, and to initiate a Phase 3 cardiovascular outcomes trial of zilebesiran, in the second half of 2025.

In July 2023, we announced a collaboration with Roche to co-develop and co-commercialize zilebesiran.

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A description of the Roche Collaboration and License Agreement is included below under the heading “Our Collaboration and Licensing Strategy.”

Elebsiran (formerly ALN-HBV02 (VIR-2218)) – Chronic Hepatitis B and D Virus Infection

Elebsiran (formerly ALN-HBV02 (VIR-2218)) is a subcutaneously administered, investigational RNAi therapeutic targeting the HBV genome for the treatment of chronic HBV infection, which is being advanced by our collaborator, Vir.

Cemdisiran — Complement-Mediated Diseases

Cemdisiran is a subcutaneously administered, investigational RNAi therapeutic targeting the C5 component of the complement pathway in development for the treatment of complement-mediated diseases.

In June 2024, we granted Regeneron global rights to develop, manufacture and commercialize cemdisiran as a monotherapy in addition to the license we previously granted Regeneron to develop, manufacture and commercialize cemdisiran in combination with anti-C5 antibodies.

Regeneron is now solely responsible for development, manufacturing, and commercialization of cemdisiran as a monotherapy and in combination with anti-C5 antibodies.

regulatory submission for cemdisiran monotherapy in the first quarter of 2026, pending discussions with the FDA.

Elebsiran — Chronic Hepatitis Delta Virus Infection

Elebsiran (formerly ALN-HBV02 (VIR-2218)) is a subcutaneously administered, investigational RNAi therapeutic targeting the HBV genome for the treatment of chronic hepatitis delta, or CHD, which is being advanced by our collaborator, Vir Biotechnology, Inc., or Vir.

Elebsiran is designed to inhibit expression of all HBV proteins, including hepatitis B surface antigen.

Almost one-third of the world’s population have previous or current HBV infection.

Worldwide, more than 250 million people are chronically infected with HBV, and an estimated 1 million people die each year from complications of chronic HBV such as cirrhosis and hepatocellular carcinoma.

Current treatment options include life-long suppressive antiviral therapies.

There is a significant need for safe and convenient novel therapeutics that restore the host immune response, leading to control of the virus after a finite duration of therapy, which is the definition of a functional cure.

The safety and efficacy of elebsiran as part of a treatment regimen for chronic HBV infection is being assessed in the ongoing Phase 2 MARCH trial.

Vir has also evaluated elebsiran in combination with tobevibart for the treatment of chronic hepatitis D virus, or CHD, and Vir expects to initiate a Phase 3 registrational study to evaluate the combination of elebsiran and tobevibart in CHD in the first half of 2025.

We have the right to opt into a profit-sharing arrangement for elebsiran prior to the start of a Phase 3 study.

Mivelsiran (formerly ALN-APP) – Alzheimer’s Disease and Cerebral Amyloid Angiopathy

Mivelsiran is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein, or APP, in development in collaboration with Regeneron for the treatment of AD, and CAA.

Genetic mutations that increase production of APP or alter its cleavage cause early-onset AD, early-onset CAA, or both.

Mivelsiran is designed to decrease APP mRNA in the CNS to decrease synthesis of APP protein and all downstream intracellular and extracellular APP-derived cleavage products, including amyloid beta (Aβ).

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.

CHD is the most severe form of chronic viral hepatitis and was recently classified as carcinogenic by the International Agency for Research on Cancer.

People living with the disease rapidly progress to cirrhosis, liver failure, and liver-related death.

There are currently no approved treatments in the U.S., and treatment options are limited in the EU and globally.

Vir is currently evaluating elebsiran in combination with tobevibart in multiple clinical trials as part of its ongoing ECLIPSE registrational program, including the ECLIPSE 1 Phase 3 clinical trial in CHD, which is fully enrolled with topline data expected in the fourth quarter of 2026, the ECLIPSE 2 Phase 3 clinical trial, which is evaluating the switch to the combination of elebsiran and tobevibart in patients who have not achieved undetectable hepatitis delta virus RNA with bulevirtide treatment, and the ECLIPSE 3 Phase 2b trial, which is evaluating the combination of elebsiran and tobevibart compared to bulevirtide monotherapy in bulevirtide treatment-naive patients.

Topline data from ECLIPSE 2 and 3 are expected in the first quarter of 2027.

In January 2026, Vir announced positive data from the ongoing Phase 2 SOLSTICE clinical trial in

CHD, in which the combination of tobevibart and elebsiran achieved an undetectable HDV RNA rate of 88% in a subset of participants evaluable at Week 96.

In March 2025, we and Vir entered into an amended and restated collaboration and license agreement relating to elebsiran, pursuant to which Vir remains solely responsible for the development, manufacturing and commercialization of elebsiran, and we remain entitled to receive milestone payments upon the achievement of specified regulatory and commercial milestones and royalties on net sales of elebsiran.

In connection with the amended and restated agreement, Vir made a payment to us of $30.0 million, and we agreed not to opt into a profit-sharing arrangement with respect to elebsiran.

In June 2024 and December 2024, Vir announced that the FDA granted Fast Track designation and Breakthrough Therapy designation, respectively, for the combination of tobevibart and elebsiran for the treatment of CHD.

In addition, the combination received PRIME designation from the EMA and European orphan drug designation in December 2024 for the same indication.

Early-Stage Clinical Development Programs

Mivelsiran — Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Mivelsiran is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein, or APP, in development for the treatment of CAA and AD.

Genetic mutations that increase production of APP or alter its cleavage cause early-onset CAA, early-onset AD, or both.

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.

Mivelsiran is the first program utilizing our C16 conjugate technology, which enables enhanced delivery to cells in the CNS, to enter clinical development.

In early 2022, we initiated a Phase 1 clinical trial of mivelsiran in patients with early-onset AD, and in April 2023 and July 2023, we reported positive interim results from the ongoing single ascending dose part of the Phase 1 clinical trial.

Further exploration of single doses of mivelsiran is ongoing in Part A of the Phase 1 clinical trial.

In addition, the multiple-dose part of the study, Part B is now enrolling.

In early 2022, we initiated a Phase 1 clinical trial of mivelsiran in patients with early-onset AD, and in April 2023 and July 2023, we reported positive interim results.

In February 2024, we announced that the FDA had provided clearance to initiate Part B of the Phase 1 clinical trial at sites in the U.S.

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for higher or more frequent dosing regimens.

In October 2024, we announced positive initial results from the multiple-dose Part B portion of the Phase 1 clinical trial, and we expect to report additional interim results from Part B of the Phase 1 clinical trial in AD in the second half of 2025.

We also expect to initiate a Phase 2 clinical trial of mivelsiran in patients with AD in the second half of 2025.

In July 2024, we initiated dosing in the cAPPricorn-1 Phase 2 clinical trial of mivelsiran in patients with CAA.

In May 2024, Regeneron notified us of its decision to opt-out of the further co-development of mivelsiran.

As a result of Regeneron’s opt-out, we now have full global development and commercialization rights to mivelsiran in all indications, and we are responsible for all development and commercialization costs of mivelsiran other than Regeneron’s share of the Phase 1 budget.

ALN-HTT02 – Huntington’s Disease

HD is an autosomal dominantly inherited, fully penetrant, severely debilitating, and fatal neurodegenerative disease, caused by an abnormal expansion of cytosine-adenine-guanine repeats in exon 1 of the HTT gene.

Typically, HD is an adult-onset neurodegenerative disease with a protracted but relentlessly progressive course.

No disease modifying treatments have been developed or approved for HD, and treatment options are limited to management of symptoms and optimization of quality of life.

Part A has now been completed, and Part B is ongoing.

In July 2025, we announced positive Phase 1 single and multiple dose data from the Phase 1 clinical trial of mivelsiran in early-onset AD.

Single and multiple doses of mivelsiran were generally well tolerated and demonstrate robust, durable, dose-dependent reductions of soluble amyloid precursor beta, or SAPPβ, in the cerebrospinal fluid.

We expect to initiate a Phase 2 clinical trial of mivelsiran in patients with AD in the first half of 2026.

In July 2024, we announced we had initiated dosing in cAPPricron-1, a phase 2 clinical trial of mivelsiran in patients with CAA.

Enrollment in cAPPricorn-1 is ongoing.

We have full global development and commercialization rights to mivelsiran in all indications, and we are responsible for all development and commercialization costs of mivelsiran other than Regeneron’s share of the Phase 1 budget.

ALN-HTT02 — Huntington’s Disease (HD)

HD is an inherited autosomal dominant neurodegenerative disease caused by abnormal expansion of cytosine-adenine-guanine repeats in exon 1 of the HTT gene, leading to production of aberrant mHTT proteins containing elongated polyglutamine tracts that are prone to aggregate in neurons.

Typically, HD is an adult-onset degenerative disease with a protracted but relentlessly progressive course.

The disease is characterized by a triad of symptom domains comprising behavioral/psychological, cognitive, and abnormal motor movements.

These symptoms, in combination, lead to severe disability and morbidity, and ultimately to a bed-bound state followed by death.

No pharmacological agent, approved or otherwise, provides long-lasting improvement in clinically meaningful outcomes.

ALN-HTT02 is an investigational, intrathecally administered RNAi therapeutic targeting huntingtin, or HTT, that is in development, in collaboration with Regeneron, for the treatment of HD.

ALN-HTT02 is designed to target a conserved sequence in exon 1 of the HTT messenger RNA, thereby reducing the expression of all isoforms of HTT protein, including shorter exon1-containing HTT fragments which have been implicated in disease pathology but are missed by many other HTT-lowering therapeutic strategies.

ALN-HTT02 is designed to target a conserved sequence in exon 1 of the HTT messenger RNA, thereby reducing the expression of all isoforms of HTT protein, including the shorter HTT1a isoform encoded by the first exon of the gene.

HTT1a has been implicated as a key contributor to disease pathology but is missed by many HTT-lowering therapeutic strategies.

Beyond the more inclusive exon 1 targeting strategy, our underlying C16-siRNA delivery platform may offer an opportunity to fully explore the potential efficacy of HTT-lowering via widespread distribution, deep and sustained lowering, and infrequent dosing regimens.

In September and November 2024, we presented nonclinical data supporting the tolerability of deep and sustained HTT-lowering in wild-type nonhuman primates after single and repeated intrathecal administration of ALN-HTT02.

We also presented the design of a Phase 1b clinical trial.

The Phase 1b clinical trial of ALN-HTT02 in adult patients with HD was initiated in late 2024, with the first patient dosed in November.

In September 2024, November 2024, February 2025, and October 2025 we presented nonclinical data supporting the tolerability of deep and sustained HTT-lowering in wild-type nonhuman primates after single and repeated intrathecal administration of ALN-HTT02.

In October 2025, we initiated a Phase 1b clinical trial of ALN-HTT02 in adult patients with HD (NCT06585449) and expect to present initial data from this trial in the second half of 2026.

ALN-6400 — Bleeding Disorders

An estimated three million people in the U.S.

are living with an inherited bleeding disorder.

Many bleeding disorders have no approved treatments, and many of the treatments that are available are burdensome.

The second most common inherited bleeding disorder, Hereditary Hemorrhagic Telangiectasia, or HHT, is a vascular bleeding disorder with no approved therapies.

It is estimated to affect approximately 70,000 people in the U.S.

and approximately 1.6 million people worldwide.

Approximately 90% of patients with HHT experience recurrent nosebleeds, which can be severe and life threatening.

The majority of patients with HHT also suffer from iron deficiency anemia, and GI bleeding and heavy menstrual bleeding are also common.

Plasminogen, or PLG, is a protein that is produced in the liver.

Once PLG is converted to plasmin, it drives fibrinolysis, which is the breakdown of the fibrin mesh that stabilizes blood clots.

ALN-6400 is a GalNAc-conjugated RNAi therapeutic that targets PLG.

In preclinical studies, ALN-6400 has demonstrated a greater than 90% reduction in circulating PLG in non-human primates with no evidence of increased risk of thrombosis.

We believe that with its mechanism of action, ALN-6400 has the potential to address a wide range of bleeding disorders.

In early 2025, we shared data from the first cohort of participants in a Phase 1 clinical trial in healthy volunteers, demonstrating favorable impact on an ex-vivo hemostasis assay.

In late 2025, we initiated a Phase 2 clinical trial in patients with HHT, and we plan to share additional data from the Phase 1 clinical trial as well as report clinical proof of concept in HHT in the second half of 2026.

We also intend to initiate a Phase 2 clinical trial in a second bleeding disorder in the first half of 2026.

Additional Early-Stage and Preclinical Programs

During 2025, we plan to file four or more new investigational new drug applications, or INDs, or CTAs from our organic product engine.

We also intend to continue to build on our progress with extrahepatic delivery during 2025, advancing our CNS programs under our collaboration with Regeneron, as well as continuing to advance our other extrahepatic delivery initiatives, including delivery to muscle and adipose tissues.

During 2026, we plan to file three or more new investigational new drug applications, or INDs, or CTAs from our organic product engine.

We also intend to continue to build on our progress with extrahepatic delivery during 2026, advancing our CNS programs under our collaboration with Regeneron, as well as continuing to advance our other extrahepatic delivery initiatives, in support of our Alnylam 2030 goal to expand to ten tissue types by the end of 2030.

Our Collaboration and Licensing Strategy

Our business strategy is to develop and commercialize a broad pipeline of RNAi therapeutic products directed across a broad range of disease areas and indications.

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.

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.

We expect these collaborations to provide us with financial support in the form of upfront cash payments, license fees, equity investments, research, development, and sales and marketing support and/or funding, milestone payments and/or royalties or profit sharing based on sales of RNAi therapeutics.

We expect these collaborations to provide us with research and development support, sales and marketing support and/or financial support.

Below is a brief description of our key collaborations.

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Under the Roche Collaboration and License Agreement, we granted to Roche (i) co-exclusive rights to develop zilebesiran worldwide and commercialize zilebesiran in the U.S., (ii) exclusive rights to commercialize zilebesiran outside of the U.S., and (iii) non-exclusive rights to manufacture zilebesiran for the development and commercialization of zilebesiran outside of the U.S.

Roche made an upfront payment of $310.0 million.

We achieved the development milestone associated with the dosing of the first patient in the KARDIA-3 Phase 2 clinical trial in April 2024 and received a $65.0 million development milestone

payment from Roche.

Roche made an upfront payment of $310.0 million and in April 2024 we achieved the development milestone associated with the dosing of the first patient in the KARDIA-3 Phase 2 clinical trial and received a $65.0 million development milestone payment from Roche.

In September 2025, we achieved the development milestone associated with dosing the first patient in the ZENITH Phase 3 clinical trial and received a $300 million development milestone payment from Roche.

In addition, we are eligible to receive up to an additional $2.15 billion in contingent payments based on the achievement of specified development, regulatory and sales-based milestones.

We are responsible for forty percent (40%), and Roche is responsible for sixty percent (60%), of development costs incurred in the conduct of development activities that support regulatory approval of zilebesiran globally.

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.

Roche will be solely responsible for costs incurred in connection with commercialization of zilebesiran outside of the U.S.

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The Regeneron Collaboration is governed by a Master Agreement, referred to as the Regeneron Master Agreement, which became effective in May 2019.

Under the terms of the Regeneron Collaboration, we are working exclusively with Regeneron to discover RNAi therapeutics for eye and CNS diseases for an initial research period of up to seven years, which we refer to as the Initial Research Term.

Regeneron has an option to extend the Initial Research Term for up to an additional five years by paying a research term extension fee of $300.0 million.

The Regeneron Collaboration also covers a select number of RNAi therapeutic programs designed to target genes expressed in the liver.

We retain broad global rights to all of our liver-directed clinical and preclinical pipeline programs that are not part of the Regeneron Collaboration.

Under the terms of the Regeneron Collaboration, we are working exclusively with Regeneron to discover RNAi therapeutics for eye and CNS diseases and a select number of target genes expressed in the liver for an initial research period, which we refer to as the Initial Research Term.

The Initial Research Term will expire in May 2026.

Regeneron leads development and commercialization for all programs targeting eye diseases (subject to limited exceptions), entitling us to certain potential milestone and royalty payments pursuant to the terms of a license agreement, the form of which has been agreed upon by the parties.

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We formed a broad strategic alliance with Sanofi in 2014.

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.

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:

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.

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;

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In April 2019, we and Sanofi amended and restated the AT3 License Terms to modify certain of the business terms.

The material collaboration terms for fitusiran were unchanged.

Under the amended and restated AT3 License Terms, we are eligible to receive tiered royalties of 15% to 30% based on global annual net sales of fitusiran by Sanofi, its affiliates and its sublicensees.

The material collaboration terms for Qfitlia were unchanged.

Under the amended and restated AT3 License Terms, we are eligible to receive tiered royalties on global annual net sales of Qfitlia by Sanofi, its affiliates and its sublicensees.

The royalty tiers and amounts that we are eligible to receive on global annual net sales of Qfitlia are the same as the royalty tiers and amounts that we owe to Sanofi on global annual net sales of AMVUTTRA.

In February 2013, we entered into an exclusive, worldwide license with MDCO (acquired by Novartis AG in January 2020) pursuant to which MDCO was granted the right to develop, manufacture and commercialize RNAi therapeutics targeting proprotein convertase subtilisin/kexin type 9 for the treatment of hypercholesterolemia and other human diseases, including Leqvio.

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In April 2020, we entered into a strategic financing collaboration with certain affiliates of Blackstone to accelerate our advancement of RNAi therapeutics.

In connection with the collaboration, Blackstone agreed to provide us up to $2.00 billion in financing, including $1.00 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and zilebesiran pursuant to a co-development agreement that was executed in August 2020.

As part of the collaboration, Blackstone provided us with $1.00 billion to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio and agreed to provide up to $150.0 million in funding towards the development of vutrisiran and zilebesiran pursuant to a co-development agreement that was executed in August 2020.

In November 2021, Blackstone opted in to Phase 2 clinical trial funding of zilebesiran and has funded $26.0 million in Phase 2 development costs of zilebesiran.

Blackstone also has the right, but is not obligated, to fund up to $54.0 million for development costs related to a Phase 3 clinical trial of zilebesiran.

As part of the strategic financing collaboration, Blackstone also purchased an aggregate of $100.0 million of our common stock.

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.

In February 2025, Blackstone opted in to fund up to $54.0 million of Phase 3 clinical trial development costs for zilebesiran.

As consideration for Blackstone’s funding under the co-development agreement, 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.

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.

Other Collaboration and License Agreements

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In addition, because delivery of RNAi therapeutics has historically been an important objective of our research activities, we have entered into various collaboration and licensing arrangements with other companies and academic institutions to gain access to delivery technologies, including various LNP delivery technologies, and we may enter into such agreements in the future to gain access to products or technologies.

Below is a brief description of certain other collaboration and license agreements we have entered into.

Below is a brief description of certain of our other collaboration and license agreements.

PeptiDream, Inc.

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Through this collaboration, we are collaborating with PeptiDream to select and optimize peptides for targeted delivery of small siRNA molecules to a wide range of cell types and tissues via specific interactions with receptors expressed on the target cells.

In December 2025, PeptiDream announced the achievement of a preclinical development milestone as part of the collaboration.

Dicerna Pharmaceuticals, Inc.

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In exchange, we granted to Ionis an exclusive, low single-digit royalty-bearing license to our chemistry, motif, mechanism and target-specific intellectual property for oligonucleotide therapeutics against four targets.

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.

We have the right to use Ionis’ intellectual property in our development programs or in collaborations, and Ionis agreed not to grant licenses under these patents to any other organization for the discovery, development and commercialization of double-stranded RNA products designed to work through an RNAi mechanism, except in the context of a collaboration in which Ionis plays an active role.

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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.

property position relevant to RNAi therapeutic products and delivery technologies.

In this regard, we have amassed a portfolio of patents, patent applications and other intellectual property covering:

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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

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** Expiration dates listed here include any granted or anticipated patent term extensions and supplemental protection certificates but exclude any pediatric extensions that may be available .

In addition, in connection with our FDA approval on August 10, 2018, the FDA granted ONPATTRO orphan drug exclusivity, or ODE, until August 10, 2025.

In connection with our EMA approval on August 26, 2018, the EMA granted ONPATTRO marketing exclusivity and ODE until August 26, 2028.

In connection with our EMA approval on August 26, 2018, the EMA granted ONPATTRO marketing exclusivity and orphan drug exclusivity, or ODE, until August 26, 2028.

Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor

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** Expiration dates listed here do not account for any patent term extensions, supplemental protection certificates or pediatric extensions that may be available.

In addition, in connection with our FDA approval on June 13, 2022, the FDA granted AMVUTTRA new chemical entity, or NCE, exclusivity until June 13, 2027.

In connection with our EMA approval on September 15, 2022, the EMA granted AMVUTTRA marketing exclusivity and ODE until September 15, 2032.

In connection with its FDA approval on June 13, 2022, AMVUTTRA received new chemical entity, or NCE, exclusivity until June 13, 2027.

AMVUTTRA was also granted ODE for hATTR-PN until June 13, 2029, and for ATTR-CM until March 20, 2032 (this date is not yet updated in the FDA’s administrative databases).

On September 15, 2022, the EMA approved AMVUTTRA for the treatment of hATTR-PN, and subsequently extended the indication to ATTR-CM in June 2025.

In connection with these approvals, AMVUTTRA benefits from eight years of data exclusivity, which expires on September 16, 2030;

ten years of market protection, which expires on September 16, 2032;

and ten years of orphan market exclusivity, which expires on September 16, 2032.

Patent Number Country/Region* Patent Type Expiration Date** Owner/Licensor

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9133461 United States Compositions of Matter & Methods of Use 5/14/2033 Alnylam/Icahn School of Medicine at Mount Sinai

9150605 United States Compositions of Matter 8/28/2025 Ionis Pharmaceuticals

9631193 United States Methods of Use 3/15/2033 Alnylam/Icahn School of Medicine at Mount Sinai

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** Expiration dates listed here do not account for any patent term extensions, supplemental protection certificates or pediatric extensions that may be available.

In addition, in connection with our FDA approval on November 23, 2020, the FDA granted OXLUMO NCE exclusivity until November 23, 2025, and ODE until November 23, 2027.

In addition, in connection with our FDA approval on November 23, 2020, the FDA granted OXLUMO ODE until November 23, 2027.

In connection with our EMA approval on November 19, 2020, the EMA granted OXLUMO Marketing Exclusivity and ODE until November 19, 2030.

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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.

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.

Competition in the pharmaceutical marketplace remains intense, with hundreds of companies competing to discover, develop, and market new drugs.

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Others are following a gene therapy approach, with the goal of treating patients with synthetic, exogenously introduced genes designed to produce siRNA-like molecules within cells.

Companies working on chemically synthesized siRNAs include Arrowhead Pharmaceuticals, Inc., or Arrowhead, and its collaborators, Takeda Pharmaceutical Company Ltd., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc, and Amgen Inc.;

Quark Pharmaceuticals, Inc.;

Hoffmann-La Roche Ltd.;

Silence Therapeutics plc and its collaborators, AstraZeneca plc, Jiangsu Hansoh Pharmaceuticals Group Co., Ltd., and Mallinckrodt plc;

Arbutus Biopharma Corp., or Arbutus;

Sylentis, S.A.U., or Sylentis;

Novo Nordisk and its collaborators, Aro Biotherapeutics, Boehringer Ingelheim, and Eli Lilly and Company;

and our collaborators Regeneron, Sanofi and Vir.

Companies working on chemically synthesized siRNAs include but are not limited to ADARx Pharmaceuticals, Inc., or ADARx, Amgen Inc., Argo Biopharmaceutical Co., Ltd., or Argo, Aro Biotherapeutics, Arrowhead Pharmaceuticals, Inc., or Arrowhead, AstraZeneca plc, or AstraZeneca, Dyne Therapeutics, Inc., Eli Lilly and Company, GlaxoSmithKline plc, Novartis, Novo Nordisk A/S, or Novo Nordisk, SanegeneBio, Sarepta Therapeutics, Inc., Silence Therapeutics plc, Takeda Pharmaceutical Company Ltd., and Wave Life Sciences Ltd., as well as our collaborators Regeneron, Roche, Sanofi and Vir.

The competitive landscape continues to expand, and we expect that additional companies will initiate programs focused on the development of RNAi therapeutic products using the approaches described above, as well as potentially new approaches that may result in more rapid development of RNAi therapeutics or more effective technologies for RNAi drug development or delivery.

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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.

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.

There are a number of product candidates in clinical development for the treatment of hATTR-PN, including nexiguran ziclumeran (nex-z, formerly NTLA-2001) which is being developed by Intellia Therapeutics, Inc., or Intellia, and Regeneron and is in Phase 3 clinical development;

and AT0-2 which is being developed by Attralus, Inc.

and is in Phase 2 clinical development .

and ART-001 which is being developed by Accuredit Therapeutics and is in Phase 2 clinical development (China only);

and YOLT-201 which is being developed by YolTech Therapeutics Co., Ltd., or YolTech, and is planned for Phase 3 clinical development after recent completion of its Phase 2 clinical study (China only) .

ATTR Amyloidosis with Cardiomyopathy (ATTR-CM).

Currently approved therapies to treat ATTR-CM include VYNDAQEL/VYNDAMAX (tafamidis) marketed by Pfizer Inc.

and recently approved ATTRUBY (acoramidis) marketed by BridgeBio Pharma, Inc., or BridgeBio.

We believe that these approved drugs will compete with AMVUTTRA for the treatment of ATTR-CM in the event that vutrisiran receives regulatory approval in the U.S.

and other jurisdictions.

In addition to AMVUTTRA, currently approved therapies to treat ATTR-CM include VYNDAQEL/VYNDAMAX (tafamidis) marketed by Pfizer Inc.

and ATTRUBY (acoramidis) marketed by BridgeBio Pharma, Inc., or BridgeBio in the U.S.

and Beyonttra (acoramidis) marketed by Bayer AG in Europe and Alexion Pharmaceuticals, Inc., a subsidiary of AstraZeneca, or Alexion, in Japan.

Additionally, there are a number of other product candidates in clinical development, including WAINUA (eplontersen), which is being developed by AstraZeneca and Ionis and is in Phase 3 clinical development, nexiguran ziclumeran (nex-z, formerly NTLA-2001) which is being developed by Intellia and Regeneron and is in Phase 3 clinical development;

ALXN2220 (formerly NI006) which is being developed by Neurimmune AG and Alexion, AstraZeneca Rare Disease and is in Phase 3 clinical development;

cliramitug (formerly ALXN2220/NI006) which is being developed by Neurimmune AG and Alexion and is in Phase 3 clinical development;

coramitug (NNC-6019-0001) which is being developed by Novo Nordisk and is in Phase 3 clinical development;

and AT0-2 which is being developed by Attralus, Inc.

ART-001 which is being developed by Accuredit

Therapeutics and is in Phase 2 clinical development (China only);

YOLT-201 which is being developed by YolTech and is in Phase 2 clinical development (China only);

AT-02 which is being developed by Attralus, Inc.

and is in Phase 1 clinical development;

and BPR-30221616 which is being developed by Chengdu Beite Pharma and is in Phase 1 clinical development (China only) .

Acute Hepatic Porphyria.

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Primary Hyperoxaluria.

In addition to OXLUMO, Novo Nordisk’s RIFVLOZA (nedosiran) is approved in the U.S.

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.

Transplantation is a costly and invasive procedure and carries significant morbidity and mortality risk In addition, several companies have investigational drugs in clinical development for the treatment of primary hyperoxaluria, including Biocodex, Inc.

in collaboration with M8 Pharmaceuticals, Inc., and YolTech Therapeutics (China only).

Transplantation is a costly and invasive procedure and carries significant morbidity and mortality risk.

In addition, several companies have investigational drugs in clinical development for the treatment of primary hyperoxaluria, including stiripentol which is being developed by Biocodex, Inc.

in collaboration with M8 Pharmaceuticals, Inc.;

ABO-101 which is being developed by Arbor Biotech and Chiesi Group;

and YOLT-203 which is being developed by YolTech (China only).

We believe that these approved products and product candidates, if approved, could compete with OXLUMO.

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(NEXLETOL), and Regeneron (EVKEEZA).

In addition, LIB Therapeutics, LLC submitted a BLA to the FDA for lerodalcibep for the treatment of primary hyperlipidemia, including heterozygous and homozygous familial hypercholesterolemia (HeFH / HoFH), There are also several companies with investigational drugs in varying stages of clinical development for the treatment of hypercholesterolemia, including Merck & Co., Inc., Jiangsu Hengrui Pharmaceuticals Co., Ltd., Arrowhead, and Verve Therapeutics, Inc.

There are several approved products for the treatment of hemophilia, including:

Factor VIII replacement products, Factor IX replacement products, factor replacement products with extended half-lives, and a bispecific antibody that mimics Factor VIII.

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.

In 2025, regulatory approvals were granted for two PCSK9 inhibitors for the treatment of primary hypercholesterolemia, including U.S.

FDA approval of lerodalcibep (LEROCHOL) from LIB Therapeutics, LLC and Chinese NMPA approval of recaticimab from Jiangsu Hengrui Pharmaceuticals Co., Ltd.

There are also several companies with investigational drugs in varying stages of clinical development for the treatment of hypercholesterolemia, including Merck & Co., Inc., Jiangsu Hengrui Pharmaceuticals Co., Ltd., AstraZeneca, Arrowhead, Ahn-Gook Pharmaceuticals Co., Ltd., AddPharma, Inc., Hasten Biopharmaceutical Co., Ltd., Visirna Therapeutics HK Limited, and Verve Therapeutics, Inc.

In addition to Qfitlia, there are several approved products for the treatment of hemophilia, including:

Factor VIII replacement products, Factor IX replacement products, factor replacement products with extended half-lives, anti-TFPI products and a bispecific antibody that mimics Factor VIII.

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.

BioMarin’s ROCTAVIAN is approved for the treatment of Hemophilia A.

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A number of companies are also actively developing similar gene therapy products for the treatment of hemophilia.

We believe that these approved products and product candidates could compete with fitusiran if it receives regulatory approval for the treatment of hemophilia.

We believe that these approved products and product candidates compete with Qfitlia.

Hypertension.

There are multiple approved hypertension treatments, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, beta blockers, mineralocorticoid receptor antagonists, and Idorsia Pharmaceuticals Ltd.’s Tryvio.

Several companies have treatments in development for uncontrolled or resistant hypertension.

Aldosterone synthase inhibitors, or ASIs, have emerged as a new class of therapeutics, with AstraZeneca and Mineralys Therapeutics Inc.

submitting NDAs to the FDA for baxdrostat and lorundrostat, respectively.

Additionally, AstraZeneca and Boehringer Ingelheim International GmbH are both investigating ASIs in combination with SGLT2 inhibitors in patients with hypertension and other comorbidities.

There are also angiotensinogen-targeting siRNAs in development from Argo (in collaboration with Novartis), ADARx and Sanegene (in collaboration with Innovent Biologics, Inc.).

We believe that these approved products and product candidates could compete with zilebesiran, if zilebesiran receives regulatory approval.

Myasthenia Gravis.

In addition to standard symptomatic or broad immunosuppressive therapies such as pyridostigmine, corticosteroids, azathioprine, and mycophenolate mofetil, several targeted products have been approved for the treatment of generalized myasthenia gravis, or gMG.

These include complement C5 inhibitors such as SOLIRIS and ULTOMIRIS (Alexion) and ZILBRYSQ (UCB S.A.), as well as neonatal Fc receptor inhibitors including VYVGART (argenx SE), RYSTIGGO (UCB S.A.), and IMAAVY (Johnson & Johnson).

UPLIZNA (Amgen Inc.), a CD19-targeted B-cell-depleting antibody, is also approved for the treatment of gMG.

Several companies have assets in late-stage clinical development for gMG, including Alexion (gefurulimab), Novartis (remibrutinib), and EMD Serono, Inc.

(cladribine).

We believe that these approved products and product candidates could compete with cemdisiran, if cemdisiran receives regulatory approval.

Regulatory Matters

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In the U.S., drugs are subject to rigorous regulation by the FDA.

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

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.

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.

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.

Failure to comply with the applicable regulatory requirements may subject a company to a variety of administrative or judicially-imposed sanctions and the inability to obtain or maintain required approvals to test or market drug products.

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An IND becomes effective 30 days after receipt by the FDA unless the FDA notifies the sponsor that the proposed investigation(s) are subject to a clinical hold.

If the FDA imposes a clinical hold, or partial clinical hold, the FDA’s concerns must be resolved prior to the commencement of clinical trials, or the FDA can enforce other changes to the clinical development program or clinical trial(s).The IND review process can result in substantial delay and expense.

The IND review process can result in substantial delay and expense.

If the FDA accepts the IND, the drug can then be studied in human clinical trials to determine if the product candidate is safe and effective.

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The cost of preparing and submitting an NDA is substantial.

Under the PDUFA, as amended, each NDA must be accompanied by an application fee.

Under the Prescription Drug User Fee Act, or PDUFA, as amended, each NDA must be accompanied by an application fee.

For fiscal year 2026, the application fee for each NDA requiring clinical data is approximately $4.7 million.

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For novel drug products or drug products that present difficult questions of safety or efficacy, the FDA may refer the application to an advisory committee, which is typically in the form of a panel that includes independent clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

The FDA 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

follows such recommendations.

In addition, before approving an NDA, the FDA may inspect the facility or facilities where the drug is manufactured and tested to gain assurance that the manufacturing facility or facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity, and are in compliance with regulations governing cGMP requirements.

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An ANDA generally provides an abbreviated approval pathway for a drug product that has the same active ingredients in the same strength, dosage form and route of administration as the listed product, has been shown to be bioequivalent to the listed product, and has the same labeling as the listed product (subject to certain exceptions).

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.

Drugs approved via an ANDA are commonly referred to as generics and can often be substituted by pharmacists under prescriptions written for the original listed drug.

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The acceptance and approval of ANDAs and 505(b)(2) applications can be delayed by patents and non-patent exclusivity covering the listed drug.

Federal law provides a five-year period of NCE exclusivity following approval of a drug that contains a new chemical entity, or NCE, that has not been previously approved by the FDA.

Federal law provides a five-year period of NCE exclusivity following approval of a drug that contains a NCE that has not been previously approved by the FDA.

If a listed drug has NCE exclusivity, ANDAs and 505(b)(2) applications referencing the listed drug cannot be submitted to the FDA for five years following the approval of the listed drug unless the application contains a certification challenging a listed patent, i.e., a paragraph IV certification (discussed further below), in which case the ANDA or 505(b)(2) application may be submitted four years following approval of the listed drug.

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however, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the nonclinical studies and clinical trials necessary to demonstrate safety and effectiveness.

NDA applicants and NDA holders must provide information about certain patents claiming their drugs, or methods of use of the drug that is the subject of the NDA, for listing in FDA’s publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly referred to as the Orange Book.

When an ANDA or 505(b)(2) application is submitted, it must contain one of several possible certifications regarding each of the patents listed in the Orange Book for the reference drug.

NDA applicants and NDA holders must provide information about certain patents claiming their drugs, or methods of use of the drug that is the subject of the NDA, for listing in the FDA’s publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” commonly referred to as the “Orange Book.” When an ANDA or 505(b)(2) application is submitted, it must contain one of several possible certifications regarding each of the patents listed in the Orange Book for the reference drug.

For a method-of-use patent, however, the applicant can submit a statement that it is not seeking approval of a use claimed by the patent instead of making a certification.

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If the ANDA or 505(b)(2) applicant certifies that it does not intend to market its product before a listed patent expires (i.e., a Paragraph III certification), then the FDA will not grant effective approval of the ANDA or 505(b)(2) application until the relevant patent expires.

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).

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.

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).

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.

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.

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.

The FDA may approve the proposed product before the expiration of the 30-month stay only if a court finds the patent invalid or not infringed, and the court may shorten or lengthen the 30-month stay under certain limited circumstances.

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Becerra adopted a broader interpretation of the scope of orphan drug exclusivity, holding that orphan drug exclusivity prevents the FDA from approving another marketing application for the same drug for the same orphan-designated disease or condition for a period of seven years.

Although the FDA announced in January 2023 that it will not apply the Catalyst decision beyond the facts at issue in that case, Catalyst could serve as a precedent for future challenges to FDA’s orphan drug-related decisions.

Although the FDA announced in January 2023 that it will not apply the Catalyst decision beyond the facts at issue in that case, in 2025 a

federal district court in Neurelis, Inc.

Brenner struck down another FDA approval, adopting the same interpretation of orphan drug exclusivity as the Eleventh Circuit.

The FDA has appealed this decision to the U.S.

Court of Appeals for the D.C.

Legislation has been introduced, but has not been passed, that would codify the scope of orphan drug exclusivity set forth in the FDA’s regulations, rather than the interpretation adopted by the Eleventh Circuit in Catalyst .

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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.

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.

The FDA must then review the information submitted, consult with the sponsor, and agree upon a final plan.

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Failure to fulfill the requirement to submit a pediatric study plan with the application may be grounds for refusal to file an application.

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.

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.

Fast Track, Breakthrough Therapy and Priority Review Designation

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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.

Fast track designation may be rescinded if the FDA believes that the product no longer meets the qualifying criteria.

A product may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

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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.

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.

A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and it shortens the FDA’s goal for taking action on a marketing application from ten months to six months from filing.

Separate from the FDA’s priority review program, in 2025 the FDA created a new Commissioner’s National Priority Voucher, or CNPV, pilot program.

A CNPV may be granted to products with significant potential to address certain national health priorities, which include:

(i) addressing a large unmet medical need, (ii) delivering innovative cures, (iii) onshoring drug development and manufacturing, (iv) increasing affordability, or (v) addressing a U.S.

public health crisis.

The FDA has said it will review marketing applications for drugs with a CNPV within approximately one to two months following filing of a complete application, though the agency retains full discretion to extend the review time if the data or application components submitted are insufficient or incomplete, if the results of pivotal trial(s) are ambiguous, or if the review is particularly complex.

In addition, applications filed with a CNPV will be evaluated by a multi-disciplinary review committee led by the FDA’s Office of the Chief Medical and Scientific Officer, and the FDA will also provide enhanced communication with companies throughout the development and review process.

Accelerated Approval

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The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly.

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.

Failure to conduct required post-approval studies with due diligence, failure to confirm a clinical benefit during the post-approval studies, or dissemination of false or misleading promotional materials would allow the FDA to withdraw the product approval on an expedited basis.

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.

Rare Pediatric Disease Designation and Priority Review Voucher

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In order to receive a rare pediatric disease priority review voucher, the product must receive designation from the FDA as a drug for a rare pediatric disease prior to submission of the marketing application.

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.

Rare pediatric disease designation does not guarantee that the sponsor will receive a PRV.

If awarded, the PRV may be transferred unlimited times before the PRV is used.

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.

Although legislation to extend the rare pediatric disease PRV program has been proposed, Congress has not yet, and may never, pass a bill to reauthorize the program and extend the sunset dates.

The FDA awarded a rare pediatric disease PRV to us upon approval of the NDA for lumasiran in November 2020, and we utilized this PRV in connection with the sNDA filing for vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy.

Pharmaceutical Coverage, Pricing and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any products for which we obtain regulatory approval.

and other countries, sales of any products for which we may receive regulatory approval for commercial sale will depend in part on the availability of reimbursement from third-party payors.

Third-party payors include government healthcare programs, managed care providers, private health insurers and other reimbursement organizations.

The coverage and reimbursement status of any drug products for which we obtain regulatory approval may vary significantly across these third-party payors.

Third-party payors may limit coverage to specific drug products on an approved list, or formulary, which might not include all of the FDA-approved drugs for a particular disease or condition.

Third-party payors may provide coverage, but place stringent limitations on such coverage, such as requiring alternative treatments to be tried first.

The process for determining whether a payor will provide coverage for a drug product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the drug product.

Eligibility for coverage does not imply that any drug will be reimbursed in all cases or at a rate that covers a manufacturer’s costs, including research, development, manufacture, sale and distribution, or that covers a particular provider’s cost of acquiring the drug.

Third-party payors are increasingly scrutinizing the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy.

Factors payors may consider in determining reimbursement include, among others, the extent to which the product and/or the use of the product is:

and other countries, patients generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.

Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, private health insurers and other organizations is critical to the commercial success of our products.

Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to cover our costs, including research, development, manufacture, sale and distribution, and otherwise realize a sufficient return on our investment.

Within the U.S., no uniform policy for coverage and reimbursement exists across all payors.

Coverage and reimbursement can differ significantly from payor to payor and may be subject to change at any time.

Third-party payors are increasingly seeking to control drug costs by examining the cost effectiveness of products and services in addition to their safety and efficacy;

managing drug utilization and challenging the price of drugs.

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;

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• neither experimental nor investigational.

A manufacturer may need to conduct additional research, including healthcare economic studies, in order to demonstrate the clinical value and cost-effectiveness of products, separate and apart from the studies required to obtain FDA approvals.

Product candidates may not be considered medically reasonable or necessary or cost-effective.

Increasingly, the third-party payors are requiring that drug companies provide them with predetermined discounts from list prices, and are seeking to reduce the prices charged or the amounts reimbursed for drug products.

Even if a product is covered, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be provided.

Lack of adequate third-party reimbursement may prevent price levels sufficient to sell current or future product(s) on a competitive basis or realize an appropriate return on investment in product development.

Some of the drugs we market need to be administered under the supervision of a physician or other healthcare professional on an outpatient basis, including ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO.

Under currently applicable U.S.

law, certain drugs that are not usually self-administered (including injectable drugs) may be eligible for coverage under the Medicare Part B program if:

• they are incident to a physician’s services;

• they are reasonable and necessary for the diagnosis or treatment of the illness or injury for which they are administered according to accepted standards of medical practice;

• they have been approved by the FDA and meet other statutory requirements.

Federal, state and local governments in the U.S.

and foreign governments have established and continue to consider policies to limit the growth of healthcare costs, including the cost of prescription drugs.

Specifically, there have been several recent U.S.

Congressional inquiries into prescription drug pricing, and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

At the federal level, for example, in August 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law.

Key provisions of the IRA include the following, among others:

Third-party payors may limit coverage of product by, for example, only covering specific products on an approved list, or formulary, which might not include all of the FDA approved indications for a particular product.

Some third-party payors may manage utilization of a particular product by requiring pre-approval (known as “prior authorization”) for coverage of particular prescriptions (to allow the payor to assess medical necessity) or otherwise restricting coverage of a product even if used consistent with its approved indication.

There may be significant delays in obtaining coverage for newly approved drugs.

Obtaining coverage and reimbursement approval from third-party payors is often a time consuming and costly process that may require us to provide supporting scientific, clinical and cost-effectiveness data, including results from additional pharmacoeconomic studies not required for FDA approval, to each third-party payor.

There is no guarantee that we will be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement, and any coverage we do obtain could be more limited than the purposes for which the product is approved by the FDA.

Interim payments for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent.

Reimbursement may be based on lower-cost drugs that are already marketed, covered, and reimbursed.

Coverage policies, third-party reimbursement rates and pharmaceutical pricing regulations may change at any time.

Even if favorable coverage and reimbursement status is attained for one or more new products, less favorable coverage policies and reimbursement rates may be implemented in the future.

In order for our products to be eligible for coverage under certain government health care programs, we are required to certify and submit complex pricing calculations to federal agencies and also to offer discounts to government programs as well as government and private purchasers, with potentially significant penalties for non-compliance.

• Our products are eligible to be reimbursed by Medicaid because we participate in the Medicaid Drug Rebate Program and pay a rebate for each unit of product reimbursed by state Medicaid programs.

The amount of the rebate for each product is set by law and includes an additional discount if certain reported prices increase faster than inflation.

State Medicaid programs and Medicaid managed care plans can seek additional “supplemental” rebates from manufacturers in connection with favorable coverage (e.g., positioning on formularies).

• We submit a calculated “average sales price” for our products under Medicare Part B.

Manufacturer price reporting requirements in connection with government programs such as the Medicaid Drug Rebate Program and Medicare Part B are often ambiguous and continue to evolve.

For example, as of 2026, there are changes in “average sales price” regulations related to “bona fide service fees,” including a required service vendor certification that service fees are not passed on to providers, and the mandatory submission of the manufacturer’s reasonable assumptions used in calculating “average sales price.” We participate in Medicare Part D discount programs in order for our products to be eligible for coverage under Medicare Part D.

Effective January 1, 2025, a new manufacturer discount program took effect, requiring manufacturers to pay a rebate of 10% of the reimbursement in the initial phase of the Part D benefit and 20% in the catastrophic phase of the benefit.

Additionally, as the result of recent changes, drug utilization under Medicare Part B and Part D may be subject to an additional discount if the pricing increases more than inflation.

• We also offer discounts on our products to federal agency purchasers under the Federal Supply Schedule, or FSS.

FSS participation is required for a drug product to be covered and reimbursed by certain federal agencies and for coverage under Medicaid, Medicare Part B and the Public Health Service, or PHS, 340B drug pricing program.

FSS pricing is determined based, in part, on manufacturer-reported prices and is further negotiated periodically with the Department of Veterans Affairs.

In addition, prices for drugs purchased by the Veterans Administration, Department of Defense (including drugs purchased by military personnel and dependents through the TRICARE retail pharmacy program), Coast Guard, and PHS are subject to a cap on pricing (known as the “federal ceiling price”) and may be subject to an additional discount if pricing increases more than the rate of inflation.

• To maintain coverage of drugs under the Medicaid Drug Rebate Program and Medicare Part B, we extend discounts (generally based on Medicaid Drug Rebate Program pricing submissions) to certain purchasers under the PHS 340B drug pricing program.

Purchasers eligible for discounts include hospitals that serve a disproportionate share of financially needy patients, community health clinics and other entities that receive health services grants from the PHS.

Changes to these government programs could affect our business.

Further, our price reporting obligations continue to evolve, and are often subject to interpretation by agencies and courts.

For instance, the PHS 340B drug pricing program continues to be subject to legal and regulatory activity, including litigation, at the federal and state levels, and any related developments could impact the scope of the program and our obligation to offer discounts.

Continued expansion of the PHS 340B drug pricing program and growth of entities claiming entitlement to 340B pricing could impact our revenue.

Price concessions may also need to be offered to private third party payors to obtain favorable coverage or to purchasers to achieve sales.

In the U.S., we have entered into value-based agreements, or VBAs, and are negotiating additional VBAs with commercial health insurers.

The goal of these agreements is to ensure that we are paid based on the ability of our commercially approved products to deliver results in the real-world setting comparable to those demonstrated in our clinical trials, and the

agreements are structured to link the performance of our approved products in real-world use to financial terms.

Consolidation in the health insurance industry has increased the leverage of large insurers and pharmacy benefit managers, or PBMs, in pricing and other negotiations and increased price or other concessions that we must offer on our products could potentially and adversely impact product sales, business and results of operations.

Local governments and private purchasers, such as hospitals or health systems, are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare purchasing programs.

These measures could reduce the demand for our products, once approved, or put pressure on our product pricing.

In addition, we have stated publicly that we will not raise the price of any product for which we receive marketing approval over the rate of inflation, as determined by the consumer price index for urban consumers absent a significant value driver.

Patient cost for covered products may also affect demand for our products.

Third party payors are increasingly adopting policies that increase out-of-pocket costs, such as copayments and deductibles, for patients.

In the U.S., to help patients access and afford our approved products, we utilize patient support programs that provide financial assistance to patients with commercial insurance to cover the cost of copayments and deductibles.

Actions by some third party payors to leverage such financial assistance to reduce payor costs (e.g., by excluding such assistance from annual limitations on member cost-sharing) have been the subject of regulatory action and litigation.

Actions that restrict or limit the impact of such financial assistance could reduce demand for our products and have a material adverse effect on our sales, business, and financial condition.

In the U.S., healthcare and pharmaceutical pricing have been the subject of reform efforts and the federal government continues to propose and implement significant and wide-ranging reforms.

Drug pricing and reimbursement reform have been a particular area of focus.

At the federal level, for example, the Inflation Reduction Act, or IRA, includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D such as the following:

• The IRA requires manufacturers to pay rebates for Medicare Part B and Part D drugs whose net price increases exceed inflation;

• The IRA eliminates the “donut hole” under Medicare Part D beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and requiring manufacturers to subsidize, through a manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs below the out-of-pocket maximum and 20% once the out-of-pocket maximum has been reached.

• The IRA delays the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

• The IRA directs allows the Centers for Medicare and Medicaid Services, or CMS, to engage in price-capped negotiation for certain Medicare Part B and Part D products.

Specifically, the IRA’s Price Negotiation Program applies to high-expenditure single-source drugs and biologics that have been approved for at least seven or 11 years, respectively, among other negotiation selection criteria, beginning with ten high-cost drugs paid for by Medicare Part D starting in 2026, followed by 15 Part D drugs in 2027, 15 Part B or Part D drugs in 2028, and 20 Part B or Part D drugs in 2029 and beyond.

• The IRA delays the rebate rule that would require pass through of PBM rebates to beneficiaries.

• The IRA authorizes the Centers for Medicare & Medicaid Services, or CMS, to engage in price negotiations with manufacturers of certain high-spend Medicare Part B and Part D products.

The negotiated prices will be capped at a statutorily determined ceiling price.

There are certain statutory exemptions from the IRA’s Price Negotiation Program, such as for a drug that has only a single orphan drug designation and is approved only for an indication or indications within the scope of such designation.

The IRA’s Price Negotiation Program is currently the subject of legal challenges.

There are certain statutory exemptions from the drug price negotiation program, such as for a drug that has one or more orphan drug designations and is approved only for an indication or indications within the scope of such designations.

Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties or a potential excise tax.

The IRA permits the Secretary of Health and Human Services, or HHS Secretary, to implement many of the IRA’s provisions through guidance, as opposed to regulation, for the initial years.

The IRA is anticipated to have significant effects on the pharmaceutical industry and may reduce the prices pharmaceutical manufacturers can charge and reimbursement pharmaceutical manufacturers can receive for approved products, among other effects.

Further, in the U.S., manufacturers are required to provide discounts or rebates on purchases of pharmaceuticals under various federal and state healthcare programs, including Medicare, Medicaid, the Veterans Administration and the 340B program.

The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the HHS Secretary, among other requirements, as a condition for payment for any of the manufacturer’s drugs under Medicaid or Medicare Part B.

The minimum basic Medicaid rebate on most branded prescription drugs and biologic products is 23.1% of average manufacturer price, or AMP.

The Medicaid Drug Rebate Program requires participating manufacturers to report certain drug-related product and pricing information to CMS monthly and quarterly.

In order for a drug product to receive federal reimbursement under the Medicare Part B and Medicaid programs, the manufacturer also must offer its innovator products on the Federal Supply Schedule for purchase at legally prescribed prices and extend discounts on its products to entities eligible to participate in the 340B drug pricing program.

The required 340B discount on a given product is calculated based on the AMP and Medicaid rebate amounts reported by the manufacturer.

Manufacturers must report and certify prices and other data to various government entities under these programs.

The related calculations are complex, and any inaccuracies or delays in reporting can result in enforcement measures or other liability.

Changes to these government programs could affect our business.

For instance, the 340B program continues to be subject to legal and regulatory activity, including litigation, at the federal and state levels, and any related developments could impact the scope of the program and our obligation to offer discounts.

Continued expansion of the 340B program and growth of entities claiming entitlement to 340B pricing, including in ways that may be inconsistent with the statutory scheme, could impact our revenue.

Changes to the calculation of rebates under the Medicaid program could increase our Medicaid rebate obligations and decrease the prices charged to 340B covered entities.

On September 20, 2024, CMS issued a final rule specifying penalties for misclassification of drugs, and otherwise altering manufacturer obligations, under the Medicaid Drug Rebate Program.

Other executive or administrative action could alter the landscape for coverage, reimbursement, and pricing.

For instance, the Center for Medicare and Medicaid Innovation is developing, new models intended to lower drug costs under Medicare and Medicaid, including designing new payment methods for drugs approved under accelerated approval, in consultation with the FDA, to encourage timely confirmatory trial completion and improve access to post-market safety and efficacy data with the goal of reducing Medicare spending on drugs that have no confirmed clinical benefit;

creating a list of generic drugs for which the out-of-pocket Part D costs will be capped at $2 a month per drug;

and establishing new approach for administering outcomes-based agreements for cell and gene therapies.

A 2021 Executive Order affirmed the Biden administration’s policy to, among other things, support legislative reforms that enhance competition and allow for the development and market entry of lower-cost generic drugs and biosimilars.

Among other things, the executive order directed the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

The FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

In response, authorities in Canada have passed rules designed to safeguard the Canadian drug supply from shortages.

On January 5, 2024, the FDA authorized Florida’s Agency for Health Care Administration’s drug importation proposal, the first step toward Florida facilitating importation of certain prescription drugs from Canada.

We cannot predict how further developments of or changes to these policies and rules will affect our business.

Insurers are increasingly adopting programs and policies that limit access to medications and increase out-of-pocket costs for patients.

In the U.S., to help patients access and afford our approved product(s), pharmaceutical manufacturers may utilize programs to assist them, including patient assistance programs and co-pay coupon programs for eligible patients.

On April 25, 2019, CMS published a regulation clarifying that where no medically appropriate generic equivalent is available, amounts paid toward cost sharing using any form of direct support offered by drug manufacturers must be counted by applicable insurers toward the Affordable Care Act’s annual limitation on cost sharing.

On May 4, 2020, CMS published a regulation allowing applicable insurers flexibility to determine whether to include or exclude support provided by drug manufacturers from the Affordable Care Act’s annual limitation on cost sharing.

On September 29, 2023, the U.S.

District Court for the District of Columbia set aside the 2020 regulation.

Further, on April 2, 2024, CMS released a final rule codifying that all prescription drugs covered by a health plan are to be considered Essential Health Benefits and therefore are subject to the limitation on cost sharing and annual and lifetime dollar limits established by the Affordable Care Act.

It is possible that further changes in insurer policies regarding co-pay coupons and patient assistance programs and/or new legislation or regulatory action, or decisions regarding enforcement of such action, could restrict or otherwise negatively affect these co-pay coupon programs and patient support programs, which could result in fewer patients using affected products, and therefore could have a material adverse effect on pharmaceutical manufacturers’ sales, business, and financial condition.

At the state level, governments have enacted and continue to consider legislation and regulations focused on pharmaceutical product pricing.

Some of these measures include considering upper payment limits on state-regulated payers;

regulating product access, copayment assistance.

and marketing;

The impact of the IRA on the pharmaceutical industry is significant and ongoing.

Beyond the IRA, changes to Medicaid effective in 2024 eliminated the Medicaid rebate cap and changes to certain Medicare price reporting requirements for drugs beginning in 2026 will likely increase the administrative and compliance burden for manufacturers.

Under the current presidential administration, there has been significant reform activity focused on drug pricing and reimbursement.

For example, President Trump issued an Executive Order in April 2025 with multiple directives aimed at lowering drug prices, including refining the Medicare drug price negotiation program established by the IRA, accelerating competition for high-cost prescription drugs by accelerating approval of generics and biosimilars and facilitating the process for re-classifying prescription drugs as over-the-counter drugs, and increasing drug importation.

In May 2025, President Trump issued another Executive Order that directed government agencies and officials to identify most-favored nation pricing targets for prescription drugs (and looked to pharmaceutical manufacturers to make significant progress towards delivering target prices to patients), prevent foreign countries from disproportionately shifting the cost of global pharmaceutical research and development to the U.S., and facilitate direct-to-consumer purchasing programs for pharmaceutical manufacturers to sell their products to patients at the most-favored-nation price.

In the wake of the Executive Orders and related executive initiatives, a number of pharmaceutical manufacturers have announced direct-to-consumer offerings with discounted prices and/or reached agreement with the federal government regarding pricing for drugs, including prices for Medicaid drugs and newly launched products.

A future website sponsored by the federal government that is anticipated to offer pharmaceutical direct-to-consumer channels has also been announced.

Federal agencies are developing new drug pricing pilot programs, such as the GENEROUS model which would authorize the federal government to negotiate Medicaid supplemental rebates with participating manufacturers on behalf of state Medicaid programs, in exchange for standardized coverage criteria for participating manufacturer drugs, and proposed Medicare Part B and Part D pilot models that, if finalized as proposed, would replace existing inflation-based Medicare rebates with rebates determined on the basis of international prices, for drugs and patients subject to the model.

Other healthcare reform efforts or actions may affect access to healthcare coverage or the funding of health care benefits, although the full impact of such efforts or actions cannot be predicted.

For example, the Congressional Budget Office has estimated that Medicaid provisions in the 2025 budget reconciliation legislation, including restrictions in eligibility and funding for Medicaid, as well as changes to the healthcare marketplace such as the elimination of certain subsidies, will increase the number of uninsured patients.

At the state level, regulators have increasingly enacted laws and other legal reforms designed to control pharmaceutical product pricing.

Some of these measures include upper payment limits on state-regulated payers;

regulating product access, copayment assistance, and marketing;

imposing drug price, cost, and marketing disclosure and transparency requirements;

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and encouraging bulk purchasing.

Further, there has been significant consolidation in the health insurance industry, increasing the leverage of large insurers and PBMs in pricing and other negotiations and potentially impacting product sales, business and results of operations.

The federal government continues to consider legislative reforms that could alter the role and operations of PBMs in the marketplace, and such reforms could have downstream implications on pharmaceutical manufacturers.

We expect continued scrutiny on drug pricing and health care from Congress, agencies, and other bodies at the federal and state levels, and potential further alterations to the coverage, reimbursement, and pricing landscape for pharmaceutical products.

For example, on January 5, 2024, the FDA authorized Florida’s Agency for Health Care Administration’s drug importation proposal, the first step toward Florida facilitating importation of certain prescription drugs from Canada.

States are also increasingly expanding or changing Medicaid supplemental rebate programs to secure additional rebates from manufacturers in exchange for drug coverage.

These and other future state-level reform activities could negatively affect Medicaid coverage and reimbursement for our products.

We cannot predict how further developments of or changes to these policies and rules will affect our business.

Healthcare Fraud and Abuse

Federal and state laws generally prohibit the payment or receipt of kickbacks, bribes or other remuneration in exchange for the referral of patients or other healthcare-related business.

We are subject to various federal, state and local laws targeting fraud and abuse in the healthcare industry, including anti-kickback and false claims laws such as the federal Anti-Kickback Statute and the federal civil False Claims Act, or FCA.

These laws regulate our interactions with healthcare providers, including prescribers, patients, third party payors and other individuals and entities in the healthcare space, and our government reporting of drug pricing and product information.

Federal and state anti-kickback laws generally prohibit the payment or receipt of kickbacks, bribes or other remuneration in exchange for the referral of patients or other healthcare-related business.

For example, the federal Anti-Kickback Statute prohibits anyone from, among other things, knowingly and willfully offering, paying, soliciting or receiving any bribe, kickback or other remuneration intended to induce the referral of patients for, or the purchase, order or recommendation of, healthcare products and services reimbursed by a federal healthcare program, including Medicare and Medicaid.

Violations of this federal law can result in significant penalties, including imprisonment, monetary fines and assessments, and exclusion from Medicare, Medicaid and other federal healthcare programs.

Exclusion of a manufacturer would preclude any federal healthcare program from paying for its products.

In addition to the Federal Anti-Kickback Statute, many states have their own laws that are analogous to the Federal Anti-Kickback Statute, but may apply regardless of whether any state healthcare program business is involved.

In addition, federal and state false claims laws prohibit anyone from presenting, or causing to be presented, claims for payment to third-party payers that are false or fraudulent.

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.

In addition to the federal Anti-Kickback Statute, there are other federal statutes that prohibit kickbacks.

For example, another federal healthcare anti-kickback statute prohibits certain payments related to referrals of patients to certain providers (such as clinical laboratories) and applies to services reimbursed by private health plans as well as government health care programs.

Additionally, many states have their own laws that are analogous to the federal Anti-Kickback Statute, but vary in scope and may apply regardless of whether any federal or state healthcare program business is involved.

Federal and state false claims laws prohibit anyone from presenting, or causing to be presented, claims for payment to third-party payers that are false or fraudulent.

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.

Some suits filed under the FCA, known as “qui tam” actions, can be brought by a “whistleblower” or “relator” on behalf of the government, and such individuals may share in any amounts paid by the entity to the government in fines or settlement.

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.

In addition, the government may assert that a claim including items and services resulting from a violation of the U.S.

federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA.

A number of states also have false claims laws, and some of these laws may apply to claims for items or services reimbursed under Medicaid and/or commercial insurance.

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.

In addition, the government may assert that a claim including items and services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA.

A number of states also have false claims laws, and some of these laws may apply to claims for items or services reimbursed private health insurance.

Sanctions under these federal and state fraud and abuse laws may include civil monetary penalties and criminal fines, exclusion from government healthcare programs and imprisonment.

Other laws and regulations have also been enacted by the federal government and various states to regulate the sales and marketing practices of pharmaceutical manufacturers.

The laws and regulations generally limit financial interactions between manufacturers and health care providers, require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, require disclosure to the government and/or public of financial interactions (so-called “sunshine laws”), and/or require registration of pharmaceutical representatives.

State laws may also require disclosure of pharmaceutical pricing information and marketing expenditures.

Manufacturers must also submit information to the FDA on the identity and quantity of drug samples requested and distributed by a manufacturer during each year.

Violations of federal and state fraud and abuse and other laws may be punishable by criminal or civil sanctions, including fines and civil monetary penalties, and/or exclusion from federal health care programs (including Medicare and Medicaid).

Exclusion of a manufacturer would preclude any federal health care program from paying for its products.

Foreign Corrupt Practices Act of 1977, as amended, or FCPA, and similar anti-bribery laws in non-U.S.

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Violation of the FCPA could result in substantial civil and criminal penalties and remedies, including fines, disgorgement, and imprisonment.

The federal Sunshine Act requires manufacturers to report certain payments to healthcare providers to CMS.

Many state laws require drug manufacturers to report similar information related to payments and other transfers of value provided to other healthcare providers.

Some states prohibit these expenditures altogether.

Laws in a number of states also require companies to adopt marketing codes of conduct, to disclose pricing information about their products, or to license pharmaceutical sales representatives.

As described above, we maintain a global compliance program designed to support the execution of our business strategy and operations in compliance with these laws.

We maintain a global compliance program designed to support the execution of our business strategy and operations in compliance with these laws.

Possible Change in Laws or Policies

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EU Regulatory Considerations

In the EU, medicinal products are subject to extensive pre- and post-market regulation by regulatory authorities at both the EU and national levels.

In the EU, medicinal products are subject to comprehensive pre- and post-market regulation by both EU and national authorities, ensuring oversight of authorization, safety, efficacy, quality, and ongoing monitoring.

Recent reforms introduced through the EU Pharma Package and the proposed Biotech Act bring significant changes, including streamlined authorization procedures, enhanced measures for access and affordability, stricter management of medicine shortages, strengthened post-market surveillance, and new requirements addressing environmental and ethical considerations.

These initiatives are designed to modernize and harmonize medicines regulation, facilitate patient access to innovative therapies, and provide robust oversight of emerging technologies across the EU.

The legislative process for the EU Pharma Package began with the European Commission’s proposal in April 2023, followed by the development of positions by the European Parliament and the Council.

This culminated in Trilogue negotiations, with a political agreement reached in December 2025.

The agreed text now awaits formal adoption by both the Parliament and Council, after which it will be published in the Official Journal of the EU.

The new Directive and Regulation will then enter into force following a transition period of 18 to 36 months, ultimately modernizing EU pharmaceutical law to better support innovation, access, and supply.

Under the agreed EU Pharma Package, companies launching new medicines will benefit from eight years of data protection and one year of market exclusivity, with a possible additional year for innovative products meeting specific criteria.

The package empowers EU countries to require adequate supply of protected medicines to meet patient needs and introduces safeguards to prevent misuse for parallel trade.

It provides an intellectual property exemption for generic manufacturers to prepare for immediate market entry post-patent expiry, extends this to procurement submissions, and establishes a transferrable exclusivity voucher to incentivize development of priority antibiotics, with a “blockbuster clause” limiting its use for products exceeding €490 million in annual sales.

Clinical Trials

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The Clinical Trials Regulation, which became applicable on January 31, 2022, establishes the procedure to enable sponsors to submit one CTA application for it to be approved in a more streamlined and coordinated manner by two or more countries in the EU/EEA where the clinical trial is to be performed.

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

application through a single on-line platform known as Clinical Trials Information System, or CTIS, for approval.

To make it more efficient to carry out such multinational trials, one national authority assumes the role as the Reporting Member State to lead the scientific review of the application for consideration by the Member States concerned by the application for agreement within the timeframe stipulated by the Clinical Trials Regulation.

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Manufacturers are afforded the opportunity to seek scientific advice from regulatory authorities to guide their research and development programs.

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.

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.

Advice is generally not viewed as binding with regard to any future marketing authorization application, or MAA, of the product concerned and departure from the adopted advice should be justified in the MAA.

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For medicines that do not fall within these categories, an applicant may voluntarily submit an application for a centralized marketing authorization to the EMA, as long as the CHMP agrees that (i) the medicine concerned contains a new active substance, (ii) the medicine is a significant therapeutic, scientific, or technical innovation, or (iii) the authorization of the medicine under the centralized procedure would be in the interest of public health.

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:

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;

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Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days.

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.

Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major interest for public health and therapeutic innovation.

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There is an increasing trend in the EU towards greater transparency in the decision-making to allow for greater access to documents held by regulatory authorities in relation to evaluation of medicinal products.

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.

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.

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

authorization has been granted.

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.

Data Exclusivity

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Where a marketing authorization is granted for a medicinal product containing a new active substance, that product benefits from eight years of data exclusivity, during which generic MAAs referring to the data of that product will not be accepted by the regulatory authorities, and a further two years of marketing protection, during which such generic products, even if approved, may not be placed on the market until the full 10-year protection period has expired.

The 10-year protection

period may be extended to 11 years if during the first eight years of the product’s authorization, one or more new therapeutic indications with significant clinical benefit over existing therapies are approved.

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.

The 10-year protection period may be extended to 11 years if during the first eight years of the product’s authorization, one or more new therapeutic indications with significant clinical benefit over existing therapies are approved.

This period of exclusivity will be reduced under the EU package as described above.

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.

For such products, the results of appropriate preclinical studies or clinical trials must be provided, and guidelines from the EMA detail the type of supplementary data to be provided for different types of biological product.

There are no such guidelines for complex biological products, such as gene or cell therapy medicinal products, and so it is unlikely that biosimilars of those products will currently be approved in the EU.

However, guidance from the EMA states that they will be considered in the future in light of the scientific knowledge and regulatory experience gained at the time.

In the absence of dedicated guidelines, biosimilar applicants may seek scientific advice from the EMA to inform their non-clinical and clinical development strategies.

Orphan Medicinal Products

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or (iii) the marketing authorization holder for the authorized product cannot supply enough orphan medicinal product.

This period may be reduced to six years if the orphan medicinal product designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of orphan designation.

This period may be reduced to six years if the orphan medicinal product designation criteria are no longer met at the end of the fifth year of approval, including where it is shown that the product is sufficiently profitable not to justify maintenance of orphan designation.

Patisiran, approved in the EU in August 2018, givosiran, approved in the EU in March 2020, lumasiran, approved in the EU in November 2020, as well as vutrisiran, approved in the EU in September 2022 and fitusiran have been granted orphan medicinal product designation.

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Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.

All new MAAs must include a risk management plan, or RMP, describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the marketing authorization.

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Medicinal products may only be manufactured in the EU, or imported into the EU from another country, by the holder of a manufacturing authorization from the competent national authority.

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.

Manufacturing facilities are subject to periodic inspections by the competent authorities for compliance with cGMP.

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Pricing and Reimbursement

Governments influence the price of medicinal products in the EU through their pricing and reimbursement rules and control of national healthcare systems that fund a large part of the cost of those products to consumers.

Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed.

Governments in the EU influence the pricing of medicinal products through their pricing and reimbursement rules and control of national healthcare systems that fund a large part of the cost of those products to consumers.

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.

Other member states allow companies to fix their own prices for medicines, but monitor and control company profits.

The downward pressure on healthcare costs in general, particularly prescription medicines, has become very intense.

In addition to an assessment of cost-effectiveness, the national health systems may consider whether market access is affordable.

Other member states allow companies to determine their own prices for medicines, but closely monitor and control company profits to manage overall healthcare expenditures.

The downward pressure to contain healthcare costs in general, particularly prescription medicines, has intensified across EU member states.

In addition to an assessment of cost-effectiveness, the national health systems may consider whether market access is affordable and the overall budgetary impact.

As a result, increasingly high barriers are being erected to the entry of new products.

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We have contracted with several third-party contract manufacturing organizations, or CMOs, for the supply of drug substance, drug product and finished goods to meet our needs for preclinical toxicology studies, clinical and commercial supply.

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.

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.

Under this agreement, we are required to provide rolling forecasts for products on a quarterly basis, a portion of which will be considered a binding, firm order.

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.

Commercial drugs will need to be manufactured in facilities, and by processes, that comply with FDA regulations and other federal, state and local regulations, as well as comparable foreign regulations.

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.

In 2020, we amended our commercial supply agreement with Agilent to provide for Agilent to supply, subject to any conflicting obligations under our third-party agreements, a specified percentage of the API for certain of our commercial products.

Under these agreements, we are required to provide forecasts for products on a quarterly basis, a portion of which will be considered a binding, firm order.

Agilent is required to reserve sufficient capacity to ensure that it can supply products in the amounts specified under such firm orders, as well as up to a certain percentage of the remaining, non-binding portions of each forecast.

Subject to any conflicting obligations under our third-party agreements, we have also agreed to negotiate in good faith to enter into separate commercial manufacturing supply agreements with Agilent for certain products, consistent with certain specified terms, including a specified minimum purchase commitment.

Currently, Agilent is the sole manufacturer of the active pharmaceutical ingredient for ONPATTRO, AMVUTTRA and GIVLAARI, and we have entered into manufacturing services agreements with Agilent for such supply of ONPATTRO, AMVUTTRA and GIVLAARI.

Pursuant to the Agilent supply agreements, we are required to provide rolling forecasts on a quarterly basis, a portion of which will be considered a binding, firm order.

Agilent is required to reserve sufficient capacity to ensure that it can supply our commercial and clinical products in the amounts specified under such firm orders, including a certain percentage of the remaining, non-binding portions of each forecast, as well as a specified number of batches each year.

Currently, Agilent is the sole manufacturer of the API for AMVUTTRA, ONPATTRO and GIVLAARI, and we have entered into manufacturing services agreements with Agilent for such supply of AMVUTTRA, ONPATTRO and GIVLAARI.

In 2012, we established a manufacturing facility in Cambridge, Massachusetts and have developed GMP capabilities and processes for the manufacture of patisiran formulated bulk drug product for late-stage clinical trial use and commercial supply.

We expect to continue to manufacture commercial supply for formulated bulk drug product for ONPATTRO in this facility for the near future.

Commercial quantities of ONPATTRO and any other drugs that we may seek to develop will have to be manufactured in facilities, and by processes, that comply with FDA regulations and other federal, state and local regulations, as well as comparable foreign regulations.

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.

In December 2020, we began GMP operations, and we believe this facility will enable us to initiate manufacturing for multiple new early-stage programs over the next few years, as well as provide us the manufacturing capabilities to support select late-stage clinical and commercial programs in the future.

We expect to continue to manufacture commercial supply for formulated bulk drug product for ONPATTRO in this facility to support forecasted global demand.

commercial use.

Since the commencement of GMP operations in December 2020, this facility has supported our manufacturing requirements for multiple of our early-stage programs and will continue to operate in this capacity.

In December 2025, we announced a planned expansion of our Norton, Massachusetts manufacturing facility to add capabilities related to our siRELIS™ (siRNA Enzymatic Ligation Synthesis) platform, a next-generation enzymatic ligation manufacturing platform that is designed to substantially increase capacity, reduce production costs and support future launches across our growing pipeline of potential new medicines.

We believe we have sufficient manufacturing capacity through our third-party CMOs and our current internal manufacturing facilities to meet our current, clinical development and commercial needs and the needs of our collaborators.

We believe that the current supply capacity we have established externally, together with the internal capabilities we developed to support preclinical development, our existing facility for patisiran formulated bulk drug product and our Norton manufacturing facility, will be sufficient to meet our and our collaborators’ anticipated needs for the next several years.

We monitor the capacity availability for the manufacture of drug substance and drug product and believe that our supply agreements with our CMOs and the lead times for new supply agreements would allow us to access additional capacity to meet our and our

collaborators’ currently anticipated needs.

We also believe that our products can be manufactured at a scale and with production and procurement efficiencies that will result in commercially competitive costs.

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We have built and continue to scale global commercial operations designed to sequentially manage product launches across multiple geographies.

Over the last several years, we have been building commercial capabilities and leveraging the internal knowledge we have accumulated as well as hiring talented people with broad industry experience to enable us to commercialize our products ourselves and with collaborators in key countries globally.

The conduct of these commercial activities will continue to be dependent upon regulatory approvals and on agreements that we have made or may make in the future with strategic collaborators, currently as follows with respect to our first five approved products and our late-stage clinical programs:

• With respect to our ATTR amyloidosis franchise, we have global rights to develop and commercialize both ONPATTRO and AMVUTTRA;

Over the last several years, we have been building commercial capabilities and leveraging the internal knowledge we have accumulated as well as hiring world-class talent with broad industry and biotech experience to enable us to commercialize our products directly in key markets and with partners in smaller global markets.

These commercial activities will continue to be dependent upon regulatory approvals and on agreements that we have made or may make in the future with strategic collaborators, currently as follows with respect to our first six approved products and our late-stage clinical programs:

• With respect to our ATTR amyloidosis franchise, we have global rights to develop and commercialize both AMVUTTRA and ONPATTRO;

• With respect to our Global Rare franchise, we have global rights to develop and commercialize GIVLAARI and OXLUMO;

• We granted MDCO, which was acquired by Novartis in January 2020, global rights to develop and commercialize Leqvio;

• We granted Sanofi global rights to develop and commercialize fitusiran and any back-ups.

• We granted MDCO global rights to develop and commercialize Leqvio;

• We granted Sanofi global rights to develop and commercialize Qfitlia and any back-ups.

Throughout the development of our product candidates, we have remained focused on keeping patients at the center of everything we do.

This patient focus has continued as we have transitioned into commercialization.

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.

In addition, consistent with our Alnylam P 5 x25 strategy, we are now advancing RNAi therapeutics beyond rare diseases across a broad range of disease areas and indications.

Beginning with the approval of Leqvio, which was the first RNAi therapeutic approved for a prevalent disease (hypercholesterolemia), we believe the RNAi therapeutic profile supports the potential for expansion to prevalent diseases, including hypertension, NASH and diabetes, where there remains significant unmet need.

We are scaling our global commercial organization and infrastructure to support our eventual expansion to commercialize RNAi therapeutics in prevalent diseases.

We have a proactive market access strategy that includes entering into value-based agreements, or VBAs, with commercial payers in the U.S.

and certain state Medicaid programs.

We have entered into VBAs with multiple commercial payers, including for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO.

In our VBAs for GIVLAARI and OXLUMO we offer a prevalence-based adjustment that provides that we will pay a rebate if the number of patients identified within a plan population exceeds the expected disease prevalence.

For OXLUMO, we offer a VBA component called a patient need adjustment that provides payers with greater budget certainty for medicines administered across a broad range of patient age groups by paying a rebate if the average number of vials utilized by a plan member exceeds an established threshold.

These adjustment seek to address an unknown that exists in the context of an ultra-rare disease.

Discussions with additional payers continue for our marketed products.

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 addition, we are now advancing RNAi therapeutics beyond rare diseases across a broad range of disease areas and indications.

Beginning with the approval of Leqvio, which was the first RNAi therapeutic approved for a prevalent disease (hypercholesterolemia), we believe the RNAi therapeutic profile supports the potential to address diseases ranging from rare, specialty areas, including CNS and hematological diseases, to more common diseases that impact public health, including hypertension, as well as other metabolic disorders where there remains significant unmet need.

We have expended significant effort to build and continue to strive to improve our goal of increasing access to medicines across the world.

We have developed and succeeded in proactive market access strategies that include entering into value-based agreements.

We believe our access strategies enable us to maximize the value of our transformative medicines while proactively managing global dynamics.

Our ability to engage U.S.

payers, including CMS (Medicare), certain state Medicaid programs as well as commercial payers, through VBAs has been instrumental in providing patients with rapid and favorable access to our medicines.

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.

In addition, we have been encouraged by the strength of the adoption of AMVUTTRA in hATTR amyloidosis with polyneuropathy in key markets and expect continued expansion across global markets.

We are continuing to augment the key components of our global commercial organization with a focus on successfully launching our commercially approved products around the world and preparing for the anticipated commercial launches of additional RNAi therapeutics, assuming successful development and regulatory approval.

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.

We have augmented the key components of our global commercial organization with a focus on successfully launching our commercially approved products around the world and preparing for the anticipated commercial launches of additional RNAi therapeutics, assuming successful development and regulatory approval.

We are continuing to scale our global commercial organization and infrastructure to support our planned expansion to commercialize RNAi therapeutics in prevalent diseases.

With respect to our approved products, throughout 2025, we continued to build our commercial capabilities and to expand these capabilities to additional countries globally.

We are building a focused commercial team with broad experience in marketing, sales, patient access, patient services, distribution and product reimbursement, and incorporating and enhancing appropriate quality systems, compliance policies, systems and procedures, as well as implementing internal systems and infrastructure to support global commercial sales, and the establishment of patient-focused programs.

We intend to leverage our existing commercial infrastructure to also support the launch of vutrisiran in ATTR-CM, assuming regulatory approval.

In preparation for potential regulatory approvals, we have implemented a compliance program to ensure that our promotional activities remain focused solely on AMVUTTRA in hATTR amyloidosis with polyneuropathy until we obtain approval to market vutrisiran for ATTR amyloidosis with cardiomyopathy in each market.

Our Ethics & Compliance team has partnered with our Commercial and Medical Affairs leadership teams in the implementation of this program, which is focused on proactive messaging and training, field monitoring, and data analysis.

We believe we have built a focused commercial team with broad experience in marketing, sales, patient access, patient services, distribution and product reimbursement, and incorporating and enhancing appropriate quality systems, compliance policies, systems and procedures, as well as implementing internal systems and infrastructure to support global commercial sales, and the establishment of patient-focused programs.

Leveraging our experience in hereditary ATTR polyneuropathy and our established commercial infrastructure, we expanded our customer-facing organization to support the launch of AMVUTTRA for the treatment of ATTR amyloidosis with cardiomyopathy in the U.S.

Our launch strategy in the U.S.

is based on three core pillars:

health system set-up, which includes engagement and education across health systems to support appropriate adoption;

access, focused on securing payer coverage and establishing reimbursement pathways to facilitate patient access;

and treatment choice, emphasizing physician education and patient support programs to enable informed decision-making.

Outside of the U.S., we have launched AMVUTTRA for ATTR-CM in Japan and Germany and we are advancing regulatory review and launch preparation activities for AMVUTTRA in additional markets globally.

Our Ethics & Compliance team has partnered with our Commercial and Medical Affairs leadership teams to maintain a robust compliance program designed to ensure that our promotional activities are consistent with the approved labeling for AMVUTTRA in each jurisdiction.

This program includes proactive messaging and training, field monitoring and data analysis.

For many territories/countries, we may also utilize strategic partners, distributors or contract sales forces to assist in the commercialization of our products.

Our objective is to execute successful product launches leveraging our positive experience with the launches of our approved products.

Our objective is to execute successful product launches and market expansions leveraging our experience with the launches of our approved products.

Medical Affairs

Our Medical Affairs organization facilitates communications with the medical and scientific community through the publication of clinical trial data and participation in medical congresses, provides healthcare professionals with accurate information about our products, responds to medical inquiries, and generates data to demonstrate product value, cost-effectiveness and supporting data for market access and reimbursement.

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.

With a scalable framework for these capabilities, we believe our Medical Affairs organization is well positioned to support potential launches of our products in new indications and to expand our addressable indications to include prevalent diseases.

Our Medical Affairs organization facilitates communications with the medical and scientific community through the publication of clinical trial data and participation in medical congresses.

It provides healthcare professionals with accurate information about our products, responds to medical inquiries, and generates data to demonstrate product value, cost-effectiveness and support for market access and reimbursement.

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.

With a scalable framework for these capabilities, we believe our Medical Affairs organization continues to be well positioned to support potential launches of additional products and to expand our addressable indications to include prevalent diseases.

Human Capital Management

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During 2025, we enhanced our capabilities by adding approximately 270 new full-time employees.

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.

We expect to continue to add additional employees in 2025, with a focus on further enhancing our capabilities and increasing our capacities in these areas, as well as expanding our geographic reach as we continue with global launches of our products and prepare for the launch of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, assuming regulatory approval.

We expect to continue to add additional employees in 2026, with a focus on further enhancing our capabilities and increasing our capacities in these areas, as well as the planned expansion of our state-of-the-art manufacturing facility in Norton, Massachusetts and expanded geographic reach as we continue with the global launch of AMVUTTRA for the treatment of ATTR-CM and other products.

We consider the intellectual capital, skills and experience of our employees to be an essential driver of our business and key to our future prospects.

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Our reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, including our annual reports on Form 10-K, our quarterly reports on Form 10-Q and our current reports on Form 8-K, and amendments to those reports, are accessible through our website, free of charge, as soon as reasonably practicable after these reports are filed electronically with, or otherwise furnished to, the SEC.

We also make available on our website the charters of our audit committee, people, culture and compensation committee, nominating and corporate governance committee, and science and technology committee, as well as our corporate governance guidelines and

our code of business conduct and ethics.

We intend to disclose on our website any amendments to, or waivers from, our code of business conduct and ethics that are required to be disclosed pursuant to SEC rules.

2 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business