What changed in this filing

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Item 1. Business

2023-02-23 compared with 2022-02-10 · 357 added, 358 removed, 892 unchanged (44% of the section changed)

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We believe this is a revolutionary approach with the potential to transform the care of patients with rare and prevalent diseases.

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

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).

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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For delivery to the central nervous system, or CNS, and the eye (ocular delivery), we are utilizing an alternative conjugate approach based on a hexadecyl (C16) moiety as a lipophilic ligand.

During 2021, we also advanced approaches for lung, muscle and adipose tissue delivery of siRNAs.

During 2022, we also advanced approaches for heart, skeletal muscle, and adipose tissue delivery of siRNAs.

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

Based on our track record of setting and exceeding five-year goals, in 2021, we launched our Alnylam P 5 x25 strategy which focuses on our planned transition to a top five biotech company, as measured by market capitalization, by the end of 2025.

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

With Alnylam P 5 x25 , we aim to deliver transformative rare and prevalent disease medicines for patients around the world through sustainable innovation, while delivering exceptional financial performance.

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Achieve sustainable non-GAAP (generally accepted accounting principles) profitability within the period

We ended 2021 making meaningful progress towards these goals, with four marketed products and 13 clinical programs, including five in late-stage development, across four Strategic Therapeutic Areas, or “STArs:” Genetic Medicines;

We ended 2022 making meaningful progress on these goals, and currently have five marketed products and more than ten clinical programs, including several in late-stage development, across four Strategic Therapeutic Areas, or “STArs:” Genetic Medicines;

Cardio-Metabolic Diseases;

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and CNS/Ocular Diseases.

Three of our marketed products are within the Genetic Medicines STAr, ONPATTRO, GIVLAARI and OXLUMO.

ONPATTRO is approved by the United States Food and Drug Administration, or FDA, for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, or 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 transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries, including Brazil.

Regulatory filings in other territories are pending and additional filings are planned for 2022 and beyond.

Four of our marketed products are within the Genetic Medicines STAr, ONPATTRO, GIVLAARI, OXLUMO and AMVUTTRA.

ONPATTRO is approved by the United States Food and Drug Administration, or the FDA, for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, or 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 transthyretin, or TTR, type familial amyloidosis with polyneuropathy, and in multiple additional countries, including Brazil.

In August 2022, we reported positive results from the APOLLO-B Phase 3 study of patisiran (the non-branded name of ONPATTRO) in patients with ATTR amyloidosis with cardiomyopathy, and in December 2022, we submitted a supplemental New Drug Application, or sNDA, to the FDA for ONPATTRO as a potential treatment of the cardiomyopathy of ATTR amyloidosis.

In February 2023, the FDA accepted the sNDA for filing and set an action date of October 8, 2023 under the Prescription Drug User Fee Act, or PDUFA.

The FDA also indicated in the sNDA filing communication letter that it is planning to hold an advisory committee meeting to discuss the application and that it had not identified any potential review issues at such time.

GIVLAARI is approved in the U.S.

for the treatment of adults with acute hepatic porphyria, or AHP, in the EU for the treatment of AHP in adults and adolescents aged 12 years and older, and in several additional countries, including Brazil, Canada, Switzerland and Japan.

We have also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Colombia and additional regulatory filings are pending or planned for 2022 and beyond.

In November 2020, we received regulatory approval for OXLUMO in the U.S.

and EU for the treatment of primary hyperoxaluria type 1, or PH1, in all age groups.

In June 2021, we received marketing authorization approval for OXLUMO in Brazil for the treatment of PH1 in both children and adult patients.

Regulatory filings in other territories are pending and additional filings are planned for 2022 and beyond.

Our fourth product, Leqvio (inclisiran), is being developed and commercialized by our partner 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 is in the Cardio-Metabolic Diseases STAr.

With respect to regulatory review by the FDA of the NDA filed with the FDA for inclisiran, the FDA issued a complete response letter on December 18, 2020, due to unresolved facility inspection-related conditions at a third-party manufacturing facility in Europe.

In July 2021, Novartis announced that the resubmission to the FDA for the inclisiran NDA to address the complete response letter was filed, and listed its own site in Schaftenau, Austria, as the manufacturing location for the final finished product within its NDA resubmission.

In December 2021, Leqvio was approved by 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 LDL-C.

As of January 2022, Leqvio has been approved in more than 50 countries.

In addition to our marketed products, we have five late-stage investigational programs advancing toward potential commercialization.

Regulatory filings for givosiran (the non-branded drug name for GIVLAARI) in other territories are pending or planned during 2023 and beyond.

OXLUMO is approved in the U.S.

and EU for the treatment of primary hyperoxaluria type 1, or PH1, in all age groups, and in several additional countries including Brazil and Switzerland.

In October 2022, we announced that the FDA approved our sNDA for lumasiran (the non-branded drug name for OXLUMO), for the treatment of PH1 to lower urinary oxalate and plasma oxalate levels in pediatric and adult patients.

Regulatory filings in other territories are pending and additional filings are planned during 2023 and beyond.

In June 2022, we received regulatory approval for AMVUTTRA in the U.S.

for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

In September 2022, AMVUTTRA was granted marketing authorization in Europe and the United Kingdom, or UK, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, and in Japan for the treatment of TTR type familial amyloidosis with polyneuropathy.

In December 2022, AMVUTTRA was approved in Brazil for the treatment of

hATTR amyloidosis in adults.

Regulatory filings in other territories are currently under review and additional filings are planned for 2023.

Our fifth product, Leqvio (inclisiran), is being developed and commercialized by our partner 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 LDL-C.

As of the end of January 2023, Leqvio has been approved in 70 countries.

In addition to our marketed products, we have multiple late-stage investigational programs advancing toward potential commercialization.

These programs include our wholly owned programs:

lumasiran (the non-branded name for OXLUMO) for the treatment of advanced PH1 and recurrent renal stones;

patisiran (the non-branded drug name for ONPATTRO) for the treatment of transthyretin amyloidosis, or ATTR amyloidosis, with cardiomyopathy;

vutrisiran for the treatment of ATTR amyloidosis and Stargardt Disease;

as well as fitusiran for the treatment of hemophilia, which is being advanced by our partner Genzyme Corporation, a Sanofi company, or Sanofi, and cemdisiran for the treatment of complement-mediated diseases, which is being advanced by our partner Regeneron Pharmaceuticals, Inc., or Regeneron, in a Phase 3 study of cemdisiran and pozelimab combination in myasthenia gravis.

In further support of our Alnylam P 5 x25 strategy and in view of our evolving risk profile, we remain focused on 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.

patisiran (the non-branded drug name for ONPATTRO) for the treatment of transthyretin amyloidosis, or ATTR amyloidosis, (wild-type or hereditary) with cardiomyopathy;

vutrisiran (the non-branded drug name for AMVUTTRA) for the treatment of ATTR (wild-type or hereditary) amyloidosis with cardiomyopathy;

as well as fitusiran for the treatment of hemophilia, which is being advanced by our partner Genzyme Corporation, a Sanofi Company, or Sanofi;

and cemdisiran for the treatment of complement-mediated diseases, where our partner Regeneron Pharmaceuticals, Inc., or Regeneron, is advancing cemdisiran in combination with pozelimab in Phase 3 studies in myasthenia gravis and paroxysmal nocturnal hemoglobinuria.

As part of our Alnylam P 5 x25 strategy, we have multiple drivers of future growth, including the development of transformative prevalent disease medicines.

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

In November 2021, we reported positive interim data from the ongoing Phase 1 study of zilebesiran, and initiated the KARDIA Phase 2 clinical studies for zilebesiran.

KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually.

KARDIA-2 will 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.

Topline results from the KARDIA-1 and KARDIA-2 Phase 2 studies are anticipated in mid-2023 and at or around year-end 2023, respectively.

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 maintain focus on our global compliance program to drive its evolution and enhancement in view of the Alnylam P 5 x25 strategy.

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.

Comprised of components such as risk assessment and monitoring;

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and systems and processes supporting activities such as third party relationships and investigations and remediation;

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

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 alliances with leading pharmaceutical and life scie nces companies to support our development and commercialization efforts, including Regeneron, Novartis (which acquired our partner The Medicines Company, or MDCO, in 2020), Sanofi, Vir Biotechnology, Inc., or Vir, Dicerna Pharmaceuticals, Inc.

(acquired by Novo Nordisk A/S, or Novo Nordisk, in December 2021), or Dicerna, and PeptiDream, Inc., or PeptiDream.

Convertible Senior Notes

In September 2022, we issued $1.04 billion aggregate principal amount of 1.00% Convertible Senior Notes due 2027, or Notes.

The Notes will mature on September 15, 2027, unless earlier converted, redeemed or repurchased.

The Notes will bear interest from September 15, 2022 at a rate of 1.00% per year payable semiannually in arrears on March 15 and September 15 of each year, beginning on March 15, 2023.

Before June 15, 2027, noteholders will have the right to convert their Notes in certain circumstances and during specified periods.

From and after June 15, 2027, the Notes will be convertible at the option of the noteholders at any time prior to the close of business on the second scheduled trading day immediately preceding the maturity date.

We will settle any conversions of Notes by paying or delivering, as applicable, cash 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 Notes, we paid $118.6 million, including expenses, to enter into privately negotiated capped call transactions with certain initial purchasers of the 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 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 Notes, and is subject to anti-dilution adjustments generally similar to those applicable to the conversion rate of the Notes.

The cap price of the capped call transactions will initially be $424.00 per share, which represents a premium of approximately 100% based on the last reported sale price of our common stock of $212.00 per share on September 12, 2022,

and is subject to certain adjustments under the terms of the capped call transactions.

If, however, the market price per share of our common stock, as measured under the terms of the capped call transactions, exceeds the cap price of the capped call transactions, there would nevertheless be dilution upon conversion of the Notes to the extent that such market price exceeds the cap price of the capped call transactions.

We used approximately $762.0 million of the net proceeds from the offering to repay borrowings, inclusive of prepayment premiums, under our credit agreement with Blackstone, and intend to use the remainder of the net proceeds for general corporate purposes.

The COVID-19 Pandemic

In March 2020, the World Health Organization declared the outbreak of COVID-19 as a pandemic.

More recently, other, more infectious, variants of COVID-19 have been identified, which continue to spread throughout the U.S.

and worldwide.

We could be materially and adversely affected by the risks, or the public perception of the risks, related to an epidemic, pandemic, outbreak, or other public health crisis, such as the current COVID-19 pandemic.

Since the onset of the global pandemic in 2020, we have been closely monitoring the spread of COVID-19 and its variants, and plan to continue taking steps to identify and mitigate the adverse impacts on, and risks to, our business posed by its spread and actions taken by governmental and health authorities to address the COVID-19 pandemic.

The spread of COVID-19 caused us to modify our business practices, including implementing a temporary global work from home policy in March 2020 for all employees who were able to perform their duties remotely and temporarily restricting all nonessential business travel, and we expect to continue to take actions as may be required or recommended by government authorities or as we determine are in the best interests of our employees, the patients we serve and other business partners in light of COVID-19 and variants thereof.

Where and to the extent permitted to be open under local regulations, our office sites are operational with appropriate safety precautions based on vaccination rates and local guidance, and in October 2021, we formally re-opened our offices in the U.S., following openings in other territories, to those employees who have been fully vaccinated.

The effects of the COVID-19 pandemic continue to evolve and, at this time, we cannot predict when certain restrictions that remain in place to protect our employees, customers and patients will no longer be needed.

Recognizing that local conditions vary for our offices around the world and that the trajectory of the virus continues to be uncertain, we may adjust our plans for employees returning to our offices as deemed necessary.

Since early 2021, global vaccination efforts have been underway to control the pandemic.

However, due to the speed and fluidity with which the COVID-19 pandemic continues to evolve, and the emergence of highly contagious variants, we do not yet know the full extent of the impact of COVID-19 on our business operations.

The ultimate extent of the impact of any epidemic, pandemic, outbreak, or other public health crisis on our business, financial condition and results of operations will depend on future developments, which are highly uncertain and cannot be predicted, including new information that may emerge concerning the severity of such epidemic, pandemic, outbreak, or other public health crisis and actions taken to contain or prevent the further spread, including the effectiveness of vaccination and booster vaccination campaigns, among others.

Accordingly, we cannot predict the extent to which our business, financial condition and results of operations will be affected.

We remain focused on maintaining a strong balance sheet, liquidity and financial flexibility and continue to monitor developments as we deal with the disruptions and uncertainties from a business and financial perspective relating to COVID-19 and variants thereof.

We will continue to work diligently with our partners and stakeholders to support patient access to our approved medicines, advance our product candidates under regulatory review as well as in our clinical studies to the extent safe to do so for patients, caregivers and healthcare practitioners, and ensure the continuity of our manufacturing and supply chain.

The COVID-19 pandemic has resulted in the imposition of various responses, including government-imposed quarantines, travel restrictions, and other public health safety measures to reduce the spread of disease.

We continue to closely monitor the spread of COVID-19 and its variants, and plan to continue taking steps to identify and mitigate the adverse impacts on, and risks to, our business posed by its spread and actions taken by governmental and health authorities to address the ongoing COVID-19 pandemic.

The extent to which COVID-19 ultimately impacts our business, results of operations or financial condition will depend on future developments, which remain uncertain and cannot be predicted with confidence, such as the duration of the COVID-19 pandemic, new strains of the virus, including any future variants that may emerge, which may impact rates of infection and vaccination efforts, developments or perceptions regarding the safety of vaccines, and any additional preventative and protective actions taken to contain the pandemic or treat its impact, among others.

The estimates of the impact on the Company’s business may change based on new information that may emerge concerning COVID-19 and the actions to contain it or treat its impact and the economic impact on local, regional, national and international markets.

For additional information related to the actual or potential impacts of COVID-19 on our business, please read Part I, Item 1A, "Risk Factors" of this Annual Report on Form 10-K.

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TTR Franchise

• ONPATTRO (patisiran) – hATTR Amyloidosis with Polyneuropathy

◦ Recognized ONPATTRO global net revenue of $474.7 million for the year ended December 31, 2021

◦ Attained over 2,050 patients worldwide on commercial ONPATTRO treatment as of December 31, 2021

• Vutrisiran – ATTR Amyloidosis and Stargardt Disease

◦ Reported positive results for 18-month endpoints and safety from the HELIOS-A Phase 3 study in hATTR amyloidosis patients with polyneuropathy

◦ Submitted a JNDA in Japan for the treatment of hATTR amyloidosis patients with polyneuropathy

◦ Introduced new near-term opportunity for vutrisiran in Stargardt disease, expected to enter Phase 3 development in late 2022

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

◦ Achieved global net product revenues for ONPATTRO and AMVUTTRA for the full year 2022 of $558 million and $94 million, respectively

◦ Attained over 2,975 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2022

◦ Received 760 Start Forms in the U.S.

for AMVUTTRA from launch through December 31, 2022

• Patisiran – ATTR Amyloidosis with Cardiomyopathy

◦ Reported positive results from the APOLLO-B Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy

◦ Submitted and received acceptance of the sNDA for ONPATTRO (patisiran) for the treatment of the cardiomyopathy of ATTR amyloidosis

▪ The FDA has set an action date of October 8, 2023 under the PDUFA

▪ In their file acceptance letter, the FDA stated that they have not identified any review issues, and also noted that they are planning to hold an advisory committee meeting to discuss the application

• Vutrisiran – hATTR Amyloidosis with Polyneuropathy

◦ Received FDA approval of AMVUTTRA for the treatment of the polyneuropathy of hATTR amyloidosis in adults

◦ Received marketing authorization for AMVUTTRA for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy in Europe and the UK, as well as approval for TTR type familial amyloidosis with polyneuropathy in Japan

◦ Received approval from the Brazilian Health Regulatory Agency (ANVISA) for AMVUTTRA for the treatment of hATTR amyloidosis in adults

• Vutrisiran – ATTR Amyloidosis with Cardiomyopathy

◦ Announced that we do not plan to conduct the optional interim analysis for the HELIOS-B Phase 3 study in patients with ATTR amyloidosis with cardiomyopathy;

the study remains on track for topline results in early 2024

Commercial/Late-Stage Pipeline

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◦ Recognized OXLUMO global net revenue of $69.8 million for the year ended December 31, 2022

◦ Attained over 140 patients worldwide on commercial OXLUMO treatment as of December 31, 2021

◦ Attained over 280 patients worldwide on commercial OXLUMO treatment as of December 31, 2022, up from over 230 commercial patients as of September 30, 2022

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

◦ Our partner, Novartis, received FDA approval for Leqvio as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical ASCVD who require additional lowering of LDL-C

◦ We recognized a $25 million milestone payment from Novartis related to the FDA approval of Leqvio in December 2021

• Lumasiran – Advanced Primary Hyperoxaluria Type 1 and Recurrent Kidney Stone Disease

◦ Reported positive topline results from the ILLUMINATE-C Phase 3 study in patients with advanced PH1

◦ Submitted regulatory applications to the FDA and European Medicines Agency, or EMA, to support label expansion for OXLUMO for the treatment of advanced PH1

◦ Initiated a Phase 2 study in patients with recurrent kidney stone disease

• Fitusiran - Hemophilia (in collaboration with Sanofi)

◦ Our partner, Sanofi, reported positive results from the Phase 3 ATLAS-A/B and ATLAS-INH studies, demonstrating fitusiran significantly reduced bleeds in people with hemophilia A or B, with or without inhibitors

◦ Our partner, Novartis, continued the launch of Leqvio, with focus on patient on-boarding, removing access hurdles and enhancing medical education

• Lumasiran – Primary Hyperoxaluria Type 1

◦ Based on the successful outcome of the ILLUMINATE-C study in children and adults with advanced PH1, received approval from the FDA of an sNDA for OXLUMO, expanding the indication for the treatment of PH1 to lower urinary oxalate and plasma oxalate levels in pediatric and adult patients, and received approval from the EMA of a Type II variation to include the ILLUMINATE-C data in the label

Early-Stage and Pre-Clinical Pipeline

• Cemdisiran for the treatment of complement-mediated diseases;

our partner, Regeneron, initiated Phase 3 studies of cemdisiran and pozelimab combination in myasthenia gravis and paroxysmal nocturnal hemoglobinuria

• Zilebesiran (ALN-AGT) for the treatment of hypertension;

initiated KARDIA-2 Phase 2 combination therapy study of zilebesiran in patients with inadequately controlled hypertension

completed enrollment in the KARDIA-1 Phase 2 monotherapy study of zilebesiran in patients with mild-to-moderate hypertension

• ALN-APP for the treatment of cerebral amyloid angiopathy and autosomal dominant Alzheimer’s Disease;

enrollment and dose escalation continue in the Phase 1 study of ALN-APP in patients with early onset Alzheimer’s Disease, in collaboration with Regeneron, with initial topline results expected in early 2023

• ALN-TTRsc04 for the treatment of ATTR amyloidosis;

submitted a CTA application and initiated dosing in a Phase 1 study

Corporate Highlights

◦ Ended 2022 with $2.19 billion in cash, cash equivalents and marketable securities

◦ Announced the planned transition of founding CEO John Maraganore, Ph.D., to Yvonne Greenstreet, MBChB effective January 1, 2022

◦ Issued $1.04 billion convertible senior notes with proceeds primarily used to pay down Blackstone $700 million credit facility and approximately $200 million in prepayment premiums under the credit facility, the purchase of capped call transactions, and underwriter fees

RNAi Therapeutics – A New Class of Innovative Medicines

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In recent years, a tremendous amount of progress has been made in effectively delivering RNAi therapeutics to targeted organs and cells, and we believe Alnylam has been the leader of this advancement.

We believe this success will enable us to achieve our Alnylam P 5 x25 strategy under which we expect to sustainably and organically create and commercialize transformative rare and prevalent disease medicines benefiting hundreds of thousands of patients around the world while delivering strong financial performance, resulting in a leading biotech profile by the end of 2025.

We believe this success will enable us to achieve our Alnylam P 5 x25 strategy under which we expect to sustainably and organically create and commercialize transformative rare and prevalent disease medicines benefiting patients around the world while delivering strong financial performance, resulting in a leading biotech profile by the end of 2025.

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

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This simpler delivery approach enables more convenient, subcutaneous administration of our drug candidates directed to liver expressed target genes, a key aspect of our platform.

Results from our Enhanced Stabilization Chemistry, or ESC, GalNAc-conjugate delivery platform have demonstrated a durability of effect that we believe, based on our clinical results, supports once-monthly, once-quarterly, and in some cases, bi-annual subcutaneous dose regimens.

Due to this increased potency and durability, as well as a wide therapeutic index, this conjugate platform has become our primary approach for drug development and is leveraged and we believe, strongly validated by, GIVLAARI, OXLUMO, and Leqvio, our more recently approved medicines.

Due to this increased potency and durability, as well as a wide therapeutic index, this conjugate platform has become our primary approach for drug development and is leveraged and we believe, strongly validated by, AMVUTTRA, GIVLAARI, OXLUMO, and Leqvio, our more recently approved medicines.

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 already wide therapeutic index by up to six-fold.

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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.

During 2021, we presented data utilizing an alternative conjugate approach based on a hexadecyl (C16) moiety as a lipophilic ligand, with proof-of-concept, or POC, demonstrated in rodent and non-human primates.

In July 2022, our publication in Nature Biotechnology showcased data utilizing an alternative conjugate approach based on a hexadecyl (C16) moiety as a lipophilic ligand, with proof-of-concept, or POC, demonstrated in rodent and non-human primates.

C16 conjugates provide robust CNS knockdown with wide biodistribution and long duration of action, and this technology enabled our landmark collaboration with Regeneron for the advancement of RNAi therapeutics for a broad range of diseases by addressing therapeutic targets in the eye and CNS, in addition to a select number of targets in the liver.

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

In addition, we are exploring peptide and antibody-based approaches for targeted siRNA delivery to new tissues, and in 2021 we entered into a license and collaboration agreement

with PeptiDream to discover and develop peptide-siRNA conjugates for targeted delivery of RNAi therapeutics to a broader range of extrahepatic tissues.

In 2021, we unveiled our IKARIA™ platform harboring further chemistry advancements that enables robust target knockdown with an annual dosing regimen.

We also unveiled an additional technology platform, GEMINI™, that we believe has the potential to simultaneously silence two unique gene transcripts using a single chemical entity.

We believe that this platform, could have potential applications in cardiometabolic, CNS, oncologic, and viral diseases.

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

In addition, we are exploring peptide and antibody-based approaches for targeted siRNA delivery to new tissues in partnership with PeptiDream to discover and develop peptide-siRNA conjugates for targeted delivery of RNAi therapeutics to a broader range of extrahepatic tissues.

Additional platform advancements that we are working on include our IKARIA™ platform harboring chemistry innovations that enable robust target knockdown with an annual dosing regimen, and an additional technology platform, GEMINI™, that we believe has the potential to simultaneously silence two unique gene transcripts using a single chemical entity.

We believe that these platforms, could have potential applications in cardiometabolic, CNS, oncologic, and viral diseases.

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

We have established a relationship with the UK BioBank to support the sourcing of novel, genetically validated targets and secure access to databases of genetic information.

In 2021, we furthered this effort through our partnership with Our Future Health to support the design and delivery of the research program to recruit up to five million adults from across the UK.

In 2022, we published a manuscript in Nature Communications, revealing that loss of function variants in the hepatokine gene INHBE protect against abdominal obesity and can thus serve as a potential therapeutic target for cardiometabolic disease.

The discovery leveraged sequencing data from more than 360,000 individuals in the UK Biobank.

In addition, our partnership with Our Future Health furthers our investment in human genetics supporting the design and delivery of the research program to recruit up to five million adults from across the UK.

Coupled with our proven ability to uncover novel gene targets, we believe our approach, investments and commitment to genetically validated targets has the potential to increase our success rate, streamline clinical trials and speed the development of precision medicines for patients with both rare and prevalent diseases.

We believe RNAi therapeutics represent a simplified and efficient new class of innovative medicines.

We have achieved human POC in multiple clinical trials of our investigational candidates and now have four commercially approved products, validating our approach to drug development.

Moreover, we believe that our reproducible and modular platform will support our Alnylam P 5 x25 s trategy under which we expect to sustainably and organically create and commercialize transformative rare and prevalent disease medicines benefiting hundreds of thousands of patients around the world while delivering strong financial performance, resulting in a leading biotech profile by the end of 2025.

We have achieved human POC in multiple clinical trials of our investigational candidates and now have five commercially approved products, validating our approach to drug development.

Moreover, we believe that our reproducible and modular platform will support our Alnylam P 5 x25 s trategy under which we expect to sustainably and organically create and commercialize transformative rare and prevalent disease medicines benefiting patients around the world while delivering strong financial performance, resulting in a leading biotech profile by the end of 2025.

Our Product Pipeline

Our broad pipeline, including four approved products and multiple late and early-stage investigational RNAi therapeutics, is focused in four STArs:

Our broad pipeline, including five approved products and multiple late and early-stage investigational RNAi therapeutics, is focused in four STArs:

Genetic Medicines;

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It identifies those programs for which we have received marketing approval, the stage of our programs and our commercial rights to such programs:

As indicated in the chart above, to date we have received marketing approval for ONPATTRO, 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 chart 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.

Our TTR Franchise

About Transthyretin Amyloidosis (ATTR)

ATTR amyloidosis is a rare, serious, life-threatening, multisystem disease encompassing hATTR amyloidosis and wild-type ATTR, or wtATTR, amyloidosis, which result from either hereditary (genetic mutation in TTR gene) or nonhereditary (ageing) causes, respectively.

ATTR amyloidosis is a rare, serious, life-threatening, multisystem disease encompassing hATTR amyloidosis and wild-type ATTR, or wtATTR, amyloidosis, which result from either hereditary (genetic variant in TTR gene) or nonhereditary (ageing) causes, respectively.

In ATTR amyloidosis, misfolded TTR proteins accumulate as amyloid fibrils in multiple organs and tissue types.

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The disease is estimated to impact 200,000 to 300,000 people worldwide.

ONPATTRO ( patisiran) – hATTR Amyloidosis with Polyneuropathy

ONPATTRO ( patisiran)

ONPATTRO (patisiran) is an intravenously administered RNAi therapeutic targeting TTR.

It is designed to target and silence TTR mRNA, thereby blocking the production of TTR protein before it is made.

ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body’s tissues in order to halt or improve the progression of the polyneuropathy associated with the disease.

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

It is designed to target and silence TTR mRNA, thereby reducing the production of TTR protein before it is made.

ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body’s tissues to halt or improve the progression of disease.

Patisiran has received Orphan Drug Designations in the U.S., EU and Japan;

specific Orphan Drug Designations vary by country/region.

ONPATTRO ( patisiran) – hATTR Amyloidosis with Polyneuropathy

ONPATTRO is the first ever FDA-approved RNAi therapeutic and based on data from the APOLLO Phase 3 study, it became our first product to receive marketing approval.

and Canada, ONPATTRO is indicated for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

In the EU, Switzerland, Brazil and Israel, ONPATTRO is indicated for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy, and in Japan, ONPATTRO is indicated for the treatment of TTR type familial amyloidosis with polyneuropathy.

Regulatory filings in other territories are currently under review and additional filings are planned for 2022.

Patisiran (the non-branded name for ONPATTRO) is also being investigated in a Phase 4 study in patients with polyneuropathy of hATTR amyloidosis due to a T60A or V122I variant.

Patisiran (the non-branded name for ONPATTRO) was also evaluated in a Phase 4 study in patients with polyneuropathy of hATTR amyloidosis due to a T60A or V122I variant.

The data were presented in September 2022 at the 18 th International Symposium on Amyloidosis.

Patisiran – ATTR Amyloidosis with Cardiomyopathy

Patisiran has received Orphan Drug Designations in the U.S., EU and Japan;

specific Orphan Drug Designations vary by country/region.

Patisiran is being investigated in patients with ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy in the ongoing APOLLO-B Phase 3 study.

In December 2022, we submitted an sNDA to the FDA for ONPATTRO for the treatment cardiomyopathy of ATTR amyloidosis based on the positive results from the APOLLO-B Phase 3 study.

In February 2023, the sNDA was accepted for filing and the FDA set an action date of October 8, 2023 under the PDUFA.

An sNDA submission is also planned in Brazil in 2023, however, we do not plan to pursue label expansion in other regions.

APOLLO-B Phase 3 Study

In September 2019, we initiated APOLLO-B, a randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of patisiran in patients in ATTR amyloidosis patients with cardiomyopathy.

The study enrolled 360 adult patients with confirmed cardiomyopathy and medical history of symptomatic heart failure due to ATTR amyloidosis, with enrollment completed in the second quarter of 2021.

Patients were randomized 1:1 to patisiran or placebo.

Concomitant use of on-label commercially available tafamidis is not prohibited, but is capped at 30 percent at baseline.

After 12-months of treatment, the primary endpoint of change from baseline in six-minute walk test will be evaluated, as well as other key secondary and exploratory endpoints.

Topline results are expected in mid-2022.

Vutrisiran – ATTR Amyloidosis and Stargardt Disease

Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic targeting TTR in development for the treatment of ATTR amyloidosis (wild-type or hereditary).

It is designed to target and silence TTR mRNA, thereby blocking the production of wild-type and mutant TTR protein before it is made, in the liver.

Quarterly, and potentially biannual, administration of vutrisiran may help to reduce the deposition and facilitate the clearance of TTR amyloid deposits in tissues like the nerves, heart and gastrointestinal tract;

this reduction and clearance may potentially restore function.

In April 2021, we reported positive 9-month results from our HELIOS-A Phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy, and based on these positive data, we submitted an NDA with the FDA for the approval of vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

In June 2021, the FDA accepted our NDA submission for review for vutrisiran, with an action date set for April 14, 2022 under the Prescription Drug User Fee Act, or PDUFA.

In September 2021, we submitted a marketing authorisation application, or MAA, to the EMA.

Vutrisiran is also under regulatory review by the Brazilian Health Regulatory Agency, or ANVISA and Pharmaceuticals and Medical Devices Agency, or PMDA, in Japan.

To date, vutrisiran has received both U.S.

and EU Orphan Drug Designations;

specific Orphan Drug Designations indications vary by country/region.

In September 2019, we initiated APOLLO-B, a randomized, double-blind, placebo-controlled Phase 3 study designed to evaluate the efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy.

The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 sites in 21 countries.

Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month treatment period.

Twenty-five percent of patients enrolled were receiving on-label commercially available tafamidis at baseline.

After 12 months of treatment, the primary endpoint of change from baseline in six-minute walk test, or 6-MWT, was evaluated, as well as other secondary and exploratory endpoints.

◦ Efficacy and Safety Results:

In August 2022, we announced positive topline results from the APOLLO-B study and in September 2022 we reported more fulsome results at the 18 th International Symposium on Amyloidosis, announcing that APOLLO-B met the primary endpoint of change from baseline in the 6-MWT at 12 months compared to placebo with a median difference of 14.7 meters (p-value 0.0162) favoring patisiran.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score, compared to placebo with least squares mean difference of 3.7 points (p-value 0.0397) favoring patisiran.

The study also included additional secondary composite outcomes endpoints.

A non-significant result (p-value 0.0574) was found on the composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo.

As a result, formal statistical testing was not performed on the final two composite endpoints.

During the 12 month placebo-controlled primary analysis period, patisiran also demonstrated an encouraging safety and tolerability profile in patients with ATTR amyloidosis with cardiomyopathy, including no cardiac safety concerns relative to placebo.

The majority of adverse events, or AEs, were mild or moderate in severity.

Treatment emergent AEs occurring in 5% or more patients in the patisiran group and observed at least 3% more commonly than in the placebo group included infusion-related reactions (12.2% vs 9.0%), arthralgia (7.7% vs 4.5%), and muscle spasms (6.6% vs 2.2%).

In the safety analysis there were 5 deaths (2.8%) observed in patisiran-treated patients and 8 deaths (4.5%) observed in the placebo group.

The safety profile in APOLLO-B was consistent with what was observed in our Phase 3 APOLLO study and in postmarketing use of ONPATTRO.

Based on these positive data, in December 2022, we submitted an sNDA to the FDA for ONPATTRO for the treatment of the cardiomyopathy of ATTR amyloidosis.

AMVUTTRA (vutrisiran)

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

It is designed to target and silence TTR mRNA, thereby reducing the production of TTR protein before it is made.

AMVUTTRA utilizes our ESC+ delivery platform, 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 the polyneuropathy of hATTR amyloidosis in adults based on positive 9-month results from the HELIOS-A Phase 3 study that evaluated the efficacy and safety of AMVUTTRA in patients with hATTR amyloidosis with polyneuropathy.

In September 2022, AMVUTTRA was approved in the EU and UK for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, and in Japan for the treatment of TTR type familial amyloidosis with polyneuropathy.

In December 2022, AMVUTTRA was approved in Brazil for the treatment of hATTR amyloidosis in adults.

Regulatory filings in other territories are currently under review and additional filings are planned for 2023.

HELIOS-A Phase 3 Study

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The primary endpoint is the mean change from baseline in the modified Neuropathy Impairment Score +7, or mNIS+7, at nine months as compared to the external placebo control arm of the previously completed APOLLO Phase 3 study of patisiran, upon which the approval of ONPATTRO was based.

The two secondary endpoints at nine months are changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy, or Norfolk QoL-DN, score and gait speed assessed by the timed 10-meter walk test, both compared to external placebo.

The two secondary endpoints at nine months were changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy, or Norfolk QoL-DN, score and gait speed assessed by the timed 10-meter walk test, both compared to external placebo.

Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months.

Additional secondary and exploratory endpoints were evaluated at 18 months.

In addition, following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they will receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

In addition, following the 18-month treatment period, all patients were eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they were randomized to receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

◦ Efficacy and Safety Results:

In April 2021, we reported positive 9-month results from our HELIOS-A Phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy.

The 9-month results achieved the study’s primary endpoint, with vutrisiran showing improvement in the mean change from baseline in mNIS+7 as compared to external placebo data from the APOLLO Phase 3 study of patisiran.

At 9 months, vutrisiran also met all secondary endpoints, demonstrating improvement in quality of life as assessed by the Norfolk QoL-DN instrument and improvement in gait speed as assessed by the timed 10-meter walk test, both compared to the external placebo group.

The majority of patients

experienced improvement in neuropathy and in quality of life, both relative to baseline, showing the potential for vutrisiran to reverse polyneuropathy manifestations of hATTR amyloidosis.

Vutrisiran also demonstrated an encouraging safety profile with no drug-related discontinuations or deaths.

There were two study discontinuations (1.6 percent) due to adverse events in the vutrisiran arm by month nine, both due to deaths, neither of which were considered related to study drug.

There were two serious adverse events, or SAEs, deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection.

Treatment emergent adverse events, or AEs, occurring in 10 percent or more patients included diarrhea, pain in extremity, fall and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with historical placebo.

Injection site reactions were reported in five patients (4.1 percent) and were all mild and transient.

There were no safety signals regarding hematology, renal function or liver function tests.

Based on these positive data, in April 2021, we submitted an NDA with the FDA for the approval of vutrisiran for the tr eatment of the polyneuropathy of hATTR amyloidosis in adults, with an action date under PDUFA of April 14, 2022.

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

In January 2022, we reported positive 18-month results from the HELIOS-A study.

At 18 months, the study met all secondary endpoints measured, including statistically significant improvements in neuropathy as measured by mNIS+7, quality of life, gait speed, nutritional status and overall disability, relative to external placebo data from the APOLLO Phase 3 study of patisiran.

Vutrisiran continued to demonstrate halting or reversal of polyneuropathy, with improvements in neuropathy impairment and quality of life relative to baseline.

The final secondary endpoint, reduction in serum TTR levels with vutrisiran, demonstrated non-inferiority relative to the within-study patisiran arm, as expected.

Vutrisiran achieved a rapid and sustained reduction of serum TTR at 18 months, with a mean reduction from baseline of 88 percent.

In addition, patients treated with vutrisiran showed improvements in exploratory endpoints, including the biomarker NT-proBNP and certain echocardiographic parameters, relative to placebo, and an improvement in technetium uptake relative to baseline in a majority of patients in a planned cohort, providing potential evidence for reduced cardiac amyloid burden and for vutrisiran to improve cardiac manifestations of disease.

Vutrisiran continued to demonstrate an encouraging safety and tolerability profile.

There were three study discontinuations (2.5 percent) due to AEs in the vutrisiran arm during the 18-month treatment period;

one due to a non-fatal event of heart failure and two due to deaths, neither of which was considered related to the study drug.

During the 18-month treatment period, there were two SAEs deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection.

The two deaths and the two related SAEs were previously reported in the 9-month topline results.

Treatment emergent AEs occurring in 10 percent or more patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia and dizziness;

with the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with external placebo.

Injection site reactions were reported in 5 patients (4.1 percent) and were all mild and transient.

There were no hepatic safety concerns.

At 9 months, vutrisiran met primary and all secondary endpoints, with statistically significant improvements in neuropathy, quality of life (QoL), and gait speed, relative to placebo.

In February 2023, we reported topline results from the HELIOS-A randomized treatment extension, or RTE, portion of the study, through month 9.

Non-inferiority of the 50mg biannual regimen (vs 25mg quarterly) was established, as demonstrated by mean serum TTR reduction over 9 months.

Vutrisiran also continued to demonstrate an acceptable safety profile.

In the RTE study there were 6 deaths, of which 5 occurred on the 50 mg biannual arm and 1 occurred on the 25 mg quarterly arm, after the patient dropped out of the study.

None was considered related to study drug.

We also announced a strategic decision not to pursue regulatory submissions with the biannual dosing data given the dynamics of serum TTR recovery observed toward the end of the biannual dosing interval, the strong commercial performance of the existing vutrisiran 25mg quarterly regimen, and the opportunity to focus on continued innovation with ALN-TTRsc04.

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 study.

HELIOS-B Phase 3 Study

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Enrollment was completed significantly ahead of schedule, with 655 ATTR amyloidosis patients across 123 activated sites in 33 countries.

In October 2022, we announced that we do not plan to conduct the optional interim analysis for the HELIOS-B Phase 3 trial.

Topline results from the HELIOS-B study are expected in early 2024.

Potential Opportunity in Stargardt Disease

Based on the data from the HELIOS-A Phase 3 study, we believe there may be a near term opportunity for vutrisiran as an investigational RNAi therapeutic for the potential treatment of Stargardt Disease.

Stargardt Disease is a rare, inherited form of blindness caused by accumulation of toxic vitamin A metabolites in the retina which leads to central vision loss.

It is a leading cause of blindness from inherited retinal diseases in children, and almost all people affected by this disease become legally blind as adults.

Stargardt Disease is estimated to affect about 65,000 people in the U.S.

and EU (incidence of approximately 1 in 8,000-10,000), with high unmet medical need and no approved treatments.

TTR functions as a transporter of vitamin A in the blood.

It forms a complex with retinol binding protein, or RBP4, to deliver vitamin A to extrahepatic tissues, including the eye.

In healthy individuals, the protein ABCA4 acts as a transporter for vitamin A in the eye, ensuring that toxic vitamin A metabolites do not accumulate in the retina.

In contrast, patients with Stargardt Disease have an inherited defect in ABCA4.

As a result, toxic vitamin A metabolites accumulate in the retina as lipofuscin, triggering degeneration of macular rods and cones, leading to central vision loss and eventually blindness in most patients.

We believe that RNAi-mediated serum TTR reduction with vutrisiran has the potential to reduce RBP4-mediated delivery of vitamin A to the eye and could prevent lipofuscin accumulation and resulting macular damage.

Data from the HELIOS-A Phase 3 study of vutrisiran have demonstrated a high correlation between serum TTR reduction and vitamin A reduction, supporting the therapeutic hypothesis.

We plan to initiate a Phase 3 study in patients with Stargardt Disease in late 2022, following discussions with health agencies.

Vutrisiran – Stargardt Disease

In late 2022, we announced that we would not initiate a Phase 3 study of vutrisiran in Stargardt Disease by year-end, as previously communicated, as we continue to evaluate the impact of the Inflation Reduction Act.

Our Other Marketed Products

GIVLAARI (givosiran) — Acute Hepatic Porphyria (AHP)

GIVLAARI (givosiran) is our second approved RNAi therapeutic and the world’s first-ever 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.

Our RNAi therapeutic, GIVLAARI (givosiran), is the world’s first-ever 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.

In the U.S., GIVLAARI (givosiran) injection for subcutaneous use is approved for the treatment of adults with AHP.

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GIVLAARI was r eviewed under accelerated assessment by the EMA and had previously been granted PRIME and Orphan Drug Designations in the EU.

We received additional marketing authorizations for GIVLAARI for the treatment of AHP in adults in Brazil, Canada, and marketing authorizations for GIVLAARI for the treatment of AHP in adults and adolescents in Japan, Argentina and Switzerland.

We have also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Israel, Taiwan, and Colombia and additional regulatory filings are pending or planned in 2022 and beyond.

We have also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Israel, Colombia and Australia, and additional regulatory filings are pending or planned in 2023 and beyond.

AHP refers to a family of ultra-rare, genetic diseases characterized by potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life.

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

Our third approved RNAi therapeutic, OXLUMO, is an RNAi therapeutic targeting hydroxyacid oxidase 1, or HAO1, for the treatment of PH1.

OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1, or HAO1, developed for the treatment of PH1.

HAO1 encodes glycolate oxidase, or GO, an enzyme upstream of the disease-causing defect in PH1.

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With the approval of OXLUMO, the FDA granted us a pediatric rare disease priority review voucher that entitles us to designate a single new drug application to qualify for a priority review in the future.

In June 2021, we received marketing authorization approval for OXLUMO in Brazil for the treatment of PH1 in both children and adult patients, and regulatory filings in other territories are pending and additional filings are planned for 2022 and beyond.

During 2021 and 2022, we received additional marketing authorizations for OXLUMO in Brazil, the UK, Switzerland, Canada and Israel, and regulatory filings in other territories are pending and additional filings are planned for 2023 and beyond.

PH1 is an ultra-rare genetic disease that affects an estimated one to three individuals per million in the U.S.

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and EU were based on positive results from both the ILLUMINATE-A and ILLUMINATE-B Phase 3 pivotal studies of lumasiran in patients with PH1.

We are also conducting ILLUMINATE-C – a global Phase 3 study of lumasiran in PH1 patients of all ages with advanced PH1.

In July 2021, we reported positive topline results from the ILLUMINATE-C study, and based on those positive results, in December 2021, we submitted a supplemental NDA to the FDA and Type II Filing Variation to the EMA to support label expansion for OXLUMO for the treatment of advanced PH1.

ILLUMINATE-C is a single-arm, open-label, multinational Phase 3 study evaluating the safety and efficacy of lumasiran in PH1 patients of all ages with severe renal impairment (eGFR ≤ 45 mL/min/1.73m 2 or elevated serum creatinine for patients <12 months of age).

The study is being conducted at 13 study sites across 10 countries around the world.

In December 2020, we completed enrollment in this study.

Cohort A enrolled six patients with advanced PH1 who do not yet require dialysis and Cohort B enrolled 15 patients who are hemodialysis-dependent.

The dosing regimen is based on weight with three monthly starting doses followed by ongoing monthly or quarterly doses.

The primary efficacy endpoint for Cohort A was the percent change in plasma oxalate, or POx, from baseline to month six, and the primary endpoint for Cohort B was the percent change in pre-dialysis POx from baseline to month six.

Key secondary endpoints are designed to evaluate additional measures of POx and changes in urinary oxalate, and quality of life assessments.

Kidney function, frequency and mode of dialysis, frequency of kidney stone events, and measures of systemic oxalosis, including clinical manifestations will also be evaluated in the extension period of the study.

• Efficacy and Safety Results:

At six months, treatment with lumasiran in Cohorts A and B, respectively, led to 33 percent and 42 percent mean reductions in POx and predialysis POx from baseline to month six.

Reduction in POx was evident by month one and persisted through the end of the 6-month primary analysis period.

Lumasiran also demonstrated positive results across secondary endpoints, including patients in Cohort B achieving substantial reductions in POx area under the curve 0-24h between dialysis sessions from baseline to month six, and lumasiran demonstrating consistent reductions across all measures of urinary oxalate in Cohort A.

In addition, a similar magnitude of plasma glycolate increase, an exploratory endpoint in Cohorts A and B, was observed as compared to previously completed studies in patients with relatively preserved kidney function (ILLUMINATE-A and ILLUMINATE-B), suggesting similar pharmacodynamics of lumasiran regardless of kidney function.

Mild and transient injection site reactions were the most common drug-related AE reported in 24 percent (5/21) of patients.

There were no deaths and no serious or severe AEs related to lumasiran.

Furthermore, there were no treatment discontinuations or study withdrawals.

In addition to our ILLUMINATE program, we are evaluating the safety and efficacy of lumasiran in patients with recurrent kidney stone disease in a proof-of-concept Phase 2 study which was initiated in December 2021.

The Phase 2 trial is a randomized, double-blind, placebo-controlled study to evaluate the safety, efficacy, pharmacodynamics, and pharmacokinetics of lumasiran administered subcutaneously in patients with recurrent calcium oxalate kidney stone disease and elevated urinary oxalate levels.

The global, multicenter trial is expected to enroll 120 adults with a documented diagnosis of recurrent calcium oxalate kidney stone disease, based on two or more stone events within five years prior to screening, and whose 24-hour urinary oxalate levels are greater than the upper limit of normal.

Study participants will be randomized 1:1:1 to receive either placebo or lumasiran at 567 mg or 284 mg on Day 1, Month 3, and Month 9 of a 15-Month double-blind treatment period that includes a six-month primary analysis period followed by a nine-month treatment extension period.

The primary endpoint of the Phase 2 study is the percent change in 24-hour urinary oxalate after six months of treatment.

Key secondary endpoints include the percentage of patients who achieve a 20 percent or greater reduction in 24-hour urinary oxalate and percent change in urinary calcium oxalate supersaturation after six months of treatment.

Topline results are expected in mid-2023.

Lumasiran was also evaluated in ILLUMINATE-C – a global Phase 3 study in PH1 patients of all ages with advanced PH1.

Based on the positive six-month efficacy and safety results of this study, in October 2022, we announced that the FDA approved a label expansion for OXLUMO, which is now indicated for the treatment of PH1 to lower urinary oxalate and plasma oxalate levels in pediatric and adult patients.

In addition, the CHMP of the EMA delivered a positive opinion recommending variation to the marketing authorization of OXLUMO based on ILLUMINATE-C data from patients with advanced PH1 in September 2022.

In December 2022, we announced that we discontinued the proof-of-concept Phase 2 study of lumasiran in patients with recurrent kidney stone disease that was initiated in December 2021 due to lower than anticipated levels of elevated urinary oxalate in that patient population.

Leqvio (inclisiran) — Hypercholesterolemia

Leqvio, our fourth approved RNAi therapeutic, developed and commercialized by our partner, Novartis, is the first and only siRNA therapy (or RNAi therapeutic) to lower low-density lipoprotein cholesterol (also known as “bad cholesterol” or LDL-C), and is the first RNAi therapeutic approved for a highly prevalent disease.

Our RNAi therapeutic Leqvio, developed and commercialized by our partner, Novartis, is the first and only siRNA therapy (or RNAi therapeutic) to lower low-density lipoprotein cholesterol (also known as “bad cholesterol” or LDL-C), and is the first RNAi therapeutic approved for a highly 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.

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for the treatment of homozygous familial hypercholesterolemia, or HoFH.

As of January 2022, Leqvio has been approved in more than 50 countries.

As of the end of January 2023, Leqvio has been approved in 70 countries.

Approximately 100 million people worldwide are treated with lipid lowering therapies, predominantly statins, to reduce LDL-C and the associated risk of death, nonfatal myocardial infarction and nonfatal stroke or associated events.

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This Phase 3 program represents the largest clinical program conducted to date for an investigational RNAi therapeutic program.

Two additional Phase 3 cardiovascular outcomes trials, ORION-4 and the Novartis initiated VICTORION-2-PREVENT are currently ongoing.

Most recently, in November 2022, Novartis announced results from its Phase 2 open-label extension ORION-3 trial, which showed that Leqvio provides effective and sustained LDL-C reduction over a four-year period in patients with either ASCVD or ASCVD risk equivalent, and elevated LDL-C despite maximally tolerated statin therapy.

Multiple additional Phase 3 trials are currently ongoing, including cardiovascular outcomes trials, ORION-4 and the Novartis initiated VICTORION-2-PREVENT.

Additional Late-Stage Clinical Development Programs

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There are approximately 200,000 people living with hemophilia A and hemophilia B worldwide.

Standard treatment for people with hemophilia currently involves replacement of the deficient clotting factor either as prophylaxis or on-demand therapy, which can lead to a temporary restoration of thrombin generation capacity.

Standard treatment for people with hemophilia currently involves replacement of the deficient clotting factor either as prophylaxis or on-demand

therapy, which can lead to a temporary restoration of thrombin generation capacity.

However, with current factor replacement treatments people with hemophilia are at risk of developing neutralizing antibodies, or inhibitors, to their replacement factor, a very serious complication affecting as many as one third of people with severe hemophilia A and a smaller fraction of people with hemophilia B.

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

In October 2020, Sanofi announced that it voluntarily paused dosing in all ongoing fitusiran clinical studies to assess reports of non-fatal thrombotic events in patients

participating in the ATLAS Phase 3 program.

In October 2020, Sanofi announced that it voluntarily paused dosing in all ongoing fitusiran clinical studies to assess reports of non-fatal thrombotic events in patients participating in the ATLAS Phase 3 program.

Following an assessment of available data and alignment with the FDA, in December 2020, Sanofi announced that it would resume fitusiran dosing in ongoing adolescent and adult clinical studies.

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and EU Orphan Drug Designations for the treatment of hemophilia A and B.

In December 2021, Sanofi presented positive results from the ATLAS-A/B and ATLAS-INH Phase 3 studies of fitusiran.

ATLAS-A/B is a Phase 3 randomized, open-label study investigating the efficacy and safety of fitusiran in males ≥12 years with severe hemophilia A or B without inhibitors who had previously been treated with on-demand factor therapy.

Study participants (n=120) were randomized 2:1 to receive either once-monthly 80mg subcutaneous fitusiran prophylaxis or on-demand factor therapy for bleeding episodes.

The primary endpoint is annualized bleeding rate, or ABR.

• Efficacy and Safety Results:

All key primary and secondary endpoints were met in ATLAS-A/B.

Once-monthly 80mg subcutaneous fitusiran prophylaxis demonstrated a significant reduction in annualized bleeding rate, annualized spontaneous bleeding rate, and annualized joint bleeding rate (all ~90 percent) in people with severe hemophilia A or B without inhibitors compared with on demand treatment.

This reduction in bleeding was associated with a meaningful improvement in health-related quality of life.

Reported treatment emergent SAEs were generally consistent with previously identified risks of fitusiran.

Treatment emergent SAEs in the fitusiran arm included cholelithiasis (two patients, 2.5 percent), cholecystitis, lower respiratory tract infection, and asthma (one patient each, 1.3 percent).

In the fitusiran arm, two patients (2.5 percent) experienced Treatment emergent AEs that resulted in fitusiran discontinuation (cholecystitis and increased alanine aminotransferase).

No treatment emergent AEs of thrombosis and no fatal treatment emergent AEs were reported.

The ATLAS-INH study is a randomized, open-label Phase 3 study designed to evaluate the safety and efficacy of fitusiran in males ≥12 years with severe hemophilia A or B with inhibitors to factor VIII or IX.

Study participants (n=57) receiving on-demand treatment with bypassing agents, or BPA, were randomized in a 2:1 ratio to receive once-monthly 80mg subcutaneous fitusiran prophylaxis or continue with on-demand BPA.

The primary endpoint is ABR.

Sanofi is currently investigating the efficacy and safety of fitusiran under an amended protocol which includes lower doses and an extended dosing regimen in all ongoing adult and adolescent studies.

• Efficacy and Safety Results:

In ATLAS-INH, 80mg monthly subcutaneous fitusiran significantly reduced bleeding with a median ABR of zero and significant proportion of people with zero bleeds, resulting in a meaningful improvement in health-related quality of life.

Reported treatment emergent SAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia A or B with inhibitors, or with the previously identified risks of fitusiran.

All treatment emergent SAEs were reported in one patient each;

in the fitusiran prophylaxis arm these included events of device related infection, hematuria, spinal vascular disorder, subclavian vein thrombosis, thrombosis, acute cholecystitis, chronic cholecystitis and asymptomatic COVID-19.

One patient (2.4%) in the fitusiran arm experienced treatment emergent AEs that resulted in study drug discontinuation (spinal vascular disorder and thrombosis).

There were no fatal treatment emergent AEs reported.

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

In January 2018, we and Sanofi entered into an amendment to our 2014 collaboration, as well as the ALN-AT3 Global License Terms, which as further amended in April 2019 are referred to as the A&R AT3 License Terms, pursuant to which Sanofi has global rights to develop and commercialize fitusiran and any back-up products.

The 2014 Sanofi collaboration, as amended, as well as the A&R AT3 License Terms, are described below under the heading “Strategic Alliances and Collaborations.”

Early-Stage Clinical Development Programs

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.

The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in life-threatening complications in a broad range of human diseases including paroxysmal nocturnal hemoglobinuria, amongst others.

Cemdisiran is currently being advanced by us as a monotherapy, and topline results from our Phase 2 clinical trial of cemdisiran in patients with IgA nephropathy are expected in early 2022.

Cemdisiran is also being evaluated by our partner, Regeneron, in combination with Regeneron’s pozelimab (REGN3918), an anti-C5 monoclonal antibody.

In late 2021,

Regeneron initiated a Phase 3 study of cemdisiran and pozelimab combination in myasthenia gravis, in addition to multiple Phase 2 studies and a Phase 3 study in paroxysmal nocturnal hemoglobinuria.

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 immunoglobulin A nephropathy, or IgAN, myasthenia gravis, and paroxysmal nocturnal hemoglobinuria, amongst others.

We are currently advancing cemdisiran as a monotherapy for the treatment of IgAN, and in June 2022, we announced positive topline results from the Phase 2 study of cemdisiran in adult patients with IgAN.

In November 2022, Regeneron exercised its right to opt-out of the collaboration agreement on the cemdisiran monotherapy program.

We continue to perform our obligations under the collaboration agreement and are evaluating options for further development in this disease.

Cemdisiran is also being evaluated by our partner, Regeneron, in combination with Regeneron’s pozelimab (REGN3918), an anti-C5 monoclonal antibody in Phase 3 studies in myasthenia gravis and paroxysmal nocturnal hemoglobinuria.

Regeneron's decision to opt-out of the collaboration agreement on the monotherapy program has no impact on Regeneron’s ongoing efforts under a separate license agreement to develop the cemdisiran and pozelimab combination therapy.

Early-Stage Clinical Development Programs

Zilebesiran (formerly ALN-AGT) — Hypertension

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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.

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.

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, though 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.

More than one billion people worldwide live with hypertension.

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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, difficult-to-treat and resistant hypertension, and in patients with high cardiovascular risk.

In November 2021, we reported positive interim data from the ongoing Phase 1 study of zilebesiran, and also initiated the KARDIA Phase 2 clinical studies for zilebesiran.

KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually, whereas KARDIA-2 will evaluate the safety and efficacy of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by standard of care antihypertensive medications.

ALN-HBV02 (VIR-2218) – Chronic Hepatitis B Virus Infection

KARDIA-1 and KARDIA-2, Phase 2 clinical studies for zilebesiran were initiated in June and November 2021, respectively.

KARDIA-1 is designed to evaluate zilebesiran as a monotherapy across different doses administered quarterly and biannually, whereas KARDIA-2 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 January 2023, we announced that we achieved full enrollment of patients in the KARDIA-1 Phase 2 study, with topline results anticipated in mid-2023.

We are continuing to enroll patients in the KARDIA-2 study, and expect to complete enrollment in early 2023 and report topline results at or around year-end 2023.

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

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 collaborators at Vir.

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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 VIR-2218 are currently being investigated in an ongoing Phase 2 trial.

In addition, in 2021, Vir continued to progress a Phase 2 combination trial of VIR-2218 with pegylated interferon-alpha to evaluate the potential for the combination to result in a functional cure for HBV.

VIR-2218 is also being explored in additional clinical trials with collaborators of Vir.

Vir plans to report additional results from the Phase 2 program in middle and late 2022.

The safety and efficacy of ALN-HBV02 are currently being investigated in an ongoing Phase 2 trial, and in June 2022, Vir reported preliminary results that demonstrated that a six-dose regimen provided greater and more durable reductions in hepatitis B surface antigen than a two-dose regimen, with all participants achieving a >1 log10 IU/mL reduction during the trial.

In addition, in 2022, Vir continued to progress a Phase 2 combination trial of ALN-HBV02 with pegylated interferon-alpha, as well as a triple combination with VIR-3434 and interferon, each to evaluate the potential for the combination to result in a functional cure of HBV.

ALN-HBV02 is also being explored in a Phase 2 study evaluating ALN-HBV-02 and VIR-3434 as monotherapy and in combination for the treatment of people living with chronic hepatitis D virus, or HDV.

Vir plans to report additional results from the Phase 2 studies in HBV in 2023, and data from the Phase 2 study in HDV is expected in the second half of 2023.

ALN-HBV02 is also being investigated in additional clinical trials with collaborators of Vir.

ALN-HSD – Non-alcoholic Steatohepatitis

ALN-HSD is a subcutaneously administered, investigational RNAi therapeutic targeting HSD17B13 in development in collaboration with our partner, Regeneron, for the treatment of NASH.

NASH is a highly prevalent chronic liver disease characterized by the accumulation fat within hepatocytes, hepatocyte injury, and hepatic inflammation, which can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma.

NASH is a highly prevalent chronic liver disease in which inflammation and liver cell injury are caused by accumulation of hepatic fat.

NASH is a subset of a group of conditions called nonalcoholic fatty liver disease that can lead to progressive fibrosis, cirrhosis, and hepatocellular carcinoma.

Comorbidities include obesity, metabolic syndrome, and type 2 diabetes.

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live with NASH, with prevalence of the disease increasing due to rising rates of obesity.

NASH is projected to be the leading indication for liver transplants in developed countries within the next several years.

NASH is projected to be the leading indication for liver transplants in developed countries within the next 10 years.

There are currently no approved medical therapies for NASH.

In 2021, we advanced ALN-HSD into Part B of the ongoing Phase 1 study in patients with NASH .

In September 2022, we, in collaboration with our partner, Regeneron, reported on positive results from a Phase 1 study of ALN-HSD in healthy volunteers and patients with NASH.

In December 2022, we further elaborated on these results demonstrating robust target engagement and safety profile that supports continued clinical development.

Regeneron will be leading continued development of the ALN-HSD program from Phase 2 onward.

ALN-APP – Alzheimer’s Disease and Cerebral Amyloid Angiopathy

ALN-APP is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein, or APP, in development in collaboration with Regeneron for the treatment of Alzheimer’s disease, or AD, and cerebral amyloid angiopathy.

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

ALN-APP 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 and reduce the intraneuronal APP cleavage products that trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in AD.

ALN-APP is the first program utilizing our C16 conjugate technology, which enables enhanced delivery to cells in the CNS.

In December 2021, we announced submission of our CTA to The Medicines and Healthcare Products Regulatory Agency, or MHRA, in the United Kingdom to initiate a Phase 1 study of ALN-APP, with a plan to initiate the Phase 1 study in patients with early-onset AD in early 2022, upon obtaining MHRA approval.

We expect to report topline Phase 1 results in late 2022.

ALN-XDH - Gout

ALN-XDH is an investigational, subcutaneously administered RNAi therapeutic targeting xanthine dehydrogenase, or XDH, in development for the treatment of gout.

Reducing XDH with an RNAi therapeutic is expected to result in potent urate lowering, essential in preventing gout-associated flares and managing the disease.

ALN-XDH utilizes our ESC+ GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index.

In December 2021, we announced submission of our CTA to the MHRA in the United Kingdom to initiate a Phase 1/2 study of ALN-XDH in healthy volunteers and in patients with gout in early 2022, upon obtaining MHRA approval.

We expect to report topline Phase 1 results in late 2022.

Reducing APP protein production is expected to reduce the secretion of Aβ peptides that aggregate into extracellular amyloid deposits in AD and CAA and reduce the intraneuronal APP cleavage products that trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in AD.

ALN-APP 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 study of ALN-APP in patients with early-onset AD, and in October 2022, we announced that enrollment and dose escalation continue in the Phase 1 study, and initial results are expected in early 2023.

Additional Early-Stage and Pre-clinical Programs

In addition to the programs listed above, we are also advancing other earlier-stage pipeline programs and plan to file two to four investigational new drug applications, or INDs, or CTAs from our organic product engine during 2022.

We also intend to continue to build on our progress with extrahepatic delivery during 2022, advancing our eye and CNS programs under our collaboration with Regeneron, as well as continuing to advance other extrahepatic delivery initiatives.

In addition to the programs listed above, we are also advancing other earlier-stage pipeline programs, including ALN-TTRsc04 for ATTR amyloidosis, ALN-KHK for Type 2 diabetes mellitus and ALN-PNP for NASH, and filed CTAs for each program during 2022.

During 2023, we plan to file two to four 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 2023,

advancing our eye and CNS programs under our collaboration with Regeneron, as well as continuing to advance other extrahepatic delivery initiatives.

Our Collaboration and Licensing Strategy

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In July 2021, we notified Vir that we elected to discontinue ALN-COV, in development for the treatment of COVID-19, and all other COVID-19 research and development activities, based on a portfolio prioritization in view of the availability of highly effective vaccines and alternative treatment options.

Following such discontinuation of COVID-19 related activities, we have no further obligations to work on the COVID-related targets and Vir will have no further rights to such targets under our exclusive licensing agreement.

Following such discontinuation of COVID-19 related activities, we have no further obligations to work on the COVID-related targets and Vir has no further rights to such targets under our exclusive licensing agreement.

With respect to our Genetic Medicine pipeline, 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 have the exclusive right to pursue the further global development and commercialization of all TTR products, including ONPATTRO, vutrisiran and any back-up products, and the ALN-AT3 Global License Terms, referred to as the AT3 License Terms, under which Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.

In April 2019, we and Sanofi agreed to further amend the 2014 Sanofi

collaboration to conclude the research and option phase and to amend and restate the AT3 License Terms to modify certain of the business terms.

We will continue to evaluate and explore partnership opportunities through collaboration and licensing arrangements, and may enter into new collaborations to advance certain products or disease areas.

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 have the exclusive right to pursue the further global development and commercialization of all TTR products, including ONPATTRO, AMVUTTRA and any back-up products, and the ALN-AT3 Global License Terms, referred to as the AT3 License Terms, under which Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.

In April 2019, we and Sanofi agreed to further amend the 2014 Sanofi collaboration to conclude the research and option phase and to amend and restate the AT3 License Terms to modify certain of the business terms.

We intend to continue to evaluate and explore partnership opportunities through collaboration and licensing arrangements, and may enter into new collaborations to advance certain products or disease areas.

For example, in January 2022, we announced that we and Novartis agreed to collaborate on the discovery and development of an siRNA-based targeted therapy to restore functional liver cells in patients with end-stage liver diseases.

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We have formed, and intend to continue to form, strategic alliances and collaborations to gain access to the financial, technical, clinical and commercial resources necessary to develop and market RNAi therapeutics.

We expect these alliances and 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 alliances and

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

Below is a brief description of our key strategic alliances, financial collaboration and license agreements.

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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.

In connection with the Regeneron Master Agreement, we and Regeneron entered into (i) a binding co-co collaboration term sheet covering the continued development of cemdisiran, our C5 siRNA currently in Phase 2 development for C5 complement-mediated diseases, as a monotherapy and (ii) a binding license term sheet to evaluate anti-C5 antibody-siRNA combinations for C5 complement-mediated diseases including evaluating the combination of Regeneron’s pozelimab (REGN3918), currently in Phase 3 development, and cemdisiran.

In connection with the Regeneron Master Agreement, we and Regeneron entered into (i) a binding co-co collaboration term sheet covering the continued development of cemdisiran, our C5 siRNA currently in Phase 2 development for IgAN as a monotherapy and (ii) a binding license term sheet to evaluate anti-C5 antibody-siRNA combinations for C5 complement-mediated diseases including evaluating the combination of Regeneron’s pozelimab (REGN3918), currently in Phase 3 development, and cemdisiran.

The C5 co-co collaboration and license agreements were executed in August 2019.

Under the terms of the Regeneron Collaboration, we will work exclusively with Regeneron to discover RNAi therapeutics for eye and CNS diseases for an initial five-year research period, subject to extension for up to an additional two years, or the Initial Research Term.

The Regeneron Collaboration also covers a select number of RNAi therapeutic programs designed to target genes expressed in the liver, including our previously-announced collaboration with Regeneron to identify RNAi therapeutics for the chronic liver disease NASH.

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With respect to the programs directed to C5 complement-mediated diseases, we retain control of cemdisiran monotherapy development, and Regeneron is leading combination product development.

Under the C5 co-co collaboration agreement, we and Regeneron equally share costs and potential future profits on any monotherapy program.

Pursuant to the C5 co-co collaboration agreement, Regeneron notified us in November 2022 of its decision to exercise its right to opt-out of the further development and commercialization of cemdisiran monotherapy.

As a result, Regeneron no longer shares costs and potential future profits on any monotherapy program with us and we are solely responsible for all development and commercialization costs and Regeneron will be eligible to receive tiered double-digit royalties on net sales.

Under the C5 license agreement, for cemdisiran to be used as part of a combination product, Regeneron is solely responsible for all development and commercialization costs and we will receive low double-digit royalties and commercial milestones of up to $325.0 million on any potential combination product sales.

The C5 license agreement is not impacted by Regeneron’s opt-out under the C5 co-co collaboration agreement.

We and Regeneron plan to advance programs directed to up to 30 targets under the Regeneron Collaboration during the Initial Research Term.

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In connection and simultaneously with entering into the 2018 amendment to the 2014 Sanofi collaboration, we and Sanofi also entered into the Exclusive TTR License and the AT3 License Terms.

As a result, we have the exclusive right to pursue the further global development and commercialization of all TTR products, including ONPATTRO, vutrisiran and any back-up products, and Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.

Under the 2018 amendment and 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 as of the effective date of the Exclusive TTR License, (ii) tiered royalties of 15% to 30% based on global annual net sales of vutrisiran (consistent with the royalties due to us from Sanofi on fitusiran), and (iii) tiered royalties of up to 15% based on global annual net sales of any back-up products, in each case by us, our affiliates and our sublicensees.

As a result, we have the exclusive right to pursue the further global development and commercialization of all TTR products, including ONPATTRO, AMVUTTRA and any back-up products, and Sanofi has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.

the royalties due to us from Sanofi on fitusiran), and (iii) tiered royalties of up to 15% based on global annual net sales of any back-up products, in each case by us, our affiliates and our sublicensees.

The collaboration amendment entered into in April 2019 described below made no changes to the terms described in clauses (i)-(iii) above, which remain in full force and effect.

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For more information regarding the Vir Agreement, including its ongoing financial and accounting impact on our business, please read Note 4, Net Revenues from Collaborations, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this Annual Report on Form 10-K.

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In April 2020, we and Dicerna (acquired by Novo Nordisk in December 2021) formed a development and commercialization collaboration on investigational RNAi therapeutics for the treatment of alpha-1 liver disease.

Under the development and commercialization agreement entered into between the parties, our ALN-AAT02 and Dicerna’s belcesiran (formerly DCR-A1AT), investigational RNAi therapeutics, each in Phase 1/2 development, will be explored for the treatment of alpha-1 liver disease.

Under the development and commercialization agreement entered into between the parties, our ALN-AAT02 and

Dicerna’s belcesiran (formerly DCR-A1AT), investigational RNAi therapeutics, each in Phase 1/2 development, will be explored for the treatment of alpha-1 liver disease.

In addition, in April 2020, we and Dicerna entered into a Patent Cross-License Agreement, pursuant to which each party agreed to cross-license its respective intellectual property related to our lumasiran program and Dicerna’s nedosiran program, each for the treatment of PH.

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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.

In turn, in exchange for option fees, and future milestone

and royalty payments from Ionis for RNAi programs that incorporate certain of our intellectual property, we non-exclusively licensed to Ionis our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, single stranded RNAi therapeutics and to research double-stranded RNAi compounds.

In turn, in exchange for option fees, and future milestone and royalty payments from Ionis for RNAi programs that incorporate certain of our intellectual property, we non-exclusively licensed to Ionis our patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, single stranded RNAi therapeutics and to research double-stranded RNAi compounds.

Ionis also received a license to develop and commercialize double-stranded RNAi drugs targeting a limited number of therapeutic targets on a non-exclusive basis.

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We typically obtain protection of our product candidates with patents and patent applications directed to compositions of matter and their uses.

Below is a summary of granted patents that we own or control covering products marketed by us in the U.S.

Below is a summary of selected granted patents that we own or control covering products marketed by us in the U.S.

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

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8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam

9370581 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam

9399775 United States Compositions of Matter & Methods of Use 11/16/2032 Alnylam

10131907 United States Compositions of Matter & Methods of Use 8/24/2028 Alnylam

10208307 United States Compositions of Matter & Methods of Use 7/28/2036 Alnylam

10570391 United States Compositions of Matter 11/16/2032 Alnylam

10612024 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam

10683501 United States Methods of Use 7/28/2036 Alnylam

10806791 United States Compositions of Matter 12/4/2028 Alnylam

11286486 United States Methods of Use 7/28/2036 Alnylam

11401517 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam

3301177 Europe Compositions of Matter & Methods of Use 11/16/2032 Alnylam

3329002 Europe Compositions of Matter & Methods of Use 7/28/2036 Alnylam

_________________________________________

* Shown here are selected granted patents in the U.S.

Additional granted and pending patents in the U.S., Europe and other countries may be available.

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

In addition, in connection with our FDA approval on June 13, 2022, the FDA granted AMVUTTRA 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.

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

8106022 United States Compositions of Matter & Methods of Use 12/12/2029 Alnylam

8828956 United States Compositions of Matter & Methods of Use 12/4/2028 Alnylam

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

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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 ® , Alnylam Pharmaceuticals ® and the Alnylam logo, as well as ONPATTRO ® and the ONPATTRO 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 ONPATTRO ® and the ONPATTRO logo, AMVUTTRA ® and the AMVUTTRA logo, GIVLAARI ® and the GIVLAARI logo and OXLUMO ® and the OXLUMO logo.

The pharmaceutical marketplace is extremely competitive, with hundreds of companies competing to discover, develop and market new drugs.

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the goal of treating patients not with synthetic siRNAs but with synthetic, exogenously-introduced genes designed to produce siRNA-like molecules within cells.

Companies working on chemically synthesized siRNAs include Marina Biotech, Inc., or Marina, Arrowhead Pharmaceuticals, Inc., or Arrowhead, and its collaborators Takeda Pharmaceutical Company Ltd., or Takeda, Janssen Pharmaceutics, Inc.

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

or Janssen, Horizon Therapeutics PLC, or Horizon, GlaxoSmithKline PLC, or GSK, and Amgen Inc., or Amgen, Quark Pharmaceuticals, Inc., or Quark, F.

Hoffmann-La Roche Ltd, or Roche, Silence Therapeutics plc, or Silence, and its collaborators, AstraZeneca plc, or AstraZeneca, Jiangsu Hansoh Pharmaceuticals Group Co., and Mallinckrodt plc, Arbutus Biopharma Corp., or Arbutus, Sylentis, S.A.U., or Sylentis, Novo Nordisk and its collaborators, Boehringer Ingelheim, AstraZeneca plc, or AstraZeneca, and Eli Lilly and Company, WAVE Life Sciences Ltd., or WAVE, Silenseed Ltd., Ascletis Pharma Inc., Biomics Biopharma, Avidity Biosciences Inc., Dyne Therapeutics Inc., or Dyne, Atalanta Therapeutics Inc., Sirnaomics Inc., OliX Pharmaceuticals Inc., Phio Pharmaceuticals, BioPath Holding Inc., Arcturus Therapeutics, Inc., or Arcturus, and Ascletis Pharma Inc.

Hoffmann-La Roche Ltd, or Roche, Silence Therapeutics plc, or Silence, and its collaborators, AstraZeneca plc, or AstraZeneca, Jiangsu Hansoh Pharmaceuticals Group Co., and Mallinckrodt plc, Arbutus Biopharma Corp., or Arbutus, Sylentis, S.A.U., or Sylentis, Novo Nordisk and its collaborators, Boehringer Ingelheim, AstraZeneca plc, or AstraZeneca, and Eli Lilly and Company, or Eli Lilly, WAVE Life Sciences Ltd., or WAVE, Silenseed Ltd., Ascletis Pharma Inc., Biomics Biopharma, Avidity Biosciences Inc., Dyne Therapeutics Inc., or Dyne, Atalanta Therapeutics Inc., Sirnaomics Inc., OliX Pharmaceuticals Inc., Ochre Bio, DTx Pharma, Inc., Sixfold Bioscience Inc., ProQR Therapeutics NV, or ProQR, Phio Pharmaceuticals, BioPath Holding Inc., Arcturus Therapeutics, Inc., or Arcturus, and Ascletis Pharma Inc.

Several of these companies have licensed our intellectual property.

Benitec Biopharma Ltd., or Benitec, is working on gene therapy approaches to RNAi therapeutics.

Companies working on microRNA therapeutics include Regulus Therapeutics, Inc., Rosetta Genomics Ltd., MiNA Therapeutics, Inc, and InteRNA Technologies B.V.

Companies working on microRNA therapeutics include Regulus Therapeutics, Inc., Rosetta Genomics Ltd., MiNA Therapeutics, Inc, InteRNA Technologies B.V.

and TransCode Therapeutics, Inc.

Antisense technology uses short, single-stranded, DNA-like molecules to block mRNAs encoding specific proteins.

While we believe that RNAi drugs may potentially have significant advantages over antisense oligonucleotide, or ASO, drugs, including greater potency and specificity, others are developing ASO drugs that are currently at a more advanced stage of development than RNAi drugs.

For example, Ionis has developed several ASO drugs that have received regulatory approval.

Ionis is also developing antisense drugs using ligand-conjugated GalNAc technology licensed from us, and these drugs have been shown to have increased potency at lower doses in clinical and pre-clinical studies, compared with antisense drugs that do not use such licensed GalNAc technology.

We believe that RNAi drugs may potentially have significant advantages over antisense oligonucleotide, or ASO, drugs, including greater potency and specificity.

In addition to Ionis and its collaborators, including Biogen Inc., AstraZeneca, Novartis and Bayer AG, and several other companies have ASO-based product candidates in various stages of pre-clinical and clinical development, including Roche, Akcea Therapeutics, Inc.

(acquired by Ionis in October 2020) , or Akcea, Antisense Therapeutics, Ltd., Dyne, WAVE and Sarepta Therapeutics, Inc.

(acquired by Ionis in October 2020), or Akcea, Antisense Therapeutics, Ltd., Dyne, WAVE, GSK, Sarepta Therapeutics, Inc., ProQR and Eli Lilly.

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 the more rapid development of RNAi therapeutics or more effective technologies for RNAi drug development or delivery.

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ATTR Amyloidosis.

Until recently, liver transplantation was the only treatment option for patients with hATTR amyloidosis in the U.S.

Until a few years ago, liver transplantation was the only treatment option for patients with hATTR amyloidosis in the U.S.

and in other countries.

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Even following liver transplantation, the disease continues to progress for many patients, presumably due to ongoing deposition of wild-type TTR protein.

In addition to ONPATTRO, approved treatments for hATTR amyloidosis now include inotersen (TEGSEDI, approved in many countries) and tafamidis (VYNDAQEL/VYNDAMAX, approved in many countries).

Indications vary by country/region for each product.

We believe that the following approved drugs could compete with ONPATTRO and, if approved, vutrisiran, for the treatment of the polyneuropathy of hATTR amyloidosis in adults and for the treatment of ATTR amyloidosis with cardiomyopathy if APOLLO-B and/or HELIOS-B is positive and patisiran and/or vutrisiran, respectively, are approved for that indication:

In addition to ONPATTRO and AMVUTTRA, approved treatments for hATTR amyloidosis now include inotersen (TEGSEDI, approved in many countries) and tafamidis (VYNDAQEL/VYNDAMAX, approved in many countries).

Treatment indications vary by country/region for each product.

We believe that the following approved drugs could compete with ONPATTRO and AMVUTTRA for the treatment of the polyneuropathy of hATTR amyloidosis in adults and for the treatment of ATTR amyloidosis with cardiomyopathy if patisiran is approved for that indication and/or if HELIOS-B is positive and vutrisiran is approved for that indication:

Drug Company Drug Description Phase Administration/Dosing

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Several investigational drugs also exist, in varying stages of clinical development, for ATTR amyloidosis.

We believe that the following drug candidates, if approved, could compete with ONPATTRO and, if approved, vutrisiran, for the treatment of the polyneuropathy of hATTR amyloidosis in adults and for the treatment of ATTR amyloidosis with cardiomyopathy if APOLLO-B and/or HELIOS-B is positive and patisiran and/or vutrisiran, respectively, are approved for that indication:

We believe that the following drug candidates, if approved, could compete with ONPATTRO and AMVUTTRA, for the treatment of the

polyneuropathy of hATTR amyloidosis in adults and for the treatment of ATTR amyloidosis with cardiomyopathy if patisiran is approved for that indication and/or if HELIOS-B is positive and vutrisiran is approved for that indication:

Drug Company Drug Description Phase Administration/Dosing

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Ionis & AstraZeneca

ASO to reduce production of TTR Protein Phase 3 Monthly subcutaneous injection (SC)

ASO to reduce production of TTR Protein Filed for approval in December 2022 for hATTR polyneuropathy Monthly subcutaneous injection (SC)

Acoramidis (AG10) BridgeBio Pharma, Inc.

Small molecule drug to stabilize TTR protein Phase 3 Twice daily oral dose

PRX004 Novo Nordisk mAb to clear amyloid deposits Phase 2/3 Intravenous (IV) infusion every four weeks

NI006 Neurimmune AG & AstraZeneca

mAB to clear amyloid deposits Phase 1 Intravenous (IV) infusion

& AstraZeneca in Japan Small molecule drug to stabilize TTR protein Phase 3 Twice daily oral dose

NNC-6019 (PRX004) Novo Nordisk mAb to clear TTR amyloid deposits Phase 2 Intravenous (IV) infusion every four weeks

NI006 AstraZeneca & Neurimmune AG

mAB to clear TTR amyloid deposits Phase 1 Intravenous (IV) infusion

NTLA-2001 Intellia Therapeutics, Inc.

& Regeneron CRISPR/Cas9 gene therapy Phase 1 One-time intravenous (IV) infusion

& Regeneron CRISPR/Cas9 gene therapy for TTR Phase 1 One-time intravenous (IV) infusion

We are also aware of other companies that have pre-clinical development programs for the potential treatment of ATTR amyloidosis.

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Drug Company Drug Description Phase Administration/Dosing

Nedosiran Novo Nordisk siRNA to reduce production of LDHA enzyme Phase 2 (pivotal) SC with monthly dosing

Nedosiran Novo Nordisk siRNA to reduce production of LDHA enzyme Filed with FDA in September 2022 SC with monthly dosing

BBP-711 BridgeBio Pharma, Inc.

GO inhibitor Phase 2/3 Oral

Oxabact OC5 OxThera AB Anaerobic bacteria that metabolize oxalate in the gut Phase 3 (failed to meet statistical significance) Twice daily oral dose

Stiripentol Biocodex SA GABA reuptake inhibitor Phase 2 Oral

Reloxaliase Allena Pharmaceuticals, Inc.

Oxalate-degrading enzyme for enteric hyperoxaluria Phase 3 (for enteric hyperoxaluria)

Up to five daily oral doses

CHK-336 Chinook Therapeutics, Inc.

LDHA inhibitor Phase 2 Oral

BMN-255 BioMarin Pharmaceutical, Inc.

Undisclosed Phase 1/2 Oral

We are aware of other companies that have pre-clinical development programs for the potential treatment of PH.

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Evkeeza (evinacumab) Regeneron Anti-ANGPTL3 mAb for hypercholesterolemia Approved in HoFH SC

Lerodalcibep (LIB-003) LIB Therapeutics Recombinant protein therapeutic Phase 3 SC

MK-0616 Merck Small molecule PCSK9 inhibitor Phase 2 Oral

ARO-ANG3 Arrowhead siRNA targeting ANGPTL3 Phase 2 SC

Vupanorsen Ionis / Pfizer ASO therapy to reduce levels of ANGPTL3 Phase 2b SC

LIB-003 LIB Therapeutics Recombinant protein therapeutic Phase 3 SC

VERVE-101 Verve Therapeutics CRISPR/CAS9 targeting PCSK9 Phase 1 One-time IV infusion

The global market for treatments of hemophilia and bleeding disorders is valued at more than $10.0 billion.

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Drug (Company) Drug Description Phase Administration

Advate (Takeda), Adynovate (Takeda), Kogenate (Bayer), Kovaltry (Bayer), Novoeight (Novo Nordisk), Xyntha (Pfizer), Nuwiq (Octapharma), Eloctate (Bioverativ) Recombinant FVIII factor products Approved IV

Valoctocogene roxaparvovec (BioMarin) Gene therapy Phase 3 IV - Single Administration

Advate (Takeda), Adynovate (Takeda), Kogenate (Bayer), Kovaltry (Bayer), Novoeight (Novo Nordisk), Xyntha (Pfizer), Nuwiq (Octapharma), Eloctate (Sanofi) Recombinant FVIII factor products Approved IV

Valoctocogene roxaparvovec (BioMarin) Gene therapy Approved in EU;

2023 IV - Single Administration

HEMLIBRA (Roche) Bispecific antibody mimetic of FVIII Approved SC - Monthly

RG6357 (Roche) Gene therapy Phase 3 IV – Single Administration

Rixubis (Takeda), Rebinyn (Novo Nordisk), BeneFIX (Pfizer), Alprolix (Bioverativ), Idelvion (CSL Behring) Recombinant FIX factor products Approved IV

giroctocogene fitelparvovec (Pfizer & Sangamo Therapeutics) Recombinant AAV2/6 Human Factor VIII Gene Therapy Phase 3 IV – Single Administration

RG6357 (Roche & Spark Therapeutics) Gene therapy Phase 2 IV – Single Administration

Rixubis (Takeda), Rebinyn (Novo Nordisk), BeneFIX (Pfizer), Alprolix (Sanofi), Idelvion (CSL Behring) Recombinant FIX factor products Approved IV

Etranacogene dezaparvovec (uniQure/CSL Behring)

rAAV5 FIX gene therapy Phase 3 IV - Single Administration

SPK-9001/PF06838435 (Roche, through its acquisition of Spark Therapeutics)

rAAV5 FIX gene therapy Approved IV - Single Administration

Fidanacogene elaparvovec (Spark Therapeutics)

Spark200 AAV FIX gene therapy Phase 3 IV - Single Administration

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The steps ordinarily required before a new drug product may be marketed in the U.S.

include nonclinical laboratory tests, animal tests and formulation studies, the submission to the FDA of an IND, which must become effective prior to commencement of clinical testing in the U.S., approval by an institutional review board, or IRB, at each clinical site before each trial may be initiated, completion of adequate and well-controlled clinical trials to establish that the drug product is safe and effective for the indication and other conditions of use for which FDA approval is sought, submission to the FDA of an NDA and FDA review and approval of the NDA.

Satisfaction of the FDA's pre-market approval requirements typically takes several years, but may vary substantially depending upon the complexity of the product and the nature of the disease.

Satisfaction of the FDA's pre-market approval requirements typically takes several years, but may vary

substantially depending upon the complexity of the product and the nature of the disease.

Government regulation may delay, limit or prevent marketing of potential products for a considerable period of time and impose costly procedures on a company’s activities.

Success in early-stage clinical trials does not necessarily assure success in later-stage

clinical trials.

Success in early-stage clinical trials does not necessarily assure success in later-stage clinical trials.

Data obtained from clinical activities, including but not limited to the data derived from our clinical trials for drug candidates, are not always conclusive and may be subject to alternative interpretations that could delay, limit or even prevent regulatory approval.

Even if a product receives regulatory approval, later discovery of previously unknown problems with a product, including new safety risks, may result in restrictions on the product or even complete withdrawal of the product from the market.

Even if a product receives regulatory approval, later discovery of previously unknown problems with a product, including new safety risks from clinical or nonclinical data or manufacturing issues, may result in restrictions on the product or even complete withdrawal of the product from the market.

Nonclinical Tests and Clinical Trials

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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, the FDA’s concerns must be resolved prior to the commencement of clinical trials.

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.

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In addition, clinical trials must be conducted in compliance with federal regulations and requirements, commonly referred to as good clinical practice, or GCP, to assure data integrity and protect the rights, safety and well-being of trial participants.

Among other things, GCP requires that all research subjects provide their informed consent prior to participating in any clinical study, and that an IRB for each institution participating in the clinical trial review and approve the plan for any clinical trial before it commences at that institution and conduct continuing review throughout the trial.

Among other things, GCP requires that all research subjects provide their informed consent prior to participating in any clinical study, and that a properly constituted IRB for each institution participating in the clinical trial review and approve the plan for any clinical trial before it commences at that institution and conduct continuing review throughout the trial.

The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects.

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The FDA may, at its discretion, re-evaluate, alter, suspend or terminate the testing based upon the data accumulated to that point and the FDA’s assessment of the risk/benefit ratio to the subject participating in the study.

An IRB or a clinical trial sponsor may also modify, suspend or terminate clinical trials at any time for various reasons, including a finding that the subjects or patients are being exposed to an unacceptable health risk.

The FDA can also request or require that additional clinical trials be conducted as a condition to product approval.

An IRB or a clinical trial sponsor may also modify, suspend or terminate clinical trials, or parts of clinical trials, at any time for various reasons, including a finding that the subjects or patients are being exposed to an unacceptable health risk.

The FDA can also request or require that additional clinical trials, nonclinical evaluations or changes in the manufacturing process be conducted as a condition to product approval.

Finally, sponsors are required to publicly disseminate information about certain ongoing and completed clinical trials on ClinicalTrials.gov, a government website administered by the National Institutes of Health, or NIH.

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We believe that any RNAi product candidate we develop, whether for the treatment of ATTR amyloidosis, AHP, PH1, hypercholesterolemia or the various indications targeted in our clinical development or nonclinical discovery programs, will be regulated by the FDA as a new drug that is not considered to be a biologic, and thus will require an NDA.

FDA approval of an NDA is required before commercial distribution of a new drug may begin in the U.S.

FDA approval of an

NDA is required before commercial distribution of a new drug may begin in the U.S.

An NDA must include the results of extensive nonclinical, clinical and other testing, as described above, a compilation of data relating to the product’s pharmacology, CMC, proposed labeling and other information.

In addition, an NDA for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration typically must contain data assessing the

safety and effectiveness for the claimed indication in all relevant pediatric subpopulations, although deferrals or full or partial waivers may be available in some circumstances.

In addition, an NDA for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration typically must contain data assessing the safety and effectiveness for the claimed indication in all relevant pediatric subpopulations, although deferrals or full or partial waivers may be available in some circumstances.

The cost of preparing and submitting an NDA is substantial.

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The FDA adjusts the PDUFA user fees on an annual basis.

Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

Fee waivers or reductions are available in certain circumstances.

Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the NDA also includes a non-orphan indication.

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In addition, the FDA often will conduct a bioresearch monitoring inspection of select clinical trial sites involved in conducting pivotal studies to assure data integrity and compliance with applicable GCP requirements, and could also conduct GCP inspections of the sponsor.

If the FDA's evaluation of the NDA and the various inspections are favorable, the FDA may issue an approval letter, which authorizes commercial marketing of the drug with specific prescribing information for a specific indication.

If the FDA's evaluation of an NDA and the various inspections are favorable, the FDA may issue an approval letter, which authorizes commercial marketing of the drug with specific prescribing information for a specific indication.

The approved indication may be narrower than what was proposed by the applicant or for a narrower patient population than the population studied in clinical trials.

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In addition, the FDA requires substantiation of any safety or effectiveness claims, including claims that one product is superior in terms of safety or effectiveness to another.

Superiority claims generally must be supported by adequate and well-controlled head-to-head clinical trials.

Superiority claims generally must be supported by head-to-head clinical trials.

To the extent that market acceptance of our products depends on their superiority over existing therapies, any restriction on our ability to advertise or otherwise promote claims of superiority, or requirements to conduct additional expensive clinical trials to provide proof of such claims, could negatively affect the sales of our products or our costs.

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Such approvals may be expensive and time-consuming and, if not approved, the FDA will not allow the product to be commercially distributed as modified.

If the FDA’s evaluation of the NDA submission or GCP inspections or inspection of the manufacturing facilities for the product are not favorable or cannot be completed due to COVID-19 related restrictions, the FDA may defer action on an application or refuse to approve the NDA and issue a complete response letter.

If the FDA’s evaluation of an NDA submission or GCP inspections or inspection of the manufacturing facilities for the product are not favorable or cannot be completed due to COVID-19 related restrictions, the FDA may defer action on an application or refuse to approve the NDA and issue a complete response letter.

The complete response letter describes the deficiencies that the FDA has identified in an application and may recommend actions that the applicant can take to address the deficiencies.

Such actions may include, among other things, conducting additional safety or efficacy studies.

Even with the completion of this additional testing or the submission of additional requested information, however, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

Even with the

completion of this additional testing or the submission of additional requested information, however, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

With limited exceptions, the FDA may withhold approval of an NDA regardless of prior advice it may have provided or commitments it may have made to the sponsor.

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Additionally, applicants submitting an ANDA or 505(b)(2) application referencing a listed drug generally are required to make a certification with respect to each patent for the listed drug that is listed in the FDA’s publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly referred to as the Orange Book.

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

If the applicant is not seeking

approval of a use claimed by a method-of-use patent, however, the applicant can submit a statement to that effect instead of making the certification.

These certifications (and statements) affect when the FDA can approve the ANDA or 505(b)(2) application.

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.

If the ANDA or 505(b)(2) applicant certifies 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), and certain other steps are taken, then approval of the ANDA or 505(b)(2) application will be stayed (i.e., FDA will not approve the application) until 30 months have passed or patent disputes are resolved, as described below.

Specifically, under the process set forth by the statute, the ANDA or 505(b)(2) applicant must provide notice of its patent challenge to the NDA sponsor and the patent holder within certain time limits.

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from sales in the U.S.

Orphan Drug Designation must be requested before submitting an NDA.

Orphan Drug Designation must be requested before submitting an NDA or an sNDA for the orphan indication.

After the FDA grants Orphan Drug Designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

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Specifically, new drugs and biological products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition.

Fast Track designation applies to the product and the specific indication for which it is

being studied.

Fast Track designation applies to the product and the specific indication for which it is being studied.

The sponsor of a new drug or biological product may request the FDA to designate the drug or biologic as a Fast Track product at any time during the clinical development of the product, but ideally no later than the pre-NDA or pre–biologics license application meeting because many of the features of Fast Track designation will not apply after that time.

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We intend to request Fast Track designation for our product candidates, if applicable.

For example, the FDA granted Fast Track designation to patisiran for the treatment of hATTR amyloidosis, which was approved in August 2018 for the treatment of the polyneuropathy of hATTR amyloidosis in adults, and has also granted Fast Track designation to vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis.

For example, the FDA granted Fast Track designation to patisiran for the treatment of hATTR amyloidosis, which was approved in August 2018 for the treatment of the polyneuropathy of hATTR amyloidosis in adults, and also granted Fast Track designation to vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis, which was approved in June 2022.

Any drug or biological product that receives a Fast Track designation may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

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Under accelerated approval, a product may be approved on the basis of adequate and well-controlled clinical studies establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefits.

As a condition of approval, the FDA may require that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post-marketing clinical studies to verify the predicted clinical benefit and, under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the FDA is now permitted to require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.

Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

In addition, the FDA requires as a condition for accelerated approval advance submission of promotional materials prior to use, which could limit or delay the commercial launch of the product.

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The FDA recommends that a sponsor request rare pediatric disease designation before submission of the rare pediatric disease product application.

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

The rare pediatric disease designation does not guarantee that the sponsor will receive a

The FDA will award a PRV upon approval of the marketing application if the sponsor requests such a voucher in their marketing application and if the application meets the eligibility criteria.

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and markets in 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.

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

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

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.

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

In August 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law.

The IRA includes several provisions that will impact our business to varying degrees, including provisions that create a $2,000 out-of-pocket cap for Medicare Part D beneficiaries, impose new manufacturer financial liability on all drugs in Medicare Part D, allow the U.S.

government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation, and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

The Patient Protection and Affordable Care Act, also referred to as the Affordable Care Act, or the ACA, enacted in 2010, includes measures that have significantly changed the way healthcare is financed by both governmental and private insurers.

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• The Medicaid Drug Rebate Program requires pharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of the Department of Health and Human Services as a condition for states to receive federal matching funds for the manufacturer’s outpatient drugs furnished to Medicaid patients.

The ACA increased pharmaceutical manufacturers’ rebate liability by raising the minimum basic Medicaid rebate on most branded prescription drugs and biologic products to 23.1% of average manufacturer price, or AMP, and added a new rebate calculation for “line extensions” (i.e., new formulations, such as extended release formulations) of solid oral dosage forms of branded products, and modified the statutory definition of AMP.

dosage forms of branded products, and modified the statutory definition of AMP.

In addition, the ACA provides for the public availability of retail survey prices and certain weighted average AMPs under the Medicaid program.

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In addition, because 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the required 340B discount to increase.

• The ACA imposed a requirement on manufacturers of branded drugs and biologic products to provide a 50% discount off the negotiated price of branded drugs dispensed to Medicare Part D patients in the coverage gap (i.e., “donut

Under the Bipartisan Budget Act of 2018, or the BBA, effective in 2019, the mandated manufacturer coverage gap discount increased to 70%.

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The fee would not apply to sales of certain products approved exclusively for orphan indications.

• The ACA created the Sunshine Act, which requires certain manufacturers to track certain financial arrangements with physicians and teaching hospitals, including any “transfer of value” made or distributed to such entities, as well as any investment interests held by physicians (currently defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and their immediate family members.

Legislation passed in 2018 expanded the scope of covered recipients’ non-physician providers such as to physician assistants and advanced practice nurses, effective in 2022.

Manufacturers annually report this information to CMS, which posts this information on its website.

Legislation passed in 2018 expands the scope of covered recipients' non-physician providers such as to physician assistants and advanced practice nurses, effective in 2022.

• The ACA established a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

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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.

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.

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.

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jurisdictions generally prohibit companies and their intermediaries from making improper payments to non-U.S.

officials for

the purpose of obtaining or retaining business.

officials for the purpose of obtaining or retaining business.

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

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Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Conference on Harmonization, or ICH, guidelines on GCP.

If the sponsor of the clinical trial is not established within the EU, it must appoint an entity within the EU to act as its legal representative.

If the sponsor of the clinical trial is not established within the EU, it must appoint an entity within the EU to act as its legal representative (unless all EU member states in which the trial is being conducted have chosen not to apply such rule, in which case only a contact person in the EU is required), who shall be responsible for ensuring compliance with the sponsor’s obligations under the new EU Regulation on Clinical Trials and be the addressee for all communications provided for under the Regulation.

The sponsor must take out a clinical trial insurance policy, and in most EU countries the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

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Any substantial changes to the trial protocol or other information submitted with the CTAs must be notified to or approved by the relevant competent authorities and ethics committees.

Currently, CTAs must be submitted to the competent authority in each EU member state in which the trial will be conducted.

Under the new EU Regulation on Clinical Trials, which became applicable on January 31, 2022, there is a centralized application procedure where one national authority leads the scientific review of the application leading to increased information-sharing and decision-making between member states.

information-sharing and decision-making between member states (as compared to the previous EU Directive on Clinical Trials, where a separate application to the competent authority in each EU member state in which the trial was conducted was required).

Each concerned member state will continue to complete an ethical review of any CTA.

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There is an increasing trend in the EU towards greater transparency and, while the manufacturing or quality information is currently generally protected as confidential information, the EMA and national regulatory authorities are now liable to disclose much of the nonclinical and clinical information in marketing authorisation dossiers, including the full clinical study reports, in response to freedom of information requests after the marketing authorisation has been granted.

In October 2014, the EMA adopted a policy under which clinical study reports would be posted on the agency’s website following the grant, denial or withdrawal of an MAA, subject to procedures for limited redactions and protection against unfair commercial use.

A similar requirement is contained in the new Regulation on Clinical Trials.

As of October 2016, the EMA began publishing clinical data (including clinical study reports) on the agency’s website following the grant, denial or withdrawal of an MAA for a centralised marketing authorisation, subject to procedures for limited redactions and protection against unfair commercial use.

The centralized procedure gives rise to marketing authorisations that are valid throughout the EU and, by extension (after national implementing decisions), in Norway, Iceland and Liechtenstein, which, together with the EU member states, comprise the European Economic Area, or EEA.

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The centralized procedure is compulsory for medicinal products that (1) are derived from biotechnology processes, (2) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders, viral diseases or autoimmune diseases and other immune dysfunctions, (3) are orphan medicinal products or (4) are advanced therapy medicinal products, such as gene or cell therapy medicines.

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

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

For 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:

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(2) the decentralized procedure, in which applications are submitted simultaneously in two or more EU member states;

and (3) the mutual recognition procedure, which must be used if the product has already been authorized in at least one other EU member state, and in which the EU member states are required to grant an authorization recognizing the existing authorization in the other EU member state, unless they identify a serious risk to public health.

and (3) the mutual recognition procedure, which must be used if the product has already been authorised in at least one other EU member state, and in which the EU member states are required to grant an authorisation recognizing the existing authorisation in the other EU member state, unless they identify a serious risk to public health.

A national procedure is only possible for one member state;

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However, this timeline excludes clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP, so the overall process typically takes a year or more.

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 intervention, defined by the absence or insufficiency of an appropriate alternative therapeutic approach for the disease to be treated;

and anticipation of high therapeutic benefit of the new product.

In this circumstance, EMA ensures that the opinion of the CHMP is given within 150 days.

In this circumstance, the EMA ensures that the opinion of the CHMP is given within 150 days.

The EMA granted an accelerated assessment for patisiran, which was approved in the EU in August 2018 under the centralized procedure.

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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.

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

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

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.

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Orphan medicinal product designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following marketing authorisation.

During this period, the competent authorities may not accept or approve any similar medicinal product for the same therapeutic indication, unless the second medicinal product is safer, more effective or otherwise clinically superior.

During this period, the competent authorities may not accept or approve any similar medicinal product for the same therapeutic indication, unless (i) the second medicinal product is safer, more effective or otherwise clinically superior to the authorised orphan product;

(ii) the marketing authorisation holder for the authorised product consents to a second orphan medicinal product application;

or (iii) the marketing authorisation holder for the authorised product cannot supply enough orphan medicinal product.

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.

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 and fitusiran have been granted orphan medicinal product designation.

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

Post-Approval Controls

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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 authorisation 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 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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and the EU, we are subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of our products.

In particular, during 2021, we filed for regulatory approval for our commercial products in a number of jurisdictions worldwide, and regulatory filings in additional countries are planned for ONPATTRO, GIVLAARI and OXLUMO in 2022, and we will have to follow the specific regulations in such jurisdictions and such other countries in which we file, which are complex.

In particular, during 2022, we filed for regulatory approval for our commercial products in a number of jurisdictions worldwide, and regulatory filings in additional countries are planned for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO in 2023, and we will have to follow the specific regulations in such jurisdictions and such other countries in which we file, which are complex.

Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in all or most foreign countries prior to the commencement of clinical trials or marketing of the product in those countries.

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A DIN is an eight-digit number and uniquely identifies all pharmaceutical products sold in a dosage form in Canada.

Additional obligations must be fulfilled when seeking marketing authorization for biologic medicinal products (whether innovative biologics or biosimilars) in Canada.

Additional obligations must be fulfilled when seeking marketing

authorization for biologic medicinal products (whether innovative biologics or biosimilars) in Canada.

In addition to the information required for other pharmaceuticals, biologics must include more detailed chemistry and manufacturing information, which ensures the purity and quality of the product.

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Manufacturing

To date, we have manufactured only limited supplies of drug substance for use in IND-enabling toxicology studies in animals at our own facilities, as well as patisiran formulated bulk drug product for late-stage clinical trial use and commercial supply.

To date, we have manufactured limited supplies of drug substance for use in IND-enabling toxicology studies in animals and clinical trials at our own facilities, as well as patisiran formulated bulk drug product for late-stage clinical trial use and commercial supply.

We have contracted with several third-party contract manufacturing organizations, or CMOs, for the supply of drug substance, drug product and finished product to meet our needs for pre-clinical 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 ONPATTRO, GIVLAARI and OXLUMO, as well as other product candidates, for at least the next several years, including to support the potential launch of our additional product candidates and to supply the needs of our alliance partners.

We expect to continue to rely on third-party CMOs for the supply of drug substance and drug product, including ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as other product candidates, for at least the next several years, including to support the potential launch of our additional product candidates and to supply the needs of our alliance partners.

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.

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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 and GIVLAARI for both clinical and commercial use, and we have entered into manufacturing services agreements with Agilent for such supply of ONPATTRO and GIVLAARI.

Pursuant to the Agilent supply agreement for ONPATTRO, 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 ONPATTRO 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 active pharmaceutical ingredient for ONPATTRO, AMVUTTRA and GIVLAARI for both clinical and commercial use, 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.

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

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During 2020, we completed construction and qualification of our cGMP 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 cGMP operations, and we believe this facility will enable us to initiate manufacturing for 10-15 new early-stage programs over the next few years, as well as provide us the manufacturing capabilities to support our late-stage and commercial programs in the future.

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

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

We believe that the current supply capacity we have established externally, together with the internal capacity we developed to support pre-clinical trials, our existing facility for patisiran formulated bulk drug product and our Norton manufacturing facility, will be sufficient to meet our and our alliance partners’ 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 alliance partners’ currently anticipated needs.

We monitor the capacity availability for the manufacture of drug substance and drug product and believe that our supply agreements with our CMOs and the lead times for new supply agreements would allow us to access additional capacity to meet our and our alliance partners’ 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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Over the last several years, we have been building commercial capability 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 four approved products and our late-stage clinical programs:

• With respect to our ATTR amyloidosis franchise, we have global rights to develop and commercialize both the approved product, ONPATTRO, and the investigational RNAi therapeutic, vutrisiran, the next potential product in late-stage development in this franchise;

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;

• For GIVLAARI and OXLUMO, we have global rights to develop and commercialize;

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

ONPATTRO, GIVLAARI and OXLUMO, as well as the late-stage programs we are advancing internally to commercialization are focused on orphan diseases, and we have been executing on what we believe to be a proven strategy to make ONPATTRO, GIVLAARI, OXLUMO and future orphan products successful, including through efforts to increase awareness and diagnosis.

In addition, as part of our planned transition to a top five biotech by the end of 2025 and consistent with our Alnylam P 5 x25 strategy, we are now advancing RNAi therapeutics beyond rare diseases into prevalent disease opportunities.

With the approval of Leqvio, the first RNAi therapeutic approved for a common disease, we believe the RNAi therapeutic profile supports the potential for expansion to prevalent diseases, including addressing many unmet needs in common disease settings such as hypertension, NASH, gout and diabetes.

ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as the late-stage programs we are advancing internally to commercialization are focused on orphan diseases, and we have been executing on what we believe to be a proven strategy to make ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO and future orphan products successful, including through efforts to increase awareness and diagnosis.

In addition, as part of our planned transition to a top-tier biotech by the end of 2025 and consistent with our Alnylam P 5 x25 strategy, we are now advancing RNAi therapeutics beyond rare diseases into prevalent disease opportunities.

Beginning with the approval of Leqvio, the first RNAi therapeutic approved for a common disease, we believe the RNAi therapeutic profile supports the potential for expansion to prevalent diseases, including addressing many unmet needs in common disease settings such as hypertension, NASH and diabetes.

We believe we are establishing a global commercial organization and infrastructure to successfully support an expansion to prevalent diseases.

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and certain state Medicaid programs.

As of the beginning of 2022, we have completed at least 43 VBAs with multiple commercial payers, including 19 for ONPATTRO, 13 for GIVLAARI, and 11 for OXLUMO.

As of the beginning of 2023, we have completed over 40 VBAs with multiple commercial payers, including 19 for ONPATTRO, 11 for AMVUTTRA, 15 for GIVLAARI, and 15 for OXLUMO.

In our VBAs for GIVLAARI we introduced a Prevalence Based Adjustment that provides for a rebate to be paid if the number of patients identified within a plan population exceeds the expected disease prevalence, to address an unknown that exists in the context of an ultra-rare disease.

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we believe we have made strong progress in terms of patient access and have established availability of ONPATTRO in more than 20 countries through direct reimbursement or expanded access.

In addition, we have seen strong early adoption of AMVUTTRA in key launch markets and expect continued expansion across global markets.

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

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We are also continuing to incorporate and enhance the appropriate quality systems, compliance policies, systems and procedures, as well as implementing internal systems and infrastructure in order to support global commercial sales, and the establishment of patient-focused programs.

Ultimately, we intend to leverage the commercial infrastructure that we have built for ONPATTRO, GIVLAARI and OXLUMO to also support the potential launch of vutrisiran, assuming regulatory approval.

Ultimately, we intend to leverage the commercial infrastructure that we have built for our commercially approved products to also support the potential launch of patisiran in ATTR amyloidosis patients with cardiomyopathy, assuming regulatory approval.

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

Our objective is to continue to execute successful product launches leveraging our positive experience with the launches of ONPATTRO, GIVLAARI and OXLUMO.

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

Medical Affairs

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The new employees were hired to support a variety of functions and key initiatives, including extending our research, clinical and pre-clinical pipeline development, as well as our medical affairs, manufacturing and commercialization capabilities, with hires in commercial, compliance, legal, clinical development and operations, research, medical affairs, manufacturing, and general and administrative functions.

We expect to continue to add additional employees in 2022, with a focus on further enhancing our capabilities and increasing our capacities in these areas, in particular our manufacturing, commercial and compliance teams, as well as expanding our geographic reach as we continue the global launches of our approved medicines and prepare for the planned launch of vutrisiran, assuming regulatory approval.

We expect to continue to add additional employees in 2023, with a focus on further enhancing our capabilities and increasing our capacities in these areas, in particular our manufacturing, commercial and compliance teams, as well as expanding our geographic reach as we continue the global launches of our approved medicines and prepare for the potential launch of patisiran for patients with the cardiomyopathy of ATTR amyloidosis, assuming regulatory approval.

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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As a global commercial-stage biopharmaceutical company, we believe that our long-term success and ability to deliver innovative, safe and effective medicines to patients requires a diverse and inclusive workforce.

We value diversity at all levels of the organization and continue to focus on extending our diversity, equity and inclusion initiatives across our entire workforce, from:

We value diversity at all levels of the organization and continue to focus on extending our diversity, equity and inclusion initiatives across our entire

workforce, from:

working with managers to develop strategies for building diverse, high performing teams;

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Our website address is included in this Annual Report on Form 10-K as an inactive technical reference only.

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 United States Securities and Exchange Commission, or SEC.

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 United States Securities and Exchange Commission, or 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.

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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