What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2022-02-10 compared with 2021-02-11 · 443 added, 321 removed, 807 unchanged (49% of the section changed)

Alnylam Pharmaceuticals, Inc.

(also referred to as Alnylam, we, our or us) is a global commercial-stage biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi.

(also referred to as Alnylam, we, our or us) is a global commercial-stage biopharmaceutical company developing novel therapeutics based on ribonucleic acid interference, or RNAi.

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

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

RNAi therapeutics are comprised of small interfering RNA, or siRNA, and function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in causing disease, thus preventing them from being made.

RNAi therapeutics are comprised of small interfering RNA, or siRNA, and function upstream of conventional medicines by potently silencing messenger RNA, or mRNA, that encode for proteins implicated in the cause or pathway of disease, thus preventing them from being made.

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

2 unchanged sentences

We utilize a N-acetylgalactosamine (GalNAc) conjugate approach or lipid nanoparticle (LNP) to enable hepatic delivery of siRNAs.

For delivery to the central nervous system, or CNS, and the eye (ocular delivery), we are utilizing an alternative conjugate approach.

During 2020, we also advanced approaches for lung delivery of siRNAs.

Our focus is on clinical indications where there is a high unmet need, 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.

In 2015, we charted our Alnylam 2020 goals of building a multi-product, global commercial company with a deep clinical pipeline for future growth and an organic product engine for sustainable innovation and a great potential for patient impact.

We ended 2020 exceeding these goals, with four marketed products and 12 clinical programs, including six in late-stage development, across four Strategic Therapeutic Areas, or “STArs:” Genetic Medicines;

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.

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.

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.

Specifically, we intend to end 2025 with the following profile:

Over 0.5 million on our RNAi therapeutics globally

Six or more marketed products in rare and prevalent diseases

Over 20 clinical programs, with 10 or more in late stages and four or more INDs per year

Performance :

≥40% revenue CAGR (compound annual growth rate) through YE 2025

Profitability :

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;

Cardio-Metabolic Diseases;

2 unchanged sentences

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 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 several additional countries, including Brazil.

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.

GIVLAARI is approved in the U.S.

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

We have also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Switzerland and Japan and additional regulatory filings are pending or planned for 2021 and beyond.

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 PH1 in all age groups.

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, and recently 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.

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.

Novartis is working closely with the third-party manufacturer and the FDA to obtain approval as soon as possible, and has guided for a resubmission of its NDA for inclisiran in Q2-Q3 2021.

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

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.

These programs include our wholly owned programs:

givosiran (the non-branded name for GIVLAARI) for the treatment of adolescent patients with AHP;

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;

inclisiran (the non-branded name for Leqvio) for the treatment of atherosclerotic cardiovascular disease, or ASCVD, is being advanced by our partner Novartis;

as well as fitusiran for the treatment of hemophilia, which is being advanced by our partner Sanofi Genzyme, the specialty care global business unit of Sanofi.

In early 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.

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

Specifically, we intend to end 2025 with the following profile:

Over 0.5 million on our RNAi therapeutics globally

Six or more marketed products in rare and prevalent diseases

Over 20 clinical programs, with 10 or more in late stages and four or more INDs per year

Performance :

≥40% revenue CAGR (compound annual growth rate) through YE 2025

Profitability :

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

Based on our expertise in RNAi therapeutics and broad intellectual property estate, we have formed alliances with leading pharmaceutical and life sciences companies to support our development and commercialization efforts, including Regeneron Pharmaceuticals, Inc., or Regeneron, Novartis (which acquired our partner The Medicines Company, or MDCO, in 2020), Sanofi Genzyme, Vir Biotechnology, Inc., or Vir, and Dicerna Pharmaceuticals, Inc., or Dicerna.

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.

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;

policies, procedures, and guidance;

training and communications;

dedicated resources;

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

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

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.

The COVID-19 Pandemic

In March 2020, the World Health Organization declared the outbreak of a novel strain of coronavirus, or COVID-19, as a pandemic, which continues to spread or resurge throughout the U.S.

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.

We are continuing to monitor the global pandemic and spread of COVID-19 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 has caused us to modify our business practices, including implementing a global work from home policy for all employees who are able to perform their duties remotely and 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 physical distancing, temperature screening, contact tracing and cleaning measures in place, as well as voluntary testing protocols in our Massachusetts facilities.

At this time, we cannot predict when certain restrictions that are in place to protect our employees can be safely reduced or will no longer be needed, and such restrictions are likely to remain in place until there is widespread availability and distribution of COVID-19 vaccines.

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 and SARS-CoV-2 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 availability and efficacy of vaccines, among others.

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.

6 unchanged sentences

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

◦ Attained approximately 1,350 patients worldwide on commercial ONPATTRO treatment as of December 31, 2020

◦ Received regulatory approvals in Brazil, Israel and Taiwan

◦ Achieved market access in over 20 countries

• Patisiran – ATTR Amyloidosis with Cardiomyopathy

◦ Continued enrollment in the APOLLO-B Phase 3 study in ATTR amyloidosis patients with cardiomyopathy, with plans to complete enrollment in early 2021

• Vutrisiran (ALN-TTRsc02) – ATTR Amyloidosis

◦ Reported positive topline results from the HELIOS-A Phase 3 study of vutrisiran in hATTR amyloidosis with polyneuropathy, with plans to file an NDA with the FDA in early 2021

◦ Continued enrollment in the HELIOS-B Phase 3 study in ATTR amyloidosis patients with cardiomyopathy

◦ Announced potential for a biannual dosing regimen option with plans to initiate a clinical trial of this dosing regimen in early 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

Commercial/Late-Stage Pipeline

1 unchanged sentence

◦ Recognized GIVLAARI global net revenue of $127.8 million for the year ended December 31, 2021

◦ Attained approximately 200 patients worldwide on commercial GIVLAARI treatment as of December 31, 2020

◦ Received regulatory approvals in the EU, Brazil and Canada

◦ Attained over 350 patients worldwide on commercial GIVLAARI treatment as of December 31, 2021

• OXLUMO (lumasiran) – Primary Hyperoxaluria Type 1

◦ Received regulatory approval for OXLUMO in the U.S.

◦ Achieved global net product revenues for the fourth quarter of approximately $0.3 million representing initial patient demand in Europe

◦ Reported positive topline results and six-month primary analysis results for the ILLUMINATE-B Phase 3 pivotal study in patients younger than six years of age with preserved renal function

◦ Completed enrollment in the ILLUMINATE-C Phase 3 study of lumasiran in patients of all ages with advanced PH1, with plans to report topline results in mid-2021

◦ Recognized OXLUMO global net revenue of $59.6 million for the year ended December 31, 2021

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

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

◦ Our partner, Novartis, received marketing authorization for Leqvio from the EC in December 2020

◦ Novartis received a complete response letter from the FDA in December 2020, due to unresolved facility inspection-related conditions at a third-party manufacturing facility in Europe;

Novartis is working closely with the third-party manufacturer and the FDA to obtain approval as soon as possible, and has guided for a resubmission of its NDA in Q2-Q3 2021

• Fitusiran - Hemophilia (in collaboration with Sanofi Genzyme)

◦ Continued advancement of the ATLAS Phase 3 program for fitusiran in patients with hemophilia A or B with and without inhibitors;

following an assessment of available data and alignment with several health authorities, including the FDA, Sanofi Genzyme resumed fitusiran dosing in ongoing adolescent and adult studies in certain countries with protocol amendments to address adjustments to dose and dosing regimen

◦ 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

Early-Stage and Pre-Clinical Pipeline

• Cemdisiran for the treatment of complement-mediated diseases;

continued enrollment and dosing in the Phase 2 study in IgA nephropathy, and initiated dosing in a Phase 1 study of combination therapy with pozelimab, an anti-C5 monoclonal antibody, in collaboration with Regeneron

• ALN-AGT for the treatment of hypertension;

presented positive interim results from the Phase 1 study of ALN-AGT

• ALN-HBV02 (VIR-2218) for the treatment of chronic hepatitis B virus, or HBV, infection;

Vir presented positive interim results from a Phase 2 study of patients with chronic HBV infection and continued enrollment and dosing in a Phase 2 combination trial of VIR-2218 with pegylated interferon-alpha (PEG-IFN-α)

• ALN-HSD for the treatment of nonalcoholic steatohepatitis, or NASH;

initiated dosing in Phase 1 study with the program to advance in collaboration with Regeneron

• ALN-COV (Vir-2703) for the treatment and/or prevention of COVID-19;

selected a development candidate under collaboration with Vir

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

selected a development candidate with Regeneron electing to opt-in to program co-development and an expected clinical trial application, or CTA, filing in mid-2021

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

Corporate Highlights

◦ Ended 2021 with $2.44 billion in cash, cash equivalents and marketable securities

◦ Entered into a strategic financing collaboration with certain affiliates of Blackstone, under which we will receive up to $2 billion in financing;

closed $150 million R&D funding component

◦ Expanded exclusive licensing agreement with Vir for the development and commercialization of RNAi therapeutics for infectious diseases to include the development and commercialization of RNAi therapeutics targeting SARS-CoV-2 and up to three additional targets focused on human host factors for SARS-CoV-2

◦ Entered into a development and commercialization collaboration with Dicerna, to develop and commercialize investigational RNAi therapeutics for the treatment of alpha-1 antitrypsin deficiency-associated liver disease, or alpha-1 liver disease, and completed a non-exclusive cross-licensing agreement with Dicerna regarding the companies’ respective intellectual property for our lumasiran and Dicerna’s nedosiran programs for the treatment of primary hyperoxaluria

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

RNAi Therapeutics – A New Class of Innovative Medicines

1 unchanged sentence

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.

This delivery success enabled execution on our Alnylam 2020 strategy and we expect this success will further enable us to achieve our Alnylam P 5 x25 strategy under which we expect to sustainably and organically create and commercialize transformative rare and common disease medicines benefiting hundreds of thousands of patients around the world while delivering strong financial performance and profitability, 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 hundreds of thousands of 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.

4 unchanged sentences

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 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.

Our first wave of investigational RNAi therapeutics based on this ESC+ design, ALN-HBV02, ALN-AGT and ALN-HSD, are in the clinic, with what we believe are encouraging initial results.

Our platform enhancements have also provided a strong foundation for pursuing a conjugate-based approach to extra-hepatic delivery, including delivery to the brain and spinal cord, as well as ocular delivery, with proof-of-concept, or POC, demonstrated in rodent and non-human primates, enabling 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.

In 2020, we also began to advance lung delivery of RNAi therapeutics directed to the SARS-COV-2 genome in collaboration with our partners at Vir.

Our first wave of investigational RNAi therapeutics based on this ESC+ design, zilebesiran (formerly ALN-AGT), ALN-HBV02 and ALN-HSD, are in the clinic, with what we believe are encouraging initial results.

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.

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.

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.

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, providing strong support for 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 common disease medicines benefiting hundreds of thousands of patients around the world while delivering strong financial performance and profitability, 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 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.

Our Product Pipeline

6 unchanged sentences

The investigational therapeutics described below are in various stages of clinical development and the scientific information included about these therapeutics is preliminary and investigative.

None of these investigational therapeutics have been approved by the FDA, European Medicines Agency, or EMA, or any other health authority and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics.

None of these investigational therapeutics have been approved by the FDA, EMA, or any other health authority and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics.

The chart below is a summary of our commercial products and late- and early-stage development programs as of January 31, 2022.

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 certain territories, with additional regulatory submissions pending.

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.

Our TTR Franchise

1 unchanged sentence

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.

In ATTR amyloidosis, misfolded TTR proteins accumulate as amyloid fibrils in multiple organs

and tissue types.

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

hATTR amyloidosis can include sensory and motor neuropathy, autonomic neuropathy and cardiac symptoms and is a major unmet medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide.

10 unchanged sentences

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 – ATTR Amyloidosis with Cardiomyopathy

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

Patisiran is also being investigated in other patient segments through Phase 4 studies.

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.

APOLLO-B Phase 3 Study

In September 2019, we initiated APOLLO-B, a randomized, double-blind, placebo-controlled Phase 3 study in ATTR amyloidosis patients with cardiomyopathy.

The study is enrolling patients with confirmed cardiomyopathy and medical history of symptomatic heart failure due to ATTR amyloidosis, with enrollment expected to be completed in early 2021.

Patients will be randomized 1:1 to patisiran or placebo.

Concomitant use of on-label commercially available tafamidis is not prohibited.

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.

Vutrisiran – ATTR Amyloidosis

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.

Quarterly, or perhaps 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;

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 January 2021, we reported positive topline results from our HELIOS-A Phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy, and announced our intention to submit an NDA for vutrisiran with the FDA in early 2021, with regulatory filings following in additional countries, including Brazil and Japan.

Upon obtaining results from the 18-month analysis of HELIOS-A, expected in late 2021, we plan to submit a marketing authorisation application, or MAA, in the EU as previously aligned with the EMA.

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.

6 unchanged sentences

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 time 10-meter walk test, both compared to historical placebo.

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.

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

Additional secondary and exploratory endpoints will be evaluated at 18 months.

In January 2021, we reported positive topline results from HELIOS-A.

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.

◦ Efficacy and Safety Results:

At nine months, vutrisiran met the primary endpoint (p less than 0.001) and achieved statistically significant results (p less than 0.001) for each of the Norfolk QoL-DN and 10-meter walk test secondary endpoints.

In addition, a majority of patients showed reversal of polyneuropathy manifestations of disease with

improvements in neuropathy impairment and QoL, relative to baseline.

Vutrisiran treatment also showed improvement compared to placebo on the exploratory cardiac biomarker endpoint, NT-proBNP (nominal p less than 0.05).

Vutrisiran also demonstrated an encouraging safety and tolerability profile.

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.

2 unchanged sentences

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

There were no clinically significant changes in liver function tests.

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.

HELIOS-B Phase 3 Study

The HELIOS-B Phase 3 trial, initiated in late 2019, is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vutrisiran in approximately 600 patients with ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy.

Patients will be randomized on a 1:1 basis to receive 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every three months for up to 36 months.

The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite outcome of reducing all-cause mortality and recurrent cardiovascular events.

The primary endpoint will be assessed 30 months after the last patient is randomized.

The HELIOS-B Phase 3 trial, initiated in late 2019, is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vutrisiran in patients with ATTR amyloidosis (wild-type or hereditary) with cardiomyopathy.

Patients were randomized on a 1:1 basis to receive 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every three months for up to 36 months.

The primary endpoint will evaluate the efficacy of vutrisiran versus placebo on the composite endpoint of all-cause mortality and recurrent cardiovascular events at 30 months.

Additional secondary and exploratory endpoints will also be evaluated.

1 unchanged sentence

The study protocol includes an optional interim efficacy analysis to be conducted at our discretion.

In August 2021, we announced full patient enrollment in the HELIOS-B study.

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

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.

Our Other Marketed Products

6 unchanged sentences

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 in July 2020 and in Canada in October 2020.

We have also filed for regulatory approval for givosiran (the non-branded drug name for GIVLAARI) in Switzerland, Israel, and Japan and additional regulatory filings are pending or planned in 2021 and beyond.

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.

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.

9 unchanged sentences

In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease, or liver disease including hepatocellular carcinoma.

In August 2019, we entered into a U.S.

gastrointestinal, or GI, disease education and promotional agreement with Ironwood Pharmaceuticals, Inc., or Ironwood, to leverage Ironwood’s capabilities in GI to help raise AHP awareness and bring GIVLAARI to gastroenterologists and other healthcare practitioners, or HCPs, in the U.S.

Under the agreement, Ironwood’s clinical sales specialists promote GIVLAARI in the U.S.

to the gastroenterologists and other HCPs that it already calls on for its own marketed product.

In December 2020, we amended the U.S.

GI disease education and promotional agreement with Ironwood to revise the financial structure and the minimum performance requirements, and Ironwood’s commercial field personnel continue to provide AHP disease education and promote GIVLAARI to gastroenterologists and other HCPs.

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

3 unchanged sentences

OXLUMO utilizes our ESC-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.

November 2020, the EC granted marketing authorization for OXLUMO (lumasiran) for the treatment of PH1 in all age groups, following a positive Committee for Medicinal Products for Human Use, or CHMP, opinion.

In November 2020, the EC granted marketing authorization for OXLUMO (lumasiran) for the treatment of PH1 in all age groups, following a positive Committee for Medicinal Products for Human Use, or CHMP, opinion.

OXLUMO was previously granted an Accelerated Assessment and a PRIME Designation by the EMA and an Orphan Designation in the EU.

1 unchanged sentence

OXLUMO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease Designations.

With the approval of OXLUMO, the FDA has 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.

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

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.

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

PH1 is characterized by oxalate overproduction in the liver.

The excess oxalate results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis (calcification of the kidneys).

The excess oxalate results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis.

Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones.

PH1 is associated with a progressive decline in kidney function, which exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and deposition of oxalate in bones, eyes, skin, and heart, leading to severe illness and death.

5 unchanged sentences

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 renal disease, with topline results expected in mid-2021.

• ILLUMINATE-C is an ongoing single-arm, open-label, multinational Phase 3 study to evaluate the safety and efficacy of lumasiran in PH1 patients of all ages and advanced renal disease (eGFR ≤ 45 mL/min/1.73m 2 or elevated serum creatinine for patients <12 months of age).

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 dialysis-dependent.

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 endpoint of the study is the percent change in plasma oxalate from baseline to month six.

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

Renal function, frequency and mode of dialysis, frequency of renal stone events, and measures of systemic oxalosis will also be evaluated in the extension period of the study.

• In addition to our ILLUMINATE program, we intend to evaluate the safety and efficacy of lumasiran in patients with recurrent kidney stones in a Phase 2 study planned to initiate in late 2021.

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.

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) for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, and is the first RNAi therapeutic approved for a common disease.

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

Based on the results of the ORION clinical development program, in December 2020, following a positive CHMP opinion, the EC granted marketing authorization for Leqvio (inclisiran) for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet:

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.

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.

In December 2020, following a positive CHMP opinion, the EC granted marketing authorization for Leqvio (inclisiran) for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet:

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

In December 2020, the FDA issued a complete response letter regarding Novartis' NDA for inclisiran, stating that the agency could not approve the NDA by the Prescription Drug User Fee Act, or PDUFA, action date due to unresolved facility inspection-related conditions.

Novartis is working closely with the third-party manufacturer and the FDA to obtain approval as soon as possible, and has guided for a resubmission of its NDA in Q2-Q3 2021.

Inclisiran has also been granted Orphan Drug Designation in the U.S.

In December 2021, the FDA approved 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.

Leqvio has also been granted Orphan Drug Designation in the U.S.

for the treatment of homozygous familial hypercholesterolemia, or HoFH.

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

2 unchanged sentences

Second, not all subjects tolerate statins or are able to take statins at sufficiently-intensive doses.

Third, observational studies have demonstrated that >50% of patients do not

adhere to statin therapy for more than six months.

Third, observational studies have demonstrated that >50% of patients do not adhere to statin therapy for more than six months.

Despite statins alone or in combination with other lipid lowering medications, current therapies for the management of elevated LDL-C remain insufficient in some subjects.

4 unchanged sentences

A description of the MDCO agreement is included below under the heading “Strategic Alliances and Collaborations.”

Regulatory filings for inclisiran were based on positive results from the robust ORION clinical development program that included a comprehensive set of clinical trials to assess LDL-C lowering and safety in over 3,600 patients.

Regulatory filings and approvals for Leqvio were based on positive results from the robust ORION clinical development program that included a comprehensive set of clinical trials to assess LDL-C lowering and safety in over 3,600 patients.

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.

Additional Late-Stage Clinical Development Programs

Fitusiran — Hemophilia

Fitusiran is an investigational, subcutaneously administered RNAi therapeutic targeting antithrombin, or AT, for the treatment of people with hemophilia A and B, with and without inhibitors.

Fitusiran is an investigational, subcutaneously administered RNAi therapeutic targeting antithrombin, or AT, for the treatment of people with hemophilia A and B, with and without inhibitors, in collaboration with our partner, Sanofi.

Fitusiran is designed to lower levels of AT with the goal of promoting sufficient thrombin generation to prevent bleeding.

9 unchanged sentences

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

In October 2020, Sanofi Genzyme 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 Genzyme announced that it would resume fitusiran dosing in ongoing adolescent and adult clinical studies.

Sanofi Genzyme has since resumed fitusiran dosing in ongoing adolescent and adult studies in certain countries with protocol amendments to address adjustments to dose and dosing regimen.

To allow for the appropriate collection and assessment of safety and efficacy data under the amended protocols, Sanofi Genzyme expects that global regulatory submission timelines for the adult and adolescent studies will be delayed, subject to alignment with health authorities.

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.

Sanofi has since resumed fitusiran dosing in all ongoing studies with protocol amendments to address adjustments to dose and dosing regimen.

To allow for the appropriate collection and assessment of safety and efficacy data under the amended protocols with additional lower doses, Sanofi expects that global regulatory submission timelines for the adult and adolescent studies will be delayed, subject to alignment with health authorities, and in October 2021, Sanofi announced that the potential filing date for fitusiran had been moved to 2024.

Fitusiran has received both U.S.

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

In January 2018, we and Sanofi Genzyme 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 Genzyme has global rights to develop and commercialize fitusiran and any back-up products.

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

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.

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

2 unchanged sentences

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 enrollment in our Phase 2 clinical trial of cemdisiran in patients with IgA nephropathy is ongoing.

Cemdisiran is also being evaluated by our partner, Regeneron, in combination with Regeneron’s pozelimab (REGN3918), an anti-C5 monoclonal antibody, in a Phase 1 study in normal healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria.

ALN-AGT — Hypertension

ALN-AGT is a subcutaneously administered, investigational RNAi therapeutic targeting liver-expressed angiotensinogen for the treatment of hypertension in high unmet need populations.

Hypertension is a complex multifactorial disease clinically defined as a systolic blood pressure of above 130 mm Hg or a diastolic blood pressure of greater than 80 mm Hg.

Approximately 47 percent of U.S.

adults live with hypertension with more than half of patients on medication remaining above the blood pressure target level.

Despite the availability of antihypertensive medications, there remains an unmet medical need, particularly given the poor rates of adherence to existing therapies and peak and trough effects.

In particular, there are a number of high unmet need settings where novel approaches to hypertension are warranted, including resistant and refractory hypertension, chronic kidney disease, and heart failure.

In November 2020, we reported positive interim data from the ongoing Phase 1 study of ALN-AGT, and we expect to initiate the KARDIA-1 and -2 Phase 2 studies of ALN-AGT in mid-2021.

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.

Zilebesiran (formerly ALN-AGT) — Hypertension

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen, or AGT, in development for the treatment of hypertension in high unmet need populations.

AGT is the most upstream precursor in the renin-angiotensin-aldosterone system, a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established anti-hypertensive effects.

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

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.

More than one billion people worldwide live with hypertension.

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

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

6 unchanged sentences

The safety and efficacy of VIR-2218 are currently being investigated in an ongoing Phase 2 trial.

In addition, Vir initiated a Phase 2 combination trial of VIR-2218 with pegylated interferon-alpha, with initial clinical data anticipated in 2021.

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.

ALN-HSD – Non-alcoholic Steatohepatitis

6 unchanged sentences

There are currently no approved medical therapies for NASH.

In November 2020, we announced that we had initiated dosing in a Phase 1 study to evaluate the safety and preliminary pharmacodynamic activity of ALN-HSD in healthy volunteers and patients with NASH .

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

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.

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 four or more investigational new drug applications, or INDs, or CTAs from our organic product engine per year by the end of 2025.

We also intend to continue to build on our progress with extra-hepatic delivery during 2021, advancing our eye and CNS programs under our collaboration with Regeneron, as well as continuing to advance lung delivery of RNAi therapeutics in connection with our SARS-COV-2 genome collaboration with our partners at Vir.

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.

Our Collaboration and Licensing Strategy

4 unchanged sentences

In July 2020, Regeneron exercised its co-development/co-commercialization option on our first CNS-targeted development candidate, ALN-APP, an investigational RNAi therapeutic in development for the treatment of hereditary cerebral amyloid angiopathy and autosomal dominant Alzheimer’s Disease, which we are leading.

With respect to our Cardio-Metabolic pipeline, in March 2013, we entered into an exclusive, worldwide license with MDCO (acquired by Novartis in January 2020) pursuant to which MDCO was granted the right to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases,

including inclisiran.

We are also advancing multiple other programs with Regeneron.

In March 2018, we entered into a discovery collaboration with Regeneron to identify RNAi therapeutics for NASH, and potentially other related diseases, and in November 2018, we and Regeneron entered into a separate, fifty-fifty collaboration to further research, co-develop and commercialize any therapeutic product candidates that emerge from these discovery efforts.

1 unchanged sentence

With respect to our Hepatic Infectious Disease pipeline, in October 2017, we announced an exclusive licensing agreement with Vir for the development and commercialization of RNAi therapeutics for infectious diseases, including chronic HBV infection.

In April 2020, we further expanded our broad multi-target existing collaboration for the development and commercialization of RNAi therapeutics for infectious diseases to include up to three additional targets focused on host factors for SARS-CoV-2, including angiotensin converting enzyme-2, or ACE2, and transmembrane protease, serine 2, or TMPRSS2.

With respect to our Genetic Medicine pipeline, we formed a broad strategic alliance with Sanofi Genzyme in 2014.

In January 2018, we and Sanofi Genzyme 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 Genzyme 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 Genzyme agreed to further amend the 2014 Sanofi Genzyme collaboration to conclude the research and option phase and to amend and restate the AT3 License Terms to modify certain of the business terms.

In March 2020, we announced an expansion of our exclusive licensing agreement with Vir to include the development and commercialization of RNAi therapeutics targeting SARS-CoV-2, the virus that causes the disease COVID-19, which we further expanded in April 2020 to include up to three additional targets focused on host factors for SARS-CoV-2, including angiotensin converting enzyme-2, or ACE2, and transmembrane protease, serine 2, or TMPRSS2, and potentially a third mutually selected host factor target.

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.

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.

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.

We also have entered into license agreements to obtain rights to intellectual property in the field of RNAi.

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

For example, in 2021, we entered into a license and collaboration agreement with PeptiDream to discover and develop peptide-siRNA conjugates leveraging PeptiDream's proprietary Peptide Discovery Platform System technology.

Strategic Alliances and Collaborations

16 unchanged sentences

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

In July 2020, Regeneron exercised its co-development/co-commercialization option on our first CNS-targeted development candidate, ALN-APP, an investigational RNAi therapeutic in development for the treatment of hereditary cerebral amyloid angiopathy a nd autosomal dominant Alzheimer’s Disease, which we are leading.

We are also advancing multiple other programs with Regeneron.

For more information regarding the Regeneron Collaboration, including the ongoing or expected 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.

Sanofi Genzyme.

In January 2014, we entered into a global, strategic collaboration with Sanofi Genzyme to discover, develop and commercialize RNAi therapeutics as Genetic Medicines to treat orphan diseases, referred to as the 2014 Sanofi Genzyme collaboration.

The 2014 Sanofi Genzyme collaboration superseded and replaced the previous collaboration between us and Sanofi Genzyme entered into in October 2012 to develop and commercialize RNAi therapeutics targeting TTR for the treatment of hATTR amyloidosis, including patisiran and revusiran, in Japan and the Asia-Pacific region.

In January 2018, we and Sanofi Genzyme entered into an amendment to our 2014 Sanofi Genzyme collaboration.

In connection and simultaneously with entering into the 2018 amendment to the 2014 Sanofi Genzyme collaboration, we and Sanofi Genzyme 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 Genzyme has the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products.

In January 2014, we entered into a global, strategic collaboration with Sanofi to discover, develop and commercialize RNAi therapeutics as Genetic Medicines to treat orphan diseases, referred to as the 2014 Sanofi collaboration.

The 2014 Sanofi collaboration superseded and replaced the previous collaboration between us and Sanofi entered into in October 2012 to develop and commercialize RNAi therapeutics targeting TTR for the treatment of hATTR amyloidosis, including patisiran and revusiran, in Japan and the Asia-Pacific region.

In January 2018, we and Sanofi entered into an amendment to our 2014 Sanofi collaboration.

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.

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.

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 pursuant to the A&R AT3 License Terms, to modify certain of the business terms.

The material collaboration terms for fitusiran were unchanged.

Under the A&R AT3 License Terms, we are eligible to receive tiered royalties of 15% to 30% based on global annual net sales of fitusiran and up to 15% based on global annual net sales of any back-up products controlled by Sanofi, in each case by Sanofi, its affiliates and its sublicensees.

In connection with entering into the 2019 amendment and the A&R AT3 License Terms, we agreed to advance, at our cost, a selected investigational asset in an undisclosed rare genetic disease through the end of IND-enabling studies.

Following completion of such studies, we will transition, at our cost, such asset to Sanofi Genzyme.

Thereafter, Sanofi Genzyme will fund all potential future development and commercialization costs for such asset.

Following completion of such studies, we will transition, at our cost, such asset to Sanofi.

Thereafter, Sanofi will fund all potential future development and commercialization costs for such asset.

If this asset is approved, we will be eligible to receive tiered double-digit royalties on global net sales.

For more information regarding the 2014 Sanofi Genzyme collaboration, as amended in January 2018 and April 2019, as well as the Exclusive TTR License and the A&R AT3 License Terms, including the ongoing or expected 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.

In February 2013, we and MDCO entered into a license and collaboration agreement pursuant to which we granted to MDCO an exclusive, worldwide license to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases.

1 unchanged sentence

In late 2015, MDCO assumed responsibility for all development and commercialization of inclisiran, at its sole cost.

In January 2020, MDCO was acquired by Novartis and in December 2020, the EC granted marketing authorization for Leqvio (inclisiran) for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, following a positive CHMP opinion.

Inclisiran remains under regulatory review in the U.S.

In December 2020, the FDA issued a complete response letter regarding Novartis' NDA for inclisiran, stating that the agency could not approve the NDA by the PDUFA action date due to unresolved facility inspection-related conditions.

For more information regarding the MDCO 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.

In January 2020, MDCO was acquired by Novartis and in December 2020, the EC granted marketing authorization for Leqvio (inclisiran) for the treatment of adults with hypercholest erolemia or mixed dyslipidemia, following a positive CHMP opinion.

In December 2021, Leqvio was approved by the FDA for the treatment of adults with HeFH or clinical ASCVD as an adjunct to diet and maximally tolerated dose of statin .

For more information regarding the MDCO agreement, including its ongoing financial and accounting impact on our business, p lease 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.

Vir Biotechnology, Inc.

In October 2017, we and Vir entered into a collaboration and license agreement pursuant to which we granted to Vir an exclusive license to develop, manufacture and commercialize ALN-HBV02 (VIR-2218), for all uses and purposes other than certain excluded fields, as set forth in the agreement.

In October 2017, we and Vir entered into a collaboration and license agreement, or the Vir Agreement, pursuant to which we granted to Vir an exclusive license to develop, manufacture and commercialize ALN-HBV02 (VIR-2218), for all uses and purposes other than certain excluded fields, as set forth in the agreement.

In addition, we granted Vir an exclusive option for up to four additional RNAi therapeutics programs for the treatment of infectious diseases.

In March and April 2020, we entered into amendments to the Vir Agreement to expand our collaboration to include the development and commercialization of RNAi therapeutics targeting SARS-CoV-2, the virus that causes the disease COVID-19, along with three additional targets focused on human host factors for SARS-CoV-2, including ACE2 and TMPRSS2 and potentially a third mutually selected host factor target.

We further amended the Vir Agreement in December 2020, such that we are solely responsible for conducting pre-clinical research activities under the pre-clinical development plan at our discretion and sole expense and effective as of July 1,

2020, we are responsible for all pre-clinical development costs incurred under such plan.

We further amended the Vir Agreement in December 2020, such that we were solely responsible for conducting pre-clinical research activities under the pre-clinical development plan at our discretion and sole expense and effective as of July 1, 2020, we were responsible for all pre-clinical development costs incurred under such plan.

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.

2 unchanged sentences

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

In connection with the collaboration, Blackstone will provide us up to $2.0 billion in financing, including $1.0 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and ALN-AGT pursuant to the funding agreement finalized in August 2020.

In connection with the collaboration, Blackstone agreed to provide us up to $2.0 billion in financing, including $1.0 billion in committed payments to acquire 50% of royalties and 75% of commercial milestones payable to us in connection with sales of Leqvio, up to $750.0 million in a first lien senior secured term loan, and up to $150.0 million towards the development of vutrisiran and zilebesiran (formerly ALN-AGT) pursuant to the funding agreement finalized in August 2020.

In November 2021, Blackstone elected to opt-in to Phase 2 clinical trial funding of zilebesiran, committing to fund, upon meeting certain patient enrollment thresholds, up to $26.0 million.

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

Please read Note 5 and Note 8 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this annual report on Form 10-K for additional details on our transaction with Blackstone.

Please read Note 5 and Note 8 to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this Annual Report on Form 10-K for additional details on our transaction with Blackstone, including its ongoing financial and accounting impact on our business.

Other Strategic License Agreements

Dicerna Pharmaceuticals, Inc.

In April 2020, we and Dicerna 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 DCR-A1AT, investigational RNAi therapeutics, each in Phase 1/2 development, will be explored for the treatment of alpha-1 liver disease.

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.

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.

PeptiDream, Inc.

In July 2021, we entered into a license and collaboration agreement with PeptiDream to discover and develop peptide-siRNA conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver.

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

Under the terms of the alliance, we will select a set of receptors for PeptiDream’s peptide discovery platform.

PeptiDream will select, optimize, and synthesize peptides for each receptor.

We will then generate peptide-siRNA conjugates and perform in vitro and in vivo studies to support final peptide selection.

For more information regarding the collaboration agreement with PeptiDream, 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.

In January 2022, we announced that we and Novartis, entered into a collaboration and license agreement, referred to as the Novartis License Agreement, pursuant to which we granted to Novartis an exclusive, worldwide license to develop, manufacture and commercialize siRNAs targeting end-stage liver disease, potentially leading to the development of a treatment designed to promote the regrowth of functional liver cells and to provide an alternative to transplantation for patients with liver failure.

Under the terms of the collaboration, we will develop and test potential siRNAs using target-specific assays developed by Novartis.

Upon identification of a lead candidate, further development and clinical research will be conducted by Novartis.

Pursuant to the Novartis License Agreement, we received an upfront fee, and may also receive milestone payments upon the achievement of certain development, regulatory and commercial milestones, as well as tiered royalties on the net sales of licensed products ranging from high-single-digit to sub-teen double-digit percentages.

For more information regarding the Novartis License 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.

Ionis Pharmaceuticals, Inc.

5 unchanged sentences

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.

10 unchanged sentences

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 our marketed products in the U.S.

Below is a summary of 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

54 unchanged sentences

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

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

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

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

2 unchanged sentences

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 ® , the ONPATTRO logo, GIVLAARI ® and the GIVLAARI logo with registration pending for OXLUMO ™ and the OXLUMO logo.

Intellectual Property Challenges

As the field of RNAi therapeutics is maturing, patent applications are being fully processed by national patent offices around the world.

There is uncertainty about which patents will issue, and, if they do, as to when, to whom and with what claims.

It is likely that there will be significant litigation and other proceedings, such as interference, reexamination, inter partes review, post-grant review and opposition proceedings, in various patent offices relating to patent rights in the RNAi field.

On September 16, 2012, the America Invents Act, or AIA, went into effect and provided for expanded patent challenge, i.e., inter partes review and post-grant review.

These provide additional opportunities for third parties to challenge our patents.

For example, a third party has filed an opposition in the European Patent Office, or EPO, against our owned patent EP 2723758, with claims directed to compositions and methods of ANGPTL3, arguing that the granted claims are invalid.

We expect that additional oppositions will be filed in the EPO and elsewhere, and other challenges will be raised relating to other patents and patent applications in our portfolio.

In many cases, the possibility of appeal exists for either us or our opponents, and it may be years before final, unappealable rulings are made with respect to these patents in certain jurisdictions.

Given the importance of our intellectual property portfolio to our business operations, we intend to vigorously enforce our rights and defend against challenges that have arisen or may arise in this area.

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.

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

We face a broad spectrum of current and potential competitors, ranging from very large, global pharmaceutical companies with significant resources, to other biotechnology companies with resources and expertise comparable to our own, to smaller biotechnology companies with fewer resources and expertise than we have.

We believe that

for most or all of our drug development programs, there will be one or more competing programs under development at other companies.

We believe that for most or all of our drug development programs, there will be one or more competing programs under development at other companies.

In some cases, the companies with competing programs will have access to greater resources and expertise than we do and may be more advanced in those programs.

6 unchanged sentences

Some of these companies are seeking, as we are, to develop chemically synthesized siRNAs as drugs.

Others are following a gene therapy approach, with 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 Takeda Pharmaceutical Company Ltd., or Takeda, Marina Biotech, Inc., or Marina, Arrowhead Pharmaceuticals, Inc., or Arrowhead, and its subsidiary, Calando Pharmaceuticals, Inc., or Calando, Quark Pharmaceuticals, Inc., or Quark, F.

Hoffmann-La Roche Ltd, or Roche, Silence Therapeutics plc, or Silence, and its collaborators, AstraZeneca plc, or AstraZeneca, and Mallinckrodt plc, Arbutus Biopharma Corp., or Arbutus, Sylentis, S.A.U., or Sylentis, Dicerna, and its collaborators, Boehringer Ingelheim, Novo Nordisk A/S, Alexion Pharmaceuticals, Inc.

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, Amgen Pharmaceuticals Inc., or Amgen, BioPath Holding Inc.

and Arcturus Therapeutics, Inc., or Arcturus.

Others are following a gene therapy approach, with

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.

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.

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.

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

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

2 unchanged sentences

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.

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

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.

8 unchanged sentences

Indications vary by country/region for each product.

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

We believe that the following approved drugs and, if approved, drug candidates, could compete with ONPATTRO and, if approved, vutrisiran:

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:

Drug Company Drug Description Phase Administration/Dosing

3 unchanged sentences

Small molecule drug to stabilize TTR protein Approved to treat ATTR cardiomyopathy in the U.S., EU and Japan;

(indication varies by region)

Daily oral capsule

TEGSEDI (inotersen) Ionis ASO to reduce production of TTR Protein Approved in U.S., EU, Canada and Brazil for hATTR polyneuropathy (indication varies by region) Weekly subcutaneous injection (SC)

IONIS-TTR-L Rx

Ionis ASO to reduce production of TTR Protein Phase 3 Monthly SC

Acoramidis (AG10) Eidos Therapeutics, Inc.

(indication varies by region) Daily oral capsule

TEGSEDI (inotersen) Ionis Anti-sense oligonucleotide, or ASO, to reduce production of TTR Protein Approved in U.S., EU, Canada and Brazil for hATTR polyneuropathy (indication varies by region) Weekly subcutaneous injection (SC)

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:

Drug Company Drug Description Phase Administration/Dosing

Eplontersen (IONIS-TTR-L Rx )

Ionis & AstraZeneca

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

Acoramidis (AG10) BridgeBio Pharma, Inc.

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

PRX004 Prothena Corporation plc mAb to clear amyloid deposits Phase 1 Intravenous (IV)

Diflunisal N/A (generic) Small molecule repurposed generic drug Not indicated for the treatment of ATTR amyloidosis Twice daily oral dose

Tolcapone SOM Innovation Biotech, S.L.

Small molecule repurposed generic drug Phase 1/2 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

NTLA-2001 Intellia Therapeutics, Inc.

CRISPR/Cas9 gene therapy Phase 1 Intravenous (IV)

& Regeneron CRISPR/Cas9 gene therapy 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.

7 unchanged sentences

Primary Hyperoxaluria.

In addition to OXLUMO, which was recently approved in the U.S.

In addition to OXLUMO, which was approved in the U.S.

for the treatment of primary hyperoxaluria, or PH, type 1, and in the EU for the treatment of PH type 1 in patients of all ages, currently used treatments for PH include hyper hydration, oral citrate or dual liver/kidney transplantation.

4 unchanged sentences

Drug Company Drug Description Phase Administration/Dosing

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

Oxabact OC5 OxThera AB Anaerobic bacteria that metabolize oxalate in the gut Phase 3 Twice daily oral dose

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

BBP-711 BridgeBio Pharma, Inc.

GO inhibitor Phase 1 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.

3 unchanged sentences

Hypercholesterolemia.

In addition to Leqvio, which was approved in the EU in December 2020 for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, the current standard of care for patients with hypercholesterolemia includes

the use of dietary changes, lifestyle modification and the use of pharmacologic therapy.

In addition to Leqvio, which was approved in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia and in the U.S.

for the treatment of adults with HeFH or clinical ASCVD as an adjunct to diet and maximally tolerated dose of statin, the current standard of care for patients with hypercholesterolemia includes the use of dietary changes, lifestyle modification and the use of pharmacologic therapy.

Front line therapy consists of HMG-CoA reductase inhibitors, commonly known as statins, which block production of cholesterol by the liver and increase clearance of LDL-C from the bloodstream.

Several anti-PCSK9 antibodies have also been approved for the treatment of hypercholesterolemia in the U.S.

Other PCSK9-targeted approaches are in development at a number of companies.

Other PCSK9-targeted approaches and other cholesterol lowering agents are in development at a number of companies.

We believe that the following approved drugs and, if approved, drug candidates, could compete with Leqvio:

1 unchanged sentence

Repatha Amgen Anti-PSCK9 mAb Approved SC

Praluent Sanofi Genzyme Anti-PSCK9 mAb Approved SC

Praluent Sanofi Anti-PSCK9 mAb Approved SC

Vascepa Amarin Corporation Omega-3 lipid proven to reduce LDL-C and CV Risk Approved Oral

1 unchanged sentence

Oral fatty acid and cholesterol synthesis dual inhibitor Approved Oral

REGN1500 (evinacumab) Regeneron Anti-ANGPTL3 mAb for hypercholesterolemia Phase 3 in HoFH SC

Arrowhead- ARO-ANG3 Arrowhead siRNA targeting ANGPTL3 Phase 1/2 SC

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

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

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

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

11 unchanged sentences

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

Marstacimab (Pfizer) Anti-TFPI antibody Phase 3 SC - Weekly

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

2 unchanged sentences

rAAV5 FIX gene therapy Phase 3 IV - Single Administration

SPK-9001 (Roche, through its acquisition of Spark Therapeutics) Spark200 AAV FIX gene therapy Phase 3 IV - Single Administration

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

Spark200 AAV FIX gene therapy Phase 3 IV - Single Administration

Inhibitor Patients

20 unchanged sentences

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 FDA 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.

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.

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.

2 unchanged sentences

Nonclinical tests include laboratory evaluation of product chemistry and formulation, as well as animal testing to assess the potential safety and efficacy of the product.

The conduct of the nonclinical tests and formulation of compounds for testing must comply with federal regulations and requirements including FDA’s good laboratory practice requirements.

The conduct of the nonclinical tests and formulation of compounds for testing must comply with applicable federal regulations and requirements, including in some cases the FDA’s good laboratory practice requirements and the Animal Welfare Act.

The results of nonclinical testing are submitted to the FDA as part of an IND, together with chemistry, manufacturing and controls, or CMC, information, analytical and stability data, a proposed clinical trial protocol and other information.

4 unchanged sentences

We, an IRB, or the FDA may, at any time, suspend, terminate, significantly modify, restrict or impose a clinical hold on ongoing clinical trials.

For example, in October 2016, we decided to discontinue development of revusiran, an investigational RNAi therapeutic that was in development for the treatment of patients with cardiomyopathy due to hATTR amyloidosis, due to safety concerns.

If the FDA imposes a clinical hold, clinical trials cannot commence or recommence without FDA authorization, and then the clinical trials can commence or recommence only under the terms authorized by the FDA.

13 unchanged sentences

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 also may 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.

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.

3 unchanged sentences

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.

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.

The cost of preparing and submitting an NDA is substantial.

1 unchanged sentence

For fiscal year 2022, the application fee for each NDA requiring clinical data is approximately $3.1 million.

PDUFA also imposes an annual program fee for each approved prescription drug, which has been set at approximately $336,000 for fiscal year 2021.

The PDUFA also imposes an annual program fee for each approved prescription drug, which has been set at approximately $369,000 for fiscal year 2022.

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

6 unchanged sentences

The FDA has agreed to specified performance goals regarding the timing of the completion of its review of NDAs, although the goals are not binding and the FDA does not always meet these goals.

The review process is often significantly extended by FDA requests for additional information or clarification regarding information provided in the submission.

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

The review process is often significantly extended by the FDA's requests for additional information or clarification regarding information provided in the submission.

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

The FDA may waive the review of an advisory committee and is not bound by the recommendation of an advisory committee, but it often follows such recommendations.

1 unchanged sentence

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 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 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.

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.

1 unchanged sentence

Once granted, product approvals may be further limited or withdrawn if compliance with regulatory standards is not maintained or safety or other problems are identified following initial marketing.

Post-Approval Regulation

Once an NDA is approved, a product will be subject to certain post-approval requirements, including requirements for manufacturing establishment registration and product listing, AE reporting, submission of other periodic reports, field alerts, recordkeeping, product sampling and distribution.

16 unchanged sentences

In some instances, the FDA could require separate, additional approvals or clearances for the modified device.

If the FDA does require separate, additional approvals or clearances for the modified device, the FDA could require either a premarket application, or PMA, a 510(k) clearance, or a de novo classification, depending on the risk classification of the modified device and the availability of legally marketed predicate devices.

If the FDA does require separate, additional approvals or clearances for the modified device, the FDA could require either a premarket approval application, or PMA, a 510(k) clearance, or a de novo classification, depending on the risk classification of the modified device and the availability of legally marketed predicate devices.

Approval of PMAs are required for class III medical devices, which are devices for which insufficient information exists to provide reasonable assurance of the safety and effectiveness of the device through general controls and special controls.

3 unchanged sentences

If no such legally marketed predicate device exists, but the applicant believes the device should not be automatically classified into class III, the applicant can submit an application for de novo classification, which is a request to FDA to classify the device into class I or II based on certain general and, if applicable, special controls that are necessary to provide reasonable assurance of safety and effectiveness of the device.

In addition, if the FDA requires a separate, additional approval or clearance for a delivery device to be used with our products, and the delivery device is owned by another company, we would need that company’s cooperation to implement the necessary changes to the device and to obtain any additional approvals or clearances, described above.

In addition, if the FDA requires a separate, additional approval or clearance for a delivery device to be used with our products, and the delivery device is owned by another company, we will need that company’s cooperation to implement the necessary changes to the device and to obtain any additional approvals or clearances, described above.

Obtaining such additional approvals or clearances, and cooperation of other companies, when necessary, could significantly delay, and increase the cost of obtaining marketing approval, which could reduce the commercial viability of a product candidate.

41 unchanged sentences

Pediatric Study Plans

The FDCA, as amended by the Food and Drug Administration Safety and Innovation Act of 2012, or FDASIA, requires that a sponsor who is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-phase 2 meeting or as may be agreed between the sponsor and the FDA.

The FDCA requires that a sponsor who is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-phase 2 meeting or as may be agreed between the sponsor and the FDA.

Drugs with Orphan Drug Designation are exempt from these requirements to the extent that the indication being sought under the marketing application is within the scope of the designated orphan use.

4 unchanged sentences

The FDA has a Fast Track program that is intended to facilitate development and expedite the process for reviewing new drugs and biological products that meet certain criteria.

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.

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.

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.

1 unchanged sentence

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, 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 has also granted Fast Track designation to vutrisiran for the treatment of the polyneuropathy of hATTR amyloidosis.

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.

7 unchanged sentences

Breakthrough Therapy Designation

FDASIA also amended the FDCA to create the “breakthrough therapy” designation.

A drug or biological product can be designated as a breakthrough therapy if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that it may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

15 unchanged sentences

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

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.

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

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.

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.

3 unchanged sentences

In addition, significant uncertainty exists as to the reimbursement status of newly approved healthcare products.

We may need to conduct expensive health care economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to incurring the costs required to obtain FDA approvals.

We may need to conduct expensive healthcare economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to incurring the costs required to obtain FDA approvals.

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

1 unchanged sentence

Lack of adequate third-party reimbursement may mean we are not able to maintain price levels sufficient to realize an appropriate return on our investment in product development.

Factors payors consider in determining reimbursement are based on whether the product is:

• a covered benefit under its health plan;

• safe, effective and medically necessary;

• appropriate for the specific patient;

• cost-effective;

• neither experimental nor investigational.

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

9 unchanged sentences

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.

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 health care is financed by both governmental and private insurers.

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.

Among the provisions of the ACA of greatest importance to the pharmaceutical industry are the following:

8 unchanged sentences

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 hole”).

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

• The ACA imposed an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic products;

the fee is apportioned among these entities according to their market share in

certain government healthcare programs.

the fee is apportioned among these entities according to their market share in certain government healthcare programs.

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

12 unchanged sentences

We cannot predict what affect further changes to the ACA would have on our business.

Health Care Fraud and Abuse

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

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

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

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

In addition to the federal anti-kickback law, many states have their own laws that are analogous to the federal anti-kickback law, but may apply regardless of whether any federal or state health care program business is involved.

Healthcare Fraud and Abuse

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

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

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

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 health care 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.

3 unchanged sentences

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

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

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

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

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.

As described above, the federal Sunshine Act requires manufacturers to report certain payments to health care providers to CMS.

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

provided to other healthcare providers.

As described above, the federal Sunshine Act requires manufacturers to report certain payments to healthcare providers to CMS.

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

Some states prohibit these expenditures altogether.

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

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

Possible Change in Laws or Policies

3 unchanged sentences

Federal budget uncertainties or spending reductions may reduce the capabilities of the FDA, extend the duration of required regulatory reviews, and reduce the availability of clinical research grants.

Our present and future business has been and will continue to be subject to various other laws and regulations.

Various laws, regulations and recommendations relating to safe working conditions, laboratory practices, the experimental use of animals, and the purchase, storage, movement, import, export and use and disposal of hazardous or potentially hazardous substances are or may be applicable to our activities.

As noted above, the extent of government regulation, which might result from future legislation or administrative action, cannot accurately be predicted.

EU Regulatory Considerations

8 unchanged sentences

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

Under the new Regulation on Clinical Trials, which is currently not expected to come into application before December 2021, there will be 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.

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.

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

12 unchanged sentences

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 that is currently expected to take effect no earlier than December 2021.

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

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.

17 unchanged sentences

MAAs for generic medicinal products do not need to include the results of pre-clinical studies and clinical trials, but instead can refer to the data included in the marketing authorisation of a reference product for which regulatory data exclusivity has expired.

If a marketing authorisation is granted for a medicinal product containing a new active substance, that product benefits from eight years of data exclusivity, during which generic MAAs referring to the data of that product may not be accepted by the regulatory authorities, and a further two years of market exclusivity, during which such generic products may not be placed on the market.

The two-year period may be extended to three years if during the first eight years a new therapeutic indication with significant clinical benefit over existing therapies is approved.

If a marketing authorisation is granted for a medicinal product containing a new active substance, that product benefits from eight years of data exclusivity, during which generic MAAs referring to the data of that product will not be accepted by the regulatory authorities, and a further two years of market exclusivity, during which such generic products may not be placed on the market.

The two-year market exclusivity period may be extended to three years if during the first eight years of the product's authorisation, a new therapeutic indication with significant clinical benefit over existing therapies is approved.

There is a special regime for biosimilars, or biological medicinal products that are similar to a reference medicinal product but that do not meet the definition of a generic medicinal product, for example, because of differences in raw materials or manufacturing processes.

4 unchanged sentences

The EMA’s Committee for Orphan Medicinal Products, or COMP, may recommend orphan medicinal product designation to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than five in 10,000 persons in the EU.

Additionally, designation is granted for products intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition and when, without incentives, it is unlikely that sales of the product in the EU would be sufficient to justify the necessary investment in developing the medicinal product.

The COMP may only recommend orphan medicinal product designation when the product in question offers a significant clinical benefit over existing approved products for the relevant indication.

Additionally, designation is granted for products intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition when, without incentives, it is unlikely that sales of the product in the EU would be sufficient to justify the necessary investment in developing the medicinal product.

The COMP may only recommend orphan medicinal product designation when the product in question offers a significant clinical benefit over existing approved products for the relevant indication or where no satisfactory method of diagnosis, prevention or treatment of such condition exists.

Following a positive opinion by the COMP, the EC adopts a decision granting orphan status.

1 unchanged sentence

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 the second medicinal product is safer, more effective or otherwise clinically superior.

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, as well as vutrisiran, givosiran, lumasiran 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 and fitusiran have been granted orphan medicinal product designation.

Post-Approval Controls

19 unchanged sentences

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

Foreign Regulation of New Drug Compounds

Regulation of New Drug Compounds in Other Jurisdictions

In addition to regulations in the U.S.

11 unchanged sentences

Health Canada may conduct site inspections to verify whether the conduct of a trial meets the requirements of GCP.

impose conditions in relation to the conduct of clinical trials, and may require the informed consent used in the trial to be amended to address ethical concerns and privacy considerations.

An REB may impose conditions in relation to the conduct of clinical trials, and may require the informed consent used in the trial to be amended to address ethical concerns and privacy considerations.

Likewise, in Brazil, if a human clinical trial is to be carried out within the country’s territory, in addition to the CTA-like authorization and the approval by an ethics committee, the commencement of the trials may also depend on the approval by a biosecurity commission.

38 unchanged sentences

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 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, 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.

5 unchanged sentences

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.

During 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.

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.

During 2013, we manufactured our first cGMP batch of patisiran for use in our Phase 2 OLE and Phase 3 clinical trials.

1 unchanged sentence

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

In addition, during 2020, we completed construction and qualification of our cGMP manufacturing facility in Norton, Massachusetts where we will manufacture drug substance for clinical and, eventually, commercial use.

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.

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

Commercial Operations

After successfully overcoming various challenges associated with developing a new class of innovative medicines - such as solving the issue of drug delivery, optimizing our RNAi therapeutics to exhibit potency and durability of effect, and designing and carrying out comprehensive clinical trials to demonstrate the safety and clinical efficacy of our investigational products - starting in 2018, we embarked on the next part of the journey:

introducing our RNAi therapeutics to as many eligible patients in need as possible.

launching our RNAi therapeutics, based on regulatory approvals, to reach eligible patients in need.

To that end, we have continued to build a global commercial operation which has been designed to be fully integrated and to sequentially manage multiple product launches across multiple geographies.

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 from industry to enable us to commercialize our products ourselves and with collaborators in key countries

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:

1 unchanged sentence

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

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

• For fitusiran, Sanofi Genzyme has global rights to develop and commercialize fitusiran and any back-ups as a result of the 2018 amendment to the Sanofi Genzyme collaboration and the related product-specific license terms.

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

• For fitusiran, Sanofi has global rights to develop and commercialize fitusiran and any back-ups as a result of the 2018 amendment to the Sanofi collaboration and the related product-specific license terms.

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

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

ONPATTRO, 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 orphan disease education and commercialization strategy to make ONPATTRO, GIVLAARI, OXLUMO and future orphan products successful.

This begins with our Medical Affairs efforts to engage patient groups and communities, improve disease awareness and increase patient diagnosis.

We believe our Alnylam Act program and other efforts have supported improvements in diagnosis in these under-diagnosed diseases.

In addition, as part of our planned transition to a top 5 biotech in market capitalization 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 recent approval of Leqvio, the first RNAi therapeutic approved for a common disease, we believe the RNAi therapeutic profile supports the expansion to prevalent diseases, including addressing many unmet needs in common disease settings such as hypertension, NASH, gout and diabetes.

In addition, with respect to GIVLAARI, in August 2019, we entered into a U.S.

GI disease education and promotional agreement with Ironwood to leverage Ironwood’s capabilities in GI to help raise AHP awareness and bring GIVLAARI to gastroenterologists and other HCPs.

Under the agreement, Ironwood’s clinical sales specialists promote GIVLAARI in the U.S.

to the gastroenterologists and other HCPs that it already calls on for its own marketed product.

In December 2020, we amended the U.S.

We believe this partnership represents a significant opportunity to expand medical education and diagnosis for patients with AHP.

Separately, we have a proactive market access strategy that includes using value-based agreements, or VBAs, that we have formed with commercial payers in the U.S.

As of the beginning of 2021, we have completed at least 30 VBAs with multiple commercial payers, including 19 for ONPATTRO, 10 for GIVLAARI, and one for OXLUMO.

In our VBAs for GIVLAARI we introduced an ultra-rare disease Prevalence Based Adjustment that lowers the price of the medicine if the number of patients identified within a plan population exceeds the expected disease prevalence.

For OXLUMO, we have established a new VBA component called a Patient Need Adjustment that provides payers with greater budget certainty for medicines administered across a broad range of patient age groups.

Discussions with payers continue for our marketed products.

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.

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

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

and certain state Medicaid programs.

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.

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.

For OXLUMO, we established a new VBA component called a Patient Need Adjustment with the effect of providing payers with greater budget certainty for medicines administered across a broad range of patient age groups by paying a rebate if the average number of vials utilized by a plan member exceeds an established threshold.

Discussions with additional payers continue for our marketed products.

Outside of the U.S.

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.

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 we are developing, assuming regulatory approval.

With respect to commercially approved products, throughout 2020, we continued to build our commercial capabilities, assembled field teams in the U.S.

With respect to commercially approved products, throughout 2021, we continued to build our commercial capabilities, including establishing field teams in the U.S.

and other global markets, and are continuing to expand these capabilities to additional countries globally.

We are continuing to build a focused commercial team with broad experience in marketing, sales, patient access, patient services, distribution and product reimbursement, in particular for orphan diseases.

We are also continuing to incorporate 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 and GIVLAARI to also support the launch of OXLUMO, as well as the potential launch of vutrisiran, assuming regulatory approval.

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.

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 and GIVLAARI.

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

Medical Affairs

Our Global Medical Affairs organization advances our efforts through stakeholder engagement, data dissemination, and healthcare professional education, ultimately enabling diagnosis and improving patient care.

This begins with our efforts to engage patient groups and communities, improve disease awareness and increase patient diagnosis, including through support for independent third party genetic testing programs like Alnylam Act.

With a scalable framework in these capabilities, we believe our Global Medical Affairs organization is well positioned to expand to prevalent diseases.

Human Capital Management

4 unchanged sentences

During 2021, we enhanced our capabilities by adding 212 new full-time employees.

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, clinical development and operations, research, medical affairs, manufacturing, and general and administrative functions.

We expect to continue to add additional employees in 2021, with a focus on further enhancing our capabilities and increasing our capacities in these areas, as well as expanding our geographic reach as we continue the global launches of our approved medicines and prepare for the planned launch of vutrisiran, assuming regulatory approval.

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

22 unchanged sentences

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.

3 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business