What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2021-02-11 compared with 2020-02-13 · 476 added, 352 removed, 652 unchanged (56% of the section changed)

4 unchanged sentences

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.

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

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

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

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

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

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

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.

We continue to execute on our Alnylam 2020 strategy of building a multi-product, global, commercial biopharmaceutical company with a deep and sustainable clinical pipeline of RNAi therapeutics for future growth and a robust, organic research engine for sustainable innovation and great potential for patient impact.

Based on our accomplishments in 2019, we are confident we will achieve our Alnylam 2020 goals by the end of 2020.

Specifically, our broad pipeline of investigational RNAi therapeutics is focused in four Strategic Therapeutic Areas, or “STArs:” Genetic Medicines;

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;

Cardio-Metabolic Diseases;

1 unchanged sentence

and CNS/Ocular Diseases.

We now have two marketed products that are within the Genetic Medicines STAr, ONPATTRO and GIVLAARI.

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, Japan, Canada and Switzerland.

Regulatory filings in Brazil and other territories are pending and additional filings are planned for 2020.

In November 2019, we received regulatory approval for GIVLAARI from the FDA for the treatment of adults with acute hepatic porphyria, or AHP.

Givosiran is currently being reviewed under accelerated assessment by the European Medicines Agency, or EMA, for the treatment of patients with AHP and in early 2020, we announced that the Committee for Medicinal Products for Human Use, or CHMP, of the EMA has adopted a positive opinion recommending approval of givosiran for the treatment of AHP in adults and adolescents aged 12 years and older.

We have also filed a marketing authorisation application, or MAA, for givosiran in Brazil and additional regulatory filings are planned for 2020 and beyond.

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.

Regulatory filings in other territories are pending and additional filings are planned for 2021 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.

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

and EU for the treatment of PH1 in all age groups.

Regulatory filings in other territories are pending and additional filings are planned for 2021 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.

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.

These programs include our wholly owned programs:

givosiran (the non-branded drug name for GIVLAARI) for the treatment of patients with AHP, lumasiran for the treatment of primary hyperoxaluria type 1, or PH1, for which we reported positive topline results in late 2019 and have initiated a rolling New Drug Application, or NDA, submission to the FDA, patisiran (the non-branded drug name for ONPATTRO) for the treatment of transthyretin amyloidosis, or ATTR amyloidosis, with cardiomyopathy, and vutrisiran for the treatment of ATTR amyloidosis.

Inclisiran for the treatment of hypercholesterolemia and atherosclerotic cardiovascular disease, or ASCVD, is being advanced by our partner, The Medicines Company (acquired by Novartis AG in January 2020), or MDCO, and fitusiran for the treatment of hemophilia is being advanced by our partner Sanofi Genzyme, the specialty care global business unit of Sanofi.

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, MDCO, Sanofi Genzyme and Vir Biotechnology, Inc., or Vir.

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.

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.

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.

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

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

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

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

Key 2020 and Recent Highlights

1 unchanged sentence

• ONPATTRO (patisiran) – hATTR Amyloidosis with Polyneuropathy

◦ Recognized ONPATTRO net revenue of $166.4 million for the year ended December 31, 2019

◦ Attained over 750 patients worldwide on commercial ONPATTRO treatment since launch

◦ Received regulatory approvals in Canada, Japan and Switzerland

◦ Filed for regulatory approval in Brazil

◦ Achieved reimbursement approvals in the United Kingdom, the Netherlands, Belgium, Germany, Luxembourg, Switzerland, Canada and Japan

◦ Recognized ONPATTRO global net revenue of $306.1 million for the year ended December 31, 2020

◦ 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

◦ Initiated APOLLO-B Phase 3 study of patisiran for the treatment of 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

◦ Initiated the HELIOS-B Phase 3 study in patients with hereditary and wild-type ATTR amyloidosis with cardiomyopathy

◦ Continued enrollment in the HELIOS-A Phase 3 study in hATTR amyloidosis with polyneuropathy, with the study over 85% enrolled

◦ 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

Commercial/Late-Stage Pipeline

• GIVLAARI (givosiran) – Acute Hepatic Porphyria

◦ Reported positive topline and complete results from ENVISION Phase 3 study

◦ Received FDA approval of GIVLAARI for the treatment of adults with AHP

◦ Observed strong initial demand for GIVLAARI in the U.S., with 13 Start Forms received in first six weeks after FDA approval

◦ Received a positive opinion for givosiran for the treatment of AHP in adolescents and adults from CHMP in EU

◦ Filed an MAA for givosiran in Brazil

• Lumasiran – Primary Hyperoxaluria Type 1

◦ Reported positive topline results for the ILLUMINATE-A Phase 3 pivotal study of lumasiran for the treatment of PH1

◦ Initiated NDA rolling submission to the FDA, with remaining sections expected to be submitted in early 2020

◦ Completed enrollment in the ILLUMINATE-B Phase 3 study of lumasiran in PH1 patients less than six years of age with preserved renal function

◦ Initiated the ILLUMINATE-C Phase 3 study of lumasiran for the treatment of advanced PH1 in patients of all ages with advanced renal disease

◦ Received a pediatric rare disease designation from the FDA for lumasiran for the treatment of PH1

◦ Announced positive results from the ongoing Phase 2 open-label extension, or OLE, study of lumasiran

• Inclisiran – Hypercholesterolemia (in collaboration with MDCO)

◦ MDCO reported positive topline and complete results from the ORION-11 Phase 3 study in patients with ASCVD, the ORION-9 Phase 3 study in patients with heterozygous familial hypercholesterolemia, or HeFH, and the ORION-10 Phase 3 study in patients with ASCVD

◦ MDCO submitted an NDA and an MAA for inclisiran to the FDA and EMA, respectively

◦ Recognized GIVLAARI global net revenue of $55.1 million for the year ended December 31, 2020

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

◦ Received regulatory approvals in the EU, Brazil and Canada

• 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

• 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 enrollment in the ATLAS Phase 3 program for fitusiran in patients with hemophilia A or B with and without inhibitors

Early-Stage Pipeline

◦ 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

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;

initiated dosing in Phase 1 study and reported initial positive results

• ALN-AAT02 for the treatment of alpha-1 liver disease;

reported initial positive Phase 1/2 results

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;

reported initial positive Phase 1/2 results in collaboration with our partners at Vir

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

Corporate Highlights

◦ Ended 2019 with $1.55 billion in cash, cash equivalents, marketable debt and equity securities, and restricted investments

◦ Formed a broad collaboration with Regeneron to discover, develop and commercialize new RNAi therapeutics for a broad range of diseases by addressing disease targets expressed in the eye and CNS, in addition to a select number of targets expressed in the liver

• Public Offering

◦ In January 2019, sold 5,000,000 shares of our common stock through an underwritten public offering at a price to the public of $77.50 per share, receiving aggregate net proceeds of approximately $382 million

◦ Ended 2020 with $1.87 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

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 has enabled continued execution on our Alnylam 2020 strategy and the advancement of our long-term strategic goals.

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.

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

This technology enables systemic delivery with intravenous drug administration.

Results with LNP-based investigational RNAi therapeutics demonstrated potent, rapid and durable target gene silencing in pre-clinical and clinical studies.

Further, LNP-based investigational RNAi therapeutics have been found to be generally well tolerated in clinical studies conducted to date.

This technology enables systemic delivery with intravenous drug administration and is associated with potent, rapid and durable target gene silencing and an encouraging tolerability profile in clinical studies conducted to date, as well as in our commercial experience.

Our first commercial product, ONPATTRO, is formulated utilizing LNPs.

2 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, our recently-approved second medicine.

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-AAT02, ALN-HBV02 and ALN-AGT, are in the clinic, with what we believe to be 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 during 2019 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.

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.

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 two commercially approved products, providing strong support for our approach to drug development.

Moreover, we believe that our reproducible and modular platform will support the achievement of our long-term strategic goal of building a multi-product, global, commercial biopharmaceutical company with a deep and sustainable clinical pipeline of RNAi therapeutics for future growth and a robust, organic research engine for sustainable innovation and great potential for patient impact.

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.

Our Product Pipeline

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

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

Genetic Medicines;

4 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, EMA or any other health authority and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics.

Commercial Products and Late-Stage Clinical Development Pipeline

The chart below is a summary of our commercial products and late-stage development programs as of January 31, 2020.

It identifies those programs for which we have received marketing approval, those programs for which we have received Breakthrough Therapy Designation from the FDA, 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 and GIVLAARI in certain territories, with additional regulatory submissions pending.

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.

The chart below is a summary of our commercial products and late- and early-stage development programs as of January 31, 2021.

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.

Our TTR Franchise

About Transthyretin Amyloidosis (ATTR)

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

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

hATTR amyloidosis can include sensory and motor, autonomic and cardiac symptoms and is a major unmet

medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide.

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.

The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

4 unchanged sentences

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

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

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

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

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

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

Regulatory filings in Brazil and other territories are currently under review and additional filings are planned for 2020.

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

Regulatory filings in other territories are currently under review and additional filings are planned for 2021.

Patisiran – ATTR Amyloidosis with Cardiomyopathy

2 unchanged sentences

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

specific Orphan Drug Designations vary by country/region.

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.

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.

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

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

1 unchanged sentence

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

This may help to reduce the deposition and facilitate the clearance of TTR amyloid deposits in tissues like the nerves, heart and gastrointestinal tract which may potentially restore function.

Vutrisiran is currently being evaluated in the HELIOS-A and HELIOS-B Phase 3 studies and has received both U.S.

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;

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.

To date, vutrisiran has received both U.S.

and EU Orphan Drug Designations;

specific Orphan Drug Designations indications vary by country/region.

HELIOS-A Phase 3 Study

Initiated in late 2018, the HELIOS-A Phase 3 trial is a randomized, open-label Phase 3 study in hATTR amyloidosis patients.

The study is enrolling approximately 160 patients with a 3:1 randomization where 120 patients will receive a 25 mg subcutaneous injection of vutrisiran once every three months and 40 patients will receive a 0.3 mg/kg intravenous infusion of ONPATTRO once every three weeks as a reference comparator.

The study co-primary endpoints are the mean change from baseline in the modified Neuropathy Impairment Score +7, or mNIS+7, and the Norfolk Quality of Life Diabetic Neuropathy score at nine months as compared to the mean change observed in the placebo arm of the previously completed APOLLO Phase 3 study of patisiran, upon which the approval of ONPATTRO was based.

Additional secondary and exploratory endpoints will also be evaluated.

The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries.

Patients were randomized 3:1 to receive either a 25 mg subcutaneous injection of vutrisiran once every three months or 0.3 mg/kg intravenous infusion of patisiran once every three weeks as a reference comparator for 18 months.

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.

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.

◦ 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.

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

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

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

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

There were no clinically significant changes in liver function tests.

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 low-volume 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 hospitalizations.

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.

1 unchanged sentence

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

The study protocol includes an optional interim efficacy analysis to be conducted at our discretion, that could allow the study to conclude early.

Our Second Approved RNAi Therapeutic

GIVLAARI (givosiran) — Acute Hepatic Porphyria

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

Our Other Marketed Products

GIVLAARI (givosiran) — Acute Hepatic Porphyria (AHP)

GIVLAARI (givosiran) is our second approved RNAi therapeutic and the world’s first-ever GalNAc-conjugate RNA therapeutic to be approved.

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

We launched GIVLAARI in the U.S.

in December 2019.

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

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

GIVLAARI was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations in the U.S.

Givosiran is currently being reviewed under accelerated assessment by the EMA for the treatment of patients with AHP, after receiving Priority Medicines, or PRIME, Designation and Orphan Drug Designation from the EMA.

In early 2020, we announced that the CHMP of the EMA has adopted a positive opinion recommending approval of givosiran for the treatment of AHP in adults and adolescents aged 12 years and older.

We have also filed an MAA for givosiran in Brazil and additional regulatory filings are planned for 2020 and beyond.

In March 2020, the EC granted marketing authorization in the EU for GIVLAARI for the treatment of AHP in adults and adolescents aged 12 years and older.

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.

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.

8 unchanged sentences

Consequently, patients with AHP can wait up to 15 years for a confirmed diagnosis.

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

The approval of GIVLAARI in the U.S.

was based on positive results from the randomized, double-blind, placebo-controlled ENVISION Phase 3 trial, the largest ever interventional study conducted in AHP.

Full results from the ENVISION study were reported in April 2019 at the European Association for the Study of the Liver 54th Annual International Liver Congress™.

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

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.

Ironwood’s clinical sales specialists are now promoting GIVLAARI 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.

Additional Late-Stage Clinical Development Programs

Lumasiran — PH1

Lumasiran is an investigational, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1, or HAO1, mRNA in development for the treatment of PH1.

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

In December 2019, we reported positive topline results from our ILLUMINATE-A Phase 3 study of lumasiran for the treatment of PH1 and in January 2020, we announced the initiation of a rolling NDA submission for lumasiran to the FDA.

The rolling submission allows completed sections of an NDA to be reviewed by the FDA on an ongoing basis.

Specifically, we submitted the non-clinical components to the FDA and expect to submit the remaining components in early 2020.

We intend to file an MAA with the EMA in early 2020.

To date, lumasiran has received both U.S.

and EU Orphan Drug Designations, Pediatric Rare Disease and Breakthrough Therapy designations from the FDA and a PRIME designation from the EMA.

We are also conducting ILLUMINATE-B – a global Phase 3 study of lumasiran in PH1 patients less than six years of age, with results expected in mid-2020, and ILLUMINATE-C – a global Phase 3 study of lumasiran in PH1 patients of all ages with advanced renal disease, with results expected in 2021.

HAO1 encodes glycolate oxidase, or GO.

Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate – the metabolite that directly contributes to the pathophysiology and clinical manifestations of PH1.

PH1 is an ultra-rare disease in which excessive oxalate production 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 tract obstruction by calcium oxalate stones.

Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation in bones, eyes, skin, and heart, leading to severe illness and potentially death.

Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability.

Although a small minority of patients respond to vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.

PH1 affects one to

three individuals per million in the U.S.

and Europe with a higher prevalence in some parts of the world, such as the Middle East and North Africa.

• ILLUMINATE-A was a randomized, double-blind, placebo-controlled trial, designed to enroll approximately 30 patients with PH1 ages six and above, with relatively preserved renal function, at 16 study sites, in eight countries around the world, and is the largest interventional study conducted specifically in PH1.

Patients were randomized 2:1 to lumasiran or placebo, with lumasiran administered at 3 mg/kg monthly for three months followed by quarterly maintenance doses.

The primary endpoint for the study was the percent change from baseline in 24-hour urinary oxalate excretion averaged across months 3 to 6 in patients treated with lumasiran as compared to placebo.

In December, we reported positive topline results from ILLUMINATE-A.

◦ Efficacy and Safety Results :

At six months, lumasiran met the primary endpoint in patients with PH1 (p less than 0.0001) and achieved statistically significant results for all six hierarchically-tested secondary endpoints (p less than or equal to 0.001), including the proportion of lumasiran patients that achieved near-normalization or normalization of urinary oxalate levels, relative to placebo.

There were no serious or severe adverse events in the study, and results showed that lumasiran was generally well tolerated with an overall profile generally consistent with that observed in Phase 1/2 and open-label extension studies, or OLE, of lumasiran.

• ILLUMINATE-OLE:

All but one patient enrolled into the OLE phase of the study to continue dosing with lumasiran for an additional 4.5 years.

• The ILLUMINATE-B Phase 3 trial is an open-label, global, multicenter study to evaluate the efficacy and safety of lumasiran in approximately twenty patients less than six years of age, with relatively preserved renal function and a documented diagnosis of PH1.

The dosing regimen is based on patient weight.

The primary endpoint is the reduction of urinary oxalate at six months relative to baseline.

Key secondary and exploratory endpoints will evaluate additional measures of urinary oxalate, estimated glomerular filtration rate, safety and tolerability, and quality of life.

• The ILLUMINATE-C Phase 3 trial is a single-arm, open-label, global, multicenter study to evaluate the efficacy and safety of lumasiran in approximately 16 patients with advanced renal disease and a documented diagnosis of PH1.

Cohort A will enroll patients with advanced disease who do not yet require dialysis and Cohort B will enroll patients who are dialysis-dependent.

The primary endpoint is the percentage change in plasma oxalate from baseline to six months.

Key secondary endpoints will evaluate additional measures of plasma oxalate and changes in:

urinary oxalate, renal function, nephrocalcinosis, frequency and mode of dialysis, frequency of renal stone events and measures of systemic oxalosis.

Inclisiran — Hypercholesterolemia

Inclisiran is an investigational, subcutaneously administered RNAi therapeutic targeting proprotein convertase subtilisin/kexin type 9, or PCSK9, for the treatment of hypercholesterolemia.

PCSK9 is a protein involved in the regulation of low-density lipoprotein, or LDL, receptor levels on hepatocytes and the metabolism of LDL cholesterol, or LDL-C, which is commonly referred to as “bad” cholesterol.

In September 2019, our partner, MDCO, reported positive complete results from the ORION-11 Phase 3 study of inclisiran and subsequently reported positive results in its ORION-9 and ORION-10 Phase 3 studies.

In January 2020, MDCO announced that it had completed a submission to the FDA of an NDA for inclisiran in December 2019, and that it had completed a submission to the EMA of an MAA for inclisiran.

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)

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

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

OXLUMO works by degrading HAO1 mRNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate, the toxic metabolite responsible for the clinical manifestations of PH1.

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.

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

Also, in November 2020, OXLUMO (lumasiran) subcutaneous injection was approved by the FDA for the treatment of PH1 to lower urinary oxalate levels in pediatric and adult patients.

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.

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).

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.

Management options prior to availability of OXLUMO were limited to hyperhydration, crystallization inhibitors and, in a minority of patients with a specific genotype, pyridoxine (vitamin B6).

These measures do not adequately address oxalate overproduction but instead help to delay inevitable progression to kidney failure and the need for intensive dialysis as a bridge to a dual or sequential liver/kidney transplant.

Liver transplantation is the only intervention that addresses the underlying metabolic defect, but is associated with high morbidity and mortality, and life-long immunosuppression.

Prior to the approval of OXLUMO, there were no approved pharmaceutical therapies for PH1.

The regulatory approvals of OXLUMO in the U.S.

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).

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.

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.

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:

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.

4 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.

1 unchanged sentence

There is an unmet need for additional treatment options beyond currently-available treatments for lowering of the LDL-C level to reduce cardiovascular risk.

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.

In January 2020, Novartis AG completed the acquisition of MDCO.

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

ORION Phase 3 Clinical Program and Results

In 2017, MDCO initiated the ORION Phase 3 program for inclisiran, a comprehensive set of clinical trials to assess LDL-C lowering and safety in over 3,600 patients and has reported the information below with respect to the ORION program.

The Phase 3 program includes the five Phase 3 clinical trials described below and represents the largest clinical experience for an investigational RNAi therapeutic to date:

• ORION-11 – a placebo-controlled, double-blind, randomized Phase 3 study of inclisiran versus placebo (1:1) in patients (N=1,617) with ASCVD, or ASCVD-risk equivalents, and elevated LDL-C despite maximum tolerated doses of LDL-C lowering therapies, including statins.

The primary endpoints were percentage change in LDL-C from baseline to day 510 (17 months) and time-adjusted percentage change in LDL-C from baseline after day 90 (three months) and up to day 540 (18 months).

◦ The study met all primary and secondary endpoints.

Full positive results were presented in September 2019 and demonstrated that inclisiran achieved 54% LDL-C lowering with time-adjusted reductions of 50% sustained over 18 months of treatment in patients with ASCVD, with an encouraging safety profile, including no treatment-related liver or renal abnormalities.

• ORION-10 – a placebo-controlled, double-blind, randomized Phase 3 study of inclisiran versus placebo (1:1) in ASCVD patients (N=1,561).

◦ The study met all primary and secondary endpoints.

Full results were presented in November 2019 and demonstrated that inclisiran achieved 58% LDL-C lowering with time-adjusted reductions of 56% sustained over 18 months of treatment in patients with ASCVD, with an encouraging safety profile, including no treatment-related liver or renal abnormalities.

• ORION-9 – a placebo-controlled, double-blind, randomized Phase 3 study of inclisiran versus placebo (1:1) in patients (N=482) with HeFH.

The primary endpoints were percentage change in LDL-C from baseline to day 510 (17 months) and time-adjusted percentage change in LDL-C from baseline between day 90 (three months) and up to day 540 (18 months).

◦ The study met all primary and secondary endpoints.

Full results were presented in November and demonstrated that inclisiran achieved 50% LDL-C lowering with time-adjusted reductions of 45% sustained over 18 months of treatment in patients with HeFH, with an encouraging safety profile, including no treatment-related liver or renal abnormalities.

• ORION-5 – an ongoing placebo-controlled, double-blind, randomized Phase 3 study of inclisiran versus placebo (1:1) in patients (N=45) with HoFH.

The primary endpoint of the trial is percentage change in LDL-C from baseline to day 150 (five months).

• ORION-4 – a placebo-controlled, double-blind, randomized Phase 3 study of inclisiran versus placebo (1:1) in patients (N=15,000) with ASCVD.

The primary endpoint is a composite of coronary heart disease death, myocardial infarction, fatal or non-fatal ischemic stroke and urgent coronary revascularization procedures.

The secondary endpoints include a composite of coronary heart disease death or myocardial infarction, and cardiovascular death.

In February 2013, we and MDCO (acquired by Novartis in January 2020) entered into a license and collaboration agreement pursuant to which we granted to MDCO an exclusive, worldwide license to develop, manufacture and commercialize RNAi therapeutics targeting PCSK9 for the treatment of hypercholesterolemia and other human diseases.

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

A description of the MDCO agreement is included below under the heading “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.

Additional Late-Stage Clinical Development Programs

Fitusiran — Hemophilia

8 unchanged sentences

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

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

with hemophilia B.

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

Fitusiran is currently being evaluated in the ATLAS Phase 3 program and has received both U.S.

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.

Fitusiran has received both U.S.

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

ATLAS Phase 3 Clinical Program

Trial Design:

ATLAS is a global, multicenter program designed to evaluate the safety and efficacy of fitusiran in three separate trials, including patients with hemophilia A and B with or without inhibitors.

• ATLAS-INH, a nine-month, open-label, randomized, controlled trial designed to enroll approximately 50 patients with hemophilia A or B with inhibitors receiving prior on-demand therapy with bypassing agents.

• ATLAS-A/B, a nine-month, open-label, randomized, controlled trial designed to enroll approximately 120 patients with hemophilia A or B without inhibitors receiving prior on-demand therapy with factor or bypassing agents.

• ATLAS-PPX, an open-label, one-way crossover study designed to enroll approximately 70 patients with hemophilia A or B with and without inhibitors receiving prior prophylaxis therapy with factor or bypassing agents.

In this study, patients will receive standard of care factor or bypassing agent prophylaxis therapy for six months and then transition to fitusiran treatment for seven months.

The annualized bleeding rate will be prospectively measured in both periods.

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.”

Early-Stage Clinical Development Pipeline

In addition to the late-stage 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 clinical trial applications, or CTAs, beginning in 2020 from our organic product engine.

We also intend to continue to build on our progress with extra-hepatic delivery during 2020, advancing our eye and CNS programs under our collaboration with Regeneron.

The chart below is a summary of our early-stage development programs as of January 31, 2020.

It identifies those programs in which we have achieved human POC by demonstrating target gene knockdown and/or additional evidence of activity in clinical studies, the stage of these programs, and our commercial rights to such programs, as well as programs which we believe could result in an IND or CTA filing in 2020:

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.”

Early-Stage Clinical Development Programs

Cemdisiran — Complement-Mediated Diseases

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

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

Cemdisiran is currently being advanced by us as a monotherapy, and 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.

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

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

ALN-HBV02 is designed to inhibit expression of all HBV proteins, including hepatitis B surface antigen.

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

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

Current treatment options include life-long suppressive antiviral therapies.

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

The safety and efficacy of 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.

ALN-HSD – Non-alcoholic Steatohepatitis

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

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

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

Approximately 16 million people in the U.S.

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

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

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 .

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.

Our Collaboration and Licensing Strategy

Our business strategy is to develop and commercialize a broad pipeline of RNAi therapeutic products directed towards our four STArs:

Genetic Medicines;

Cardio-Metabolic Diseases;

Hepatic Infectious Diseases;

and CNS/Ocular Diseases.

Our business strategy is to develop and commercialize a broad pipeline of RNAi therapeutic products directed towards transformative rare and prevalent diseases, including continued focus on our four STArs.

As part of this strategy, we have entered into, and expect to enter into additional, collaboration and licensing agreements as a means of obtaining resources, capabilities and funding to advance our investigational RNAi therapeutic programs.

1 unchanged sentence

Specifically, with respect to our CNS/Ocular Disease pipeline, in April 2019, we entered into a global, strategic collaboration with Regeneron to discover, develop and commercialize RNAi therapeutics for a broad range of diseases by addressing disease targets expressed in the eye and CNS, in addition to a select number of targets expressed in the liver.

With respect to our Cardio-Metabolic pipeline, in March 2013, we entered into an exclusive, worldwide license with MDCO 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.

In March 2018, we entered into a discovery collaboration with Regeneron to identify RNAi therapeutics for nonalcoholic steatohepatitis, or 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.

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

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.

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.

In April 2020, we entered into a development and commercialization collaboration with Dicerna to advance investigational RNAi therapeutics for the treatment of alpha-1 liver disease.

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 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.

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.

3 unchanged sentences

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.

Strategic Alliances

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

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

Below is a brief description of our key strategic alliance and license agreements.

Strategic Alliances and Collaborations

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

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

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

Product Alliances

12 unchanged sentences

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

For more information regarding the Regeneron Collaboration, including the ongoing or expected financial and accounting impact on our business, please read Note 4, Collaboration Agreements, 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 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.

10 unchanged sentences

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, Collaboration Agreements, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this annual report on Form 10-K.

The Medicines Company.

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.

Under the MDCO agreement, we had responsibility for the development of inclisiran until Phase 1 Completion, as defined in the MDCO agreement, at our cost.

In late 2015, MDCO assumed responsibility for all development and commercialization of inclisiran, at its sole cost, and is advancing inclisiran in a comprehensive Phase 3 development program.

In December 2019, MDCO filed for regulatory approval of inclisiran in the U.S., and in January 2020, MDCO was acquired by Novartis AG .

For more information regarding the MDCO agreement, including its ongoing financial and accounting impact on our business, please read Note 4, Collaboration Agreements, 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 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.

Vir Biotechnology, Inc.

1 unchanged sentence

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

For more information regarding the Vir agreement, including its ongoing financial and accounting impact on our business, please read Note 4, Collaboration Agreements, 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 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.

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.

Strategic Financing Collaboration

The Blackstone Group Inc.

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

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.

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.

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 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.

Ionis Pharmaceuticals, Inc.

In January 2015, we and Ionis Pharmaceuticals, Inc., or Ionis, entered into a second amended and restated strategic collaboration and license agreement, which we further amended in July 2015, or the 2015 Ionis agreement.

parties’ existing non-exclusive technology cross-license, which was originally entered into in 2004 and was amended and restated in 2009, through April 2019.

Under the original agreement, Ionis licensed to us its patent estate related to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi products.

In turn, 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.

The 2015 Ionis agreement provides for certain new exclusive target cross-licenses of intellectual property on eight disease targets, providing each company with exclusive RNA therapeutic license rights for four programs, and extended the parties’ existing non-exclusive technology cross-license, which was originally entered into in 2004 and was amended and restated in 2009, through April 2019.

Pursuant to the 2015 Ionis agreement, Ionis granted to us an exclusive, low single-digit royalty-bearing license to its chemistry, motif, mechanism and target-specific intellectual property for oligonucleotide therapeutics against four targets.

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

Under the original agreement, Ionis licensed to us its patent estate related to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi products in exchange for a previously disclosed technology access fee, participation in fees for our partnering programs and future milestone and royalty payments from us for programs that incorporate Ionis’ intellectual property.

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

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.

For more information regarding the 2015 Ionis agreement, including its ongoing financial and accounting impact on our business, please read Note 4, Collaboration Agreements, to our consolidated financial statements included in Part II, Item 8, “Financial Statements and Supplementary Data,” of this annual report on Form 10-K.

Intellectual Property, Proprietary Rights and Exclusivities

26 unchanged sentences

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

In addition, in connection with our FDA approval on August 10, 2018, the FDA granted ONPATTRO (patisiran) new chemical entity, or NCE, exclusivity until August 10, 2023, and Orphan Drug Exclusivity, or ODE, until August 10, 2025.

In connection with our EMA approval on August 26, 2018, the EMA granted ONPATTRO (patisiran) Marketing Exclusivity and ODE until August 26, 2028.

In addition, in connection with our FDA approval on August 10, 2018, the FDA granted ONPATTRO new chemical entity, or NCE, exclusivity until August 10, 2023, and Orphan Drug Exclusivity, or ODE, until August 10, 2025.

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

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

18 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 20, 2019, the FDA granted GIVLAARI (givosiran) NCE exclusivity until November 20, 2024, and ODE until November 20, 2026.

In addition, in connection with our FDA approval on November 20, 2019, the FDA granted GIVLAARI NCE exclusivity until November 20, 2024, and ODE until November 20, 2026.

In connection with our EMA approval on March 2, 2020, the EMA granted GIVLAARI Marketing Exclusivity and ODE until March 2, 2030.

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

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

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

9828606 United States Compositions of Matter 12/26/2034 Dicerna Pharmaceuticals

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

10435692 United States Methods of Use 12/26/2034 Dicerna Pharmaceuticals

10465195 United States Compositions of Matter & Methods of Use 12/26/2034 Dicerna Pharmaceuticals

10478500 United States Compositions of Matter & Methods of Use 10/9/2035 Alnylam

10487330 United States Compositions of Matter & Methods of Use 12/26/2034 Dicerna Pharmaceuticals

10612024 United States Compositions of Matter 8/14/2035 Alnylam

10612027 United States Compositions of Matter & Methods of Use 8/14/2035 Alnylam

3087184 Europe Compositions of Matter 12/26/2034 Dicerna Pharmaceuticals

_________________________________________

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

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

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

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

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

We file trademarks to protect our corporate brand and our products.

1 unchanged sentence

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 and GIVLAARI ® .

Intellectual Property Challenges

2 unchanged sentences

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.

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.

3 unchanged sentences

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.

A description of legal matters relating to certain aspects of our intellectual property portfolio is set forth in Part I, Item 3, “Legal Proceedings,” of this annual report on Form 10-K.

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.

In many 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.

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.

Competition for Our Business in General

6 unchanged sentences

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, Silence Therapeutics plc, or Silence, Arbutus Biopharma Corp., or Arbutus, Sylentis, S.A.U., or Sylentis, Dicerna Pharmaceuticals, Inc., or Dicerna, and its collaborators, Boehringer Ingelheim, Alexion Pharmaceuticals, Inc.

and Eli Lilly and Company, WAVE Life Sciences Ltd., or WAVE, Silenseed Ltd., Ascletis Pharma Inc., Biomics Biopharma, Sirnaomics Inc., Olix Pharmaceuticals Inc., Phio Pharmaceuticals, Amgen Pharmaceuticals Inc., or Amgen, BioPath Holding Inc.

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.

1 unchanged sentence

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., F.

Hoffmann-La Roche Ltd, or Roche, through its acquisition in 2014 of Santaris Pharma A/S, miRagen Therapeutics, Inc., MiNA Therapeutics, Inc.

and Asuragen, Inc.

Companies working on microRNA therapeutics include Regulus Therapeutics, Inc., Rosetta Genomics Ltd., MiNA Therapeutics, Inc.

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 PLC 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., or Akcea, Antisense Therapeutics, Ltd., WAVE and Sarepta Therapeutics, Inc.

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.

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

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

5 unchanged sentences

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

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

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

Indications vary by country/region for each product.

5 unchanged sentences

VYNDAQEL/VYNDAMAX (tafamidis meglumine / tafamidis) Pfizer Inc.

Small molecule drug to stabilize TTR protein Approved to treat ATTR cardiomyopathy in the U.S.

MAA filed in the EU (indication varies by region) Daily oral capsule

TEGSEDI (inotersen) Ionis/Akcea 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)

AKCEA-TTR-LRx or ION-TTR-LRx

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

AG10 Eidos Therapeutics, Inc.

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.

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) Non-steroid anti-inflammatory agent Approved, but not indicated for the treatment of ATTR amyloidosis Twice-daily oral dose

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.

1 unchanged sentence

NTLA-2001 Intellia Therapeutics, Inc.

CRISPR/Cas9 gene therapy IND application expected in mid-2020 Unknown

CRISPR/Cas9 gene therapy Phase 1 Intravenous (IV)

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

Acute Hepatic Porphyria.

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

for the treatment of adults with AHP, there are also two approved hemin products, Panhematin (U.S.) and Normosang (EU), for the treatment of acute porphyria attacks.

In addition to GIVLAARI, which is approved in the U.S.

for the treatment of adults with AHP, and in the EU for the treatment of AHP in adults and adolescents aged 12 years and older , there are also two approved hemin products, Panhematin (U.S.) and Normosang (EU), for the treatment of acute porphyria attacks.

Panhematin and Normosang are both administered by intravenous infusion and are blood products currently manufactured by Recordati S.p.A.

3 unchanged sentences

Primary Hyperoxaluria.

Currently used treatments for primary hyperoxaluria, or PH, include hyper hydration, oral citrate or dual liver/kidney transplantation.

In addition to OXLUMO, which was recently 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.

Transplantation is costly and is an invasive procedure, which carries significant morbidity and mortality.

1 unchanged sentence

Presently, there are several investigational drugs in varying stages of clinical development for the treatment of PH.

We believe that the following drug candidates, if approved, could compete with lumasiran:

We believe that the following drug candidates, if approved, could compete with OXLUMO:

Drug Company Drug Description Phase Administration/Dosing

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

Reloxaliase Allena Pharmaceuticals, Inc.

Oxalate-degrading enzyme for enteric hyperoxaluria Phase 3 Up to five daily oral doses

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

Reloxaliase Allena Pharmaceuticals, Inc.

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

Up to five daily oral doses

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

Hypercholesterolemia.

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 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.

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.

1 unchanged sentence

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

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

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

Drug Company Drug Description Phase Administration/Dosing

Repatha Amgen Anti-PSCK9 mAb Approved SC

Praluent Sanofi Anti-PSCK9 mAb Approved SC

Praluent Sanofi Genzyme Anti-PSCK9 mAb Approved SC

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

Bempedoic Acid (ETC-1002) Esperion Therapeutics, Inc.

Oral fatty acid and cholesterol synthesis dual inhibitor Phase 3 Oral

NEXLETOL (Bempedoic Acid) Esperion Therapeutics, Inc.

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

Akcea-ANGPTL3-Lrx Akcea / Pfizer ASO therapy to reduce levels of ANGPTL3 Phase 2 SC

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

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

10 unchanged sentences

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

Emicizumab HEMLIBRA, ACE-910 (Roche) Bispecific antibody mimetic of FVIII Approved SC - Monthly

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

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

AMT-061, FIX (uniQure) rAAV5 FIX gene therapy Phase 3 IV - Single Administration

Etranacogene dezaparvovec (uniQure/CSL Behring)

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

4 unchanged sentences

NovoSeven (Novo Nordisk) Bypassing agent Approved IV

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

Hemophilia A and B

Concizumab, anti-TFPI (Novo Nordisk) anti-TFPI antibody Phase 2 IV

PF – 06741086 Anti-TFPI antibody Phase 3 IV

Concizumab, anti-TFPI (Novo Nordisk) Anti-TFPI antibody Phase 2 SC

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

Other Competition

12 unchanged sentences

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.

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 fitusiran, lumasiran and inclisiran, are not always conclusive and may be subject to alternative interpretations that could delay, limit or even prevent regulatory approval.

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

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

1 unchanged sentence

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.

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 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.

3 unchanged sentences

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

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

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.

For example, in September 2017, we temporarily suspended dosing in all ongoing fitusiran studies pending further review of a fatal thrombotic serious adverse event, or SAE, and agreement with regulatory authorities on a risk mitigation strategy.

We reached alignment with study investigators and the FDA on safety measures and a risk mitigation strategy to enable resumption of dosing in clinical studies with fitusiran, including the Phase 2 OLE study and the ATLAS Phase 3 program, for which dosing was initiated in early 2018.

Clinical trials involve the administration of an investigational new drug to healthy volunteers or patients under the supervision of a qualified investigator.

3 unchanged sentences

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

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

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

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

5 unchanged sentences

The FDA closely monitors the progress of each of the three phases of clinical trials that are conducted in the U.S.

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 or patient participating in the study.

An IRB or a clinical trial sponsor also may 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 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.

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

1 unchanged sentence

New Drug Applications

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

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

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

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.

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

For fiscal year 2020, the application fee for each NDA requiring clinical data was approximately $2.9 million.

PDUFA also imposes an annual program fee for each approved prescription drug, which was set at approximately $325,000 for fiscal year 2020.

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

For fiscal year 2021, the application fee for each NDA requiring clinical data is approximately $2.9 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 FDA adjusts the PDUFA user fees on an annual basis.

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

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

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

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission before accepting them for filing to determine whether they are sufficiently complete to permit substantive review.

3 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 already provided in the submission.

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

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.

The FDA normally conducts a pre-approval inspection to gain assurance that the manufacturing facility or facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality, purity and stability, and are in compliance with regulations governing current good manufacturing practice, or cGMP, requirements.

1 unchanged sentence

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.

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

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.

As a condition of NDA approval, the FDA may require post-approval evaluations, sometimes referred to as Phase 4 trials, or other surveillance to monitor the drug’s safety or effectiveness and may impose other conditions, including labeling restrictions, such as a Boxed Warning, and/or distribution and use restrictions through a Risk Evaluation and Mitigation Strategy, or REMS, all of which can materially affect the potential market and profitability of the drug.

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.

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

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.

Additionally, the FDA strictly regulates the promotional claims that may be made about prescription drug products and biologics.

3 unchanged sentences

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

We must also notify the FDA of any change in an approved product beyond variations already allowed in the approval.

We must also notify the FDA of any change in an approved product beyond variations in the approved application.

Certain changes to the product, its labeling or its manufacturing require prior FDA approval and may require the conduct of further clinical investigations to support the change.

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

If the FDA’s evaluation of the NDA submission or GCP inspections or inspection of the manufacturing facilities for the product are not favorable, the FDA may refuse to approve the NDA and issue a complete response letter.

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

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

5 unchanged sentences

The FDA may regulate our product candidate when used with a specialized drug delivery system as a combination product, which could permit the combination to be approved through a single application, such as an NDA.

Alternatively, the FDA could require separate, additional approvals or clearances for the modified device.

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.

2 unchanged sentences

Clearance under section 510(k) of the FDCA is required for most class II medical devices, which are devices for which special controls are necessary to provide reasonable assurance of safety and effectiveness.

A 510(k) submission demonstrates to the FDA that the device is substantially equivalent (i.e., at least as safe and effective) as a legally marketed predicate device that is not subject to PMA requirements.

A 510(k) submission demonstrates to the FDA that the device is substantially equivalent (i.e., at least as safe and effective based on the intended use and technological characteristics) as a legally marketed predicate device that is not subject to PMA requirements.

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.

2 unchanged sentences

To the extent that we rely on previously unapproved drug delivery systems, we may be subject to additional testing and approval requirements from the FDA above and beyond those described above.

Abbreviated Applications

Abbreviated Applications and 505(b)(2) Applications

Once an NDA is approved, the product covered thereby becomes a listed drug that can, in turn, be relied upon by potential competitors in support of approval of an abbreviated NDA, or ANDA, or a 505(b)(2) application.

9 unchanged sentences

An NCE is a drug that contains an active moiety (the molecule or ion responsible for the action of the drug substance) that has never previously been approved by the FDA.

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

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

Five-year and three-year exclusivity will not delay the submission or approval of a full NDA;

3 unchanged sentences

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

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

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

until the relevant patent expires.

If the ANDA or 505(b)(2) applicant certifies that a listed patent is invalid, unenforceable, or will not be infringed by its proposed product, and thus that it is seeking approval prior to patent expiration (i.e., a paragraph IV certification), and certain other steps are taken, then approval of the ANDA or 505(b)(2) application will be stayed (i.e., FDA will not approve the application) until 30 months have passed or patent disputes are resolved, as described below.

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

4 unchanged sentences

Under the Orphan Drug Act, as amended, the FDA may grant Orphan Drug Designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the U.S.

or for which there is no reasonable expectation of recovering drug development costs in the U.S.

or affects more than 200,000 individuals and for which there is no reasonable expectation of recovering drug development costs in the U.S.

from sales in the U.S.

3 unchanged sentences

For example, the FDA granted Orphan Drug Designation for patisiran and vutrisiran as therapeutic approaches for the treatment of ATTR amyloidosis, givosiran as a therapeutic approach for AHP, lumasiran as a therapeutic approach for PH1, fitusiran as a therapeutic approach for hemophilia A and B, and inclisiran as a therapeutic approach for HoFH.

If a product that has Orphan Drug Designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve for seven years any other applications, including a full NDA, to market the same orphan drug for the same indication, except in limited circumstances.

If a product that has Orphan Drug Designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to Orphan Drug Exclusivity, which means that the FDA may not approve for seven years any other applications, including a full NDA, to market the “same drug” for the same indication, except in limited circumstances.

For purposes of small molecule drugs, the FDA defines “same drug” as a drug that contains the same active moiety and is intended for the same use as the previously approved orphan drug.

For purposes of large molecule drugs, the FDA defines “same drug” as a drug that contains the same principal molecular structural features, but not necessarily all of the same structural features, and is intended for the same use as the drug in question.

Notwithstanding the above definitions, a drug that is "clinically superior" to an orphan drug will not be considered the “same drug” and thus will not be blocked by Orphan Drug Exclusivity.

A designated orphan drug may not receive orphan drug exclusivity for a use that is broader than the indication for which it received orphan designation.

In addition, orphan drug exclusivity may be lost if the FDA later determines that the Orphan Drug Designation request was materially defective or if the manufacturer is unable to assure sufficient quantities of the drug to meet the needs of patients with the rare disease or condition.

To demonstrate a drug is “clinically superior” to the previously approved orphan drug, a sponsor must show that the drug provides a significant therapeutic advantage over and above the previously already approved drug in terms of greater efficacy, greater safety, or by providing a major contribution to patient care.

A designated orphan drug may not receive Orphan Drug Exclusivity for a use that is broader than the indication for which it received Orphan Drug Designation and regulatory approval.

In addition, Orphan Drug Exclusivity may be lost if the FDA later determines that the Orphan Drug Designation request was materially defective or if the manufacturer is unable to assure sufficient quantities of the drug to meet the needs of patients with the rare disease or condition, or if the manufacturer chooses to provide consent to approval of other applications.

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.

Drugs with Orphan Drug Designation are exempt from these requirements.

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.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The FDA and the sponsor must reach agreement on the PSP.

The FDA and the sponsor must reach agreement on the initial PSP.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the PSP need to be considered based on data collected from nonclinical studies, early phase clinical trials, and/or other clinical development programs.

1 unchanged sentence

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.

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.

Fast Track designation provides opportunities for frequent interactions with FDA to expedite drug development and review as well as the opportunity for rolling review of the NDA.

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.

Any drug or biological product submitted to the FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

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.

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.

A drug or biological product is eligible for priority review if it treats a serious condition and, if approved, would provide a significant improvement in the safety or effectiveness of treatment, diagnosis or prevention of a disease compared to available therapies.

The FDA’s goal for taking action on an application with a priority review designation is six months from the date of filing, instead of ten months from the date of filing, except that two months are added to these time periods for drugs that contain a new molecular entity.

The FDA’s goal for taking action on an application with a priority review designation is six months from the date of receipt, instead of ten months from the date of receipt, except that two months are added to these time periods for drugs that contain a new molecular entity.

Additionally, a drug or biological product may be eligible for accelerated approval if it is intended to treat a serious or life-threatening disease or condition, and the product would provide meaningful therapeutic benefit over existing treatments.

6 unchanged sentences

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.

A sponsor may request that a drug or biological product be designated as a breakthrough therapy at any time during the clinical development of the product.

A sponsor may request that a drug or biological product be designated as a breakthrough therapy at any time during the clinical development of the product and ideally before initiation of the pivotal clinical trial intended to serve as the primary basis for demonstration of efficacy to obtain the full benefits of the designation.

If so designated, the FDA shall act to expedite the development and review of the product’s marketing application, including by meeting with the sponsor throughout the product’s development, providing timely advice to the sponsor to ensure that the development program is as efficient as practicable, involving senior managers and experienced review staff in a cross-disciplinary review, assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor, taking steps to ensure that the design of the clinical trials is as efficient as practicable, and allowing a rolling review of the marketing application.

The FDA granted breakthrough therapy designation for patisiran, approved in August 2018, givosiran, approved in November 2019, as well as lumasiran.

The FDA granted breakthrough therapy designation for patisiran, approved in August 2018, givosiran, approved in November 2019, as well as lumasiran, approved in November 2020.

We intend to request breakthrough therapy designation for our other product candidates, if applicable.

Rare Pediatric Disease Designation and Priority Review Voucher

In addition, the FDCA provides a rare pediatric disease priority review voucher, or PRV, program.

The program is intended to incentivize the development of new drug and biological products for the prevention and treatment of “rare pediatric diseases,” that is, any disease that is a rare disease and is serious or life-threatening with the serious or life-threatening manifestations primarily affecting individuals from birth to 18.

Under this program, the sponsor of an application for a rare pediatric disease drug may be eligible to obtain a voucher that can be used to obtain a priority review for a subsequent human drug application.

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

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

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

If awarded, the PRV may be transferred unlimited times.

The rare pediatric disease PRV program was initially created in 2012, and Congress has extended the PRV program through September 30, 2024, with the potential for PRVs to be granted through September 30, 2026.

The FDA awarded a rare pediatric disease PRV to us upon approval of the NDA for lumasiran in November 2020.

Pharmaceutical Coverage, Pricing and Reimbursement

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.

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.

12 unchanged sentences

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

The American Taxpayer Relief Act of 2012, among other things, further reduced Medicare payments to several types of providers and increased the statute of

limitations period for the government to recover overpayments to providers from three to five years.

Future legislation could limit payments for pharmaceuticals such as the drug candidates that we are developing.

Different pricing and reimbursement schemes exist in other countries.

In the EU, governments influence the price of drug products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers.

Some jurisdictions operate systems under which products may be marketed only after a reimbursement price has been agreed.

To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular product candidate to currently available therapies.

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

The downward pressure on health care costs in general, particularly prescription drugs, has become very intense.

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

In addition, in some countries, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country.

Likewise, the Biden administration has indicated that lowering prescription drug prices is a priority, but we do not yet know what steps the administration will take or whether such steps will be successful.

The marketability of any products for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement.

17 unchanged sentences

• 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.

13 unchanged sentences

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-related business.

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.

13 unchanged sentences

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.

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.

15 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 expected to come into application in the second half of 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 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.

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

2 unchanged sentences

During the development of a medicinal product, the EMA and national medicines regulators within the EU provide the opportunity for dialogue and guidance on the development program.

At the EMA level, this is usually done in the form of scientific advice, which is given by the Scientific Advice Working Party of the Committee for Medicinal Products for Human Use, or CHMP.

At the EMA level, this is usually done in the form of scientific advice, which is given by the Scientific Advice Working Party of the CHMP.

A fee is incurred with each scientific advice procedure.

7 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 in the second half of 2021.

A similar requirement is contained in the new Regulation on Clinical Trials that is currently expected to take effect no earlier than December 2021.

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.

Applicants file MAAs with the EMA, where they are reviewed by relevant scientific committees, including the CHMP.

The EMA forwards CHMP opinions to the European Commission, or EC, which uses them as the basis for deciding whether to grant a marketing authorisation.

The EMA forwards CHMP opinions to the EC, which uses them as the basis for deciding whether to grant a marketing authorisation.

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

1 unchanged sentence

For those medicinal products for which the centralized procedure is not available, the applicant must submit MAAs to the national medicines regulators through one of three procedures:

(1) a national procedure, which results in a marketing

authorisation in a single EU member state;

(1) a national procedure, which results in a marketing authorisation in a single EU member state;

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

23 unchanged sentences

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.

5 unchanged sentences

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

Such risk-minimization measures or post-authorisation obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct

of additional clinical trials or post-authorisation safety studies.

Such risk-minimization measures or post-authorisation obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorisation safety studies.

RMPs and PSURs are routinely available to third parties requesting access, subject to limited redactions.

16 unchanged sentences

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

In particular, during 2019, we filed for regulatory approval of ONPATTRO in Brazil and regulatory filings in additional countries are planned for ONPATTRO and GIVLAARI in 2020, and we will have to follow the specific regulations in Brazil and such other countries, which are complex.

In particular, during 2020, we filed for regulatory approval for our commercial products in a number of jurisdictions worldwide, and regulatory filings in additional countries are planned for ONPATTRO, GIVLAARI and OXLUMO in 2021, and we will have to follow the specific regulations in such jurisdictions and such other countries in which we file, which are complex.

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

8 unchanged sentences

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

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.

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.

4 unchanged sentences

Thus, there can be substantial delays in obtaining required approvals from foreign regulatory authorities after the relevant applications are filed.

Additionally, foreign governments lately are encouraging manufacturers to submit approval application in their jurisdictions with a variety of incentives including favorable reimbursement ratemaking.

In Canada, while Health Canada has developed service standards for regulatory review time, those are target or estimated timelines that we can reasonably expect to receive

from the regulator under normal circumstances, and as such, there may be delays in certain situations.

Additionally, foreign governments lately are encouraging manufacturers to submit marketing applications in their jurisdictions with a variety of incentives including favorable reimbursement ratemaking.

In Canada, while Health Canada has developed service standards for regulatory review time, those are target or estimated timelines that we can reasonably expect to receive from the regulator under normal circumstances, and as such, there may be delays in certain situations.

In Brazil, obtaining the approval to begin human clinical trials can take from 180 to 360 days, and the marketing approval process itself usually takes between nine to 12 months.

8 unchanged sentences

Because slight variations in the manufacturing process can lead to a different product, sponsors must include details of the method of manufacturing in its submission.

Product licensing, pricing and reimbursement vary as well.

Product pricing and reimbursement vary as well.

Canada’s pricing of patented pharmaceuticals is controlled by the Patented Medicine Prices Review Board, or PMPRB, whose regulatory authority is established by the Patented Medicines Regulations under Canada’s Patent Act.

18 unchanged sentences

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

We have contracted with several third-party contract manufacturing organizations, or CMOs, for the supply of drug substance 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 and GIVLAARI, 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 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.

In 2015, we amended our manufacturing services agreement with Agilent Technologies, Inc., or Agilent, to provide for Agilent to supply, subject to any conflicting obligations under our third-party agreements, a specified percentage of the active pharmaceutical ingredients required for certain of our products in clinical development, as well as other products the parties may agree upon in the future.

Under this agreement, we

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

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

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

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

Currently, Agilent is the sole manufacturer of the active pharmaceutical ingredient for ONPATTRO and GIVLAARI for both clinical and commercial use.

We entered into a manufacturing services agreement with Agilent for ONPATTRO commercial supply and are finalizing an agreement for commercial supply of GIVLAARI.

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

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

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

We are also constructing a cGMP manufacturing facility in Norton, MA for drug substance for clinical and eventually, commercial use, which we currently expect to be operational in 2020.

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.

2 unchanged sentences

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.

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 the new facility we are completing, will be sufficient to meet our and our alliance partners’ anticipated needs for the next several years.

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.

4 unchanged sentences

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.

As a recent commercial-stage biopharmaceutical company, 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 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 two approved products and our late-stage clinical programs:

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

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

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

• For GIVLAARI, approved in the U.S., and lumasiran, we have global rights to develop and commercialize;

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

• 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.

1 unchanged sentence

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

ONPATTRO and GIVLAARI, 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 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.

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, with respect to GIVLAARI, in August 2019, we announced that we entered into a U.S.

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.

Ironwood’s clinical sales specialists are now promoting GIVLAARI to the gastroenterologists and other HCPs that it already calls on for its marketed product, and we believe this partnership represents a significant opportunity to expand medical education and diagnosis for patients with AHP.

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.

With respect to ONPATTRO, as of the beginning of 2020, we have completed VBAs with multiple commercial payers, including each of the top five commercial payers and eight of the top ten, with signed VBAs now covering over 130 million U.S.

lives in the aggregate.

In addition, we have made significant progress toward establishing VBAs for GIVLAARI, including a new ultra-rare disease Prevalence Based Adjustment framework, with multiple discussions ongoing with payers.

We believe we have also been making strong progress in the EU with government payers with respect to ONPATTRO.

Once a patient is diagnosed and is prescribed ONPATTRO or GIVLAARI in the U.S., our own patient services hub, Alnylam Assist, is aimed at supporting patient access and retention in the U.S.

We have similar patient support efforts ongoing in Europe and planned for other geographies outside of the U.S.

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, including lumasiran, assuming regulatory approval.

With respect to commercially approved products, throughout 2019, we continued to build our commercial capabilities, and now have approximately 250 employees in customer facing activities in the U.S.

and across the world.

We also assembled field teams 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.

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.

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

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

1 unchanged sentence

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 to also support the launch of GIVLAARI, as well as the potential launches of lumasiran, assuming regulatory approval, and vutrisiran, assuming positive Phase 3 results and regulatory approval.

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.

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 launch of ONPATTRO.

At December 31, 2019, we had 1,323 employees.

None of our employees are represented by a labor union or covered by a collective bargaining agreement, nor have we experienced work stoppages.

We believe that relations with our employees are good.

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

Human Capital Management

As of December 31, 2020, we employed 1,453 full-time employees, of whom approximately 1,147 were employed in the U.S.

and approximately 306 were employed outside of the U.S.

None of our employees in the U.S.

are represented by a labor union or covered by collective bargaining agreements, and we believe our relationship with our employees is good.

During 2020, we enhanced our capabilities by adding 130 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.

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.

We face intense competition for qualified individuals from numerous pharmaceutical and biotechnology companies, universities, governmental entities and other research institutions, and we believe that our future success will depend in large part on our continued ability to attract and retain highly skilled employees.

To attract qualified applicants to our company and retain our employees, we offer a total rewards package consisting of base salary and cash target bonus targeting the 50 th to 65 th percentile of market based on geography, a comprehensive benefit package and equity compensation for every employee.

Annual cash bonus opportunity and equity compensation increase as a percentage of total compensation based on level of responsibility.

Any actual bonus payout is based solely on our performance against our corporate goals in the case of executive officers and is based on a combination of individual performance and corporate performance (or regional or national commercial performance metrics, as applicable) in the case of all other employees.

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

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

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

to ensuring that we attract, develop and retain diverse talent from all backgrounds;

to increasing awareness within our company of unconscious biases, and supporting affinity groups comprised of individuals who are underrepresented in our company, industry or society, such as women, members of the LGBTQ community and people of color.

In addition, we pride ourselves on an open culture that respects co-workers, values employees’ health and well-being and fosters professional development.

We support employee growth and development in a variety of ways including with group training, individual mentoring and coaching, conference attendance and tuition reimbursement.

Our management conducts annual employee engagement surveys and reports to our board of directors on human capital management topics, including corporate culture, diversity, equity and inclusion, employee development and retention, and compensation and benefits.

Similarly, our board of directors regularly provides input on important decisions relating to these matters, including with respect to employee compensation and benefits, talent retention and development.

Corporate Information

9 unchanged sentences

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, compensation committee, nominating and corporate governance committee, and science and technology committee, as well as our corporate governance guidelines and our code of business conduct and ethics.

We also make available on our website the charters of our audit committee, people, culture and compensation committee, nominating and corporate governance committee, and science and technology committee, as well as our corporate governance guidelines and our code of business conduct and ethics.

In addition, we intend to disclose on our web site any amendments to, or waivers from, our code of business conduct and ethics that are required to be disclosed pursuant to SEC rules.

2 unchanged sentences

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

What changed 10-K

Item 1. Business