Alnylam Completes Enrollment in APOLLO-B Phase 3 Study of Patisiran in Transthyretin-Mediated (ATTR) Amyloidosis Patients with Cardiomyopathy

− APOLLO-B is the Industry’s Furthest Progressed Randomized, Double-Blind, Placebo-Controlled Pivotal Study of an Investigational TTR Silencer in Hereditary and Wild-type ATTR Amyloidosis with Cardiomyopathy −

− Topline Results Expected in Mid-2022 −

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that it has achieved full patient enrollment in its APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of cardiomyopathy in patients with transthyretin-mediated (ATTR) amyloidosis. Enrollment was completed with over 300 ATTR amyloidosis patients across 90 sites in more than 20 countries. ATTR amyloidosis is a rare, progressively debilitating, and fatal disease that is caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid deposits in multiple tissues, including the nerves, heart and gastrointestinal (GI) tract and encompasses hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. hATTR amyloidosis is estimated to impact approximately 50,000 people worldwide and is a multisystem disease that can include sensory and motor, autonomic, and cardiac symptoms. wtATTR amyloidosis is estimated to impact between 200,000 and 300,000 people worldwide and primarily manifests as cardiomyopathy, which can lead to heart failure and mortality. APOLLO-B is the industry’s furthest progressed randomized, double-blind, placebo-controlled study of a TTR silencer investigational medicine for the treatment of cardiomyopathy in hATTR and wtATTR amyloidosis patients.

Patisiran is the established name for ONPATTRO^®, which is approved in the United States, Canada and Japan for the treatment of the polyneuropathy of hATTR amyloidosis in adults and in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy.

“The APOLLO-B trial was initiated based on encouraging data from previous studies that support further investigation of patisiran in ATTR amyloidosis patients with cardiomyopathy. Specifically, encouraging results were obtained from the landmark Phase 3 APOLLO study in hATTR amyloidosis patients with polyneuropathy on a number of exploratory cardiac endpoints. Today’s milestone marks an important step forward as we continue to study the safety and efficacy of patisiran in the treatment of cardiovascular-related manifestations of ATTR amyloidosis, which can often be devastating for these patients,” said Rena Denoncourt, Vice President, TTR Franchise Lead. “We look forward to announcing topline APOLLO-B results in mid-2022 and are excited about the potential of patisiran to treat multiple manifestations of this rapidly progressive disease and further advance our aspiration to build the industry leading franchise of RNAi therapeutics for the treatment of ATTR amyloidosis.”

About the APOLLO-B Phase 3 Study Design

The APOLLO-B study is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed to evaluate the efficacy and safety of patisiran in patients with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, which enrolled over 300 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized on a 1:1 basis to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension period. The primary outcome measure of APOLLO-B is the change from baseline in the 6-minute walk test at 12 months compared to placebo. Key secondary and exploratory endpoints will evaluate the efficacy of patisiran on health-related quality of life, mortality and cardiovascular events, cardiac biomarkers and additional manifestations of cardiac amyloid involvement. For more information on APOLLO-B (NCT03997383) please visit www.clinicaltrials.gov.

About ONPATTRO^® (Patisiran)

ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, 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. For more information about ONPATTRO, including full Prescribing Information and Important Safety Information, visit ONPATTRO.com.

ONPATTRO Indication and Important Safety Information

Indication

ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Infusion-Related Reactions

Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO^® (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

Reduced Serum Vitamin A Levels and Recommended Supplementation

ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Adverse Reactions

The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

About ATTR Amyloidosis

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract. There are two different types of ATTR amyloidosis – Hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and Wild-type ATTR amyloidosis (wtATTR), which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, while wtATTR amyloidosis is estimated to impact 200,000 – 300,000 people worldwide.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals

Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO^® (patisiran), GIVLAARI^® (givosiran), OXLUMO^® (lumasiran), and Leqvio^® (inclisiran) being developed and commercialized by Alnylam’s partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P⁵x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam’s expectations, plans, aspirations, and goals, including those related to patisiran and its potential to treat cardiovascular-related manifestations of ATTR amyloidosis in both in hATTR and wtATTR amyloidosis patients, the expected timing for topline results from the APOLLO-B Phase 3 study, Alnylam’s aspiration to build the industry leading franchise of RNAi therapeutics for the treatment of ATTR amyloidosis, and the achievement of its “Alnylam P⁵x25” strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.

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