• Treatment with an RNAi Therapeutic Preserved Functional Capacity and Health Status and Quality of Life Compared with Placebo at 12 Months
• Patisiran Demonstrated an Encouraging Safety and Tolerability Profile in Patients with the Cardiomyopathy of ATTR Amyloidosis

CAMBRIDGE, Mass. / Oct 25, 2023 / Business Wire / Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that results from the APOLLO-B Phase 3 study of investigational patisiran in patients with the cardiomyopathy of transthyretin-mediated (ATTR) amyloidosis were published online in the New England Journal of Medicine (NEJM). The data reported in the APOLLO-B Phase 3 study publication demonstrate that patisiran, an RNAi therapeutic targeting transthyretin (TTR), preserved functional capacity and health status and quality of life compared with placebo at 12 months. In addition, treatment with patisiran demonstrated favorable effects on biomarkers of cardiac stress and injury and on measures of cardiac structure and function. The full manuscript, titled “Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis,” will appear in the October 26, 2023 issue of NEJM.

“ATTR amyloidosis is a rapidly progressive disease, with cardiac manifestations that can have a devastating impact on patients’ lives, and include arrhythmias, conduction disease, and heart failure. Current treatment options are limited, with many patients still experiencing declines in their functional capacity and quality of life, underscoring the need for additional therapeutic approaches,” said Mathew Maurer, M.D., Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, principal investigator of the APOLLO-B Phase 3 study, and lead author of the manuscript. “The results of the APOLLO-B Phase 3 study published in the New England Journal of Medicine support the hypothesis that a reduction in circulating TTR protein can provide benefit in patients with the cardiomyopathy of ATTR amyloidosis, warranting further evaluation of investigational RNAi therapeutics to treat this devastating disease.”

The APOLLO-B Phase 3 study achieved its primary endpoint at 12 months, with patisiran demonstrating a significant difference in the change from baseline in functional capacity compared with placebo, as measured by the 6-Minute Walk Test (6-MWT). The study also met its first secondary endpoint, with patisiran demonstrating a significant difference in the change from baseline in health status and quality of life compared with placebo, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score. For the composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared with placebo, the win ratio favored patisiran but did not reach statistical significance.

“The APOLLO-B Phase 3 study results published in the New England Journal of Medicine further our conviction that TTR silencing with an RNAi therapeutic can have a positive therapeutic impact on patients with the cardiomyopathy of ATTR amyloidosis – a disease characterized by unrelenting symptom progression due to ongoing amyloid deposition in the heart,” said Pushkal Garg, M.D., Chief Medical Officer at Alnylam. “While the supplemental New Drug Application (sNDA) that would have expanded the indication for patisiran in the U.S. to include the cardiomyopathy of ATTR amyloidosis received a Complete Response Letter (CRL), we remain dedicated to the ATTR amyloidosis community. We look forward to early 2024, when we expect to share topline results from the HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic subcutaneously administered once every three months in development for the treatment of the cardiomyopathy of ATTR amyloidosis.”

Select exploratory endpoints in APOLLO-B included changes in cardiac biomarkers NT-proBNP, a measure of cardiac stress, and Troponin I, a measure of cardiac injury, as well as echocardiographic measures of cardiac structure and function. At 12 months, the change from baseline in NT-proBNP and Troponin I levels favored patisiran compared with placebo, and differences between patisiran and placebo in the change from baseline in left ventricular (LV) global longitudinal strain, a measure of systolic function, LV mass, and LV stroke volume all favored patisiran.

Additional findings in the NEJM publication were from a post-hoc analysis of the primary endpoint evaluating patients without walking impairment due to neuropathy at baseline (polyneuropathy disability score [PND] of 0; N=205). The results were consistent with those of the primary analysis, suggesting that the treatment effect of patisiran on 6-MWT was not a result of effects on polyneuropathy.

Patisiran demonstrated an encouraging safety and tolerability profile in the APOLLO-B Phase 3 study, including no cardiac safety concerns relative to placebo, through 12 months. The majority of adverse events (AEs) were mild or moderate in severity. AEs occurring in 5% or more of patients in the patisiran group and observed at least 3% more commonly in the patisiran group included infusion-related reactions (12% vs. 9%), arthralgia (8% vs. 4%), and muscle spasm (7% vs. 2%). In the safety analysis, 5 deaths (3%) were observed in patisiran-treated patients, none of which were considered related to study drug, and 8 deaths (4%) were observed in the placebo group.

Upon completion of dosing in the 12-month double-blind period, patients were eligible to enroll in a 36-month open-label extension (OLE) period to receive patisiran on an ongoing basis. Results from an interim analysis of the ongoing OLE period of the APOLLO-B Phase 3 study were recently presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting (ASM) 2023, demonstrating the sustained treatment effect of patisiran on functional status and health status and quality of life, as well as cardiac biomarkers, through 24 months.

Patisiran is the established name for ONPATTRO^®, which is currently approved by the U.S. FDA for the treatment of the polyneuropathy of hereditary ATTR (hATTR) amyloidosis in adults.

The Company recently announced that the U.S. Food and Drug Administration (FDA) issued a CRL in response to the sNDA for patisiran for the treatment of the cardiomyopathy of ATTR amyloidosis, indicating that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established, and therefore, the sNDA for patisiran could not be approved in its present form. The CRL does not pertain to, nor impact commercial availability of, ONPATTRO in the U.S. or in other countries where it has previously been approved for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

ONPATTRO^® (patisiran) Indication and Important Safety Information

Indication

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

Important Safety Information

Infusion-Related Reactions

Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. 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%).

For additional information about ONPATTRO, please see the full U.S. Prescribing Information.

About ONPATTRO^® (patisiran)

ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hereditary ATTR (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 reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

About ATTR Amyloidosis

Transthyretin-mediated (ATTR) amyloidosis is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR amyloidosis – hereditary ATTR (hATTR) amyloidosis, which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant and impacts an estimated 200,000 – 300,000 people worldwide.

About the APOLLO-B Phase 3 Study

APOLLO-B is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 sites in 21 countries. Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month treatment period. After 12 months, all patients received patisiran in a 36-month open-label extension period.

About LNP Technology

Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

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 or disease pathway 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 Pharmaceuticals (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO^® (patisiran), AMVUTTRA^® (vutrisiran), GIVLAARI^® (givosiran), OXLUMO^® (lumasiran), and Leqvio^® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple 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 X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram.

Alnylam Forward Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P⁵x25” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, Alnylam’s projected commercial and financial performance, and Alnylam’s belief that TTR silencing with an RNAi therapeutic could have a positive therapeutic impact on patients with the cardiomyopathy of ATTR amyloidosis, should be considered forward-looking statements. 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; Alnylam’s ability to successfully execute on its “Alnylam P⁵x25” strategy; 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 Alnylam’s product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam’s research and development programs, including as may arise from recent disruptions in the supply of non-human primates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication AMVUTTRA 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 Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the risks of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q 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 discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.