Alnylam Presents Additional 9-Month Data from HELIOS-A Phase 3 Study of Vutrisiran at the European ATTR (EU-ATTR) Amyloidosis Meeting

- Subgroup Analyses and Exploratory Endpoints Demonstrated that Vutrisiran Improved Important Areas of Patient Health and Function Compared with Placebo at 9 Months –

- Additional Analyses Showed Similar Improvements in Progression of Neuropathy and Quality of Life Measures with Vutrisiran Treatment Compared with Placebo, Regardless of Prior TTR Stabilizer Use –

- Company Remains On Track to Announce Topline 18-Month Results, Including Additional Exploratory Cardiac Endpoint Data, in Late 2021 –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced additional positive results from subgroup analyses and exploratory endpoints of the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis. Data presented at the 3^rd European ATTR Amyloidosis Meeting further supports and builds on the previously reported primary and secondary endpoint results of the HELIOS-A study in hereditary ATTR amyloidosis patients with polyneuropathy, with improvements observed across important areas of patient health and function, including neuropathy impairment, Quality of Life (QoL), ability to perform daily activities and social engagement, nutritional status, and cardiac stress.

“Hereditary ATTR amyloidosis is a multisystem, rapidly progressive disease with significant impact on the daily lives of patients, and which worsens over time without appropriate management,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “These additional data from the HELIOS-A study show the potential of vutrisiran in treating a broad group of patients with hATTR amyloidosis with polyneuropathy, with encouraging improvements seen across a range of important health and functional measures. Additionally, patients experienced improvements in neuropathy impairment and quality of life scores regardless of prior TTR stabilizer use. We look forward to sharing additional results at the 18-month readout, expected later this year. With the recent NDA submission accepted for review by the U.S. FDA and planned regulatory submission in Europe ahead of schedule, we are continuing our progress to bring vutrisiran forward as a potential new treatment option for hATTR amyloidosis patients with polyneuropathy, with subcutaneous administration and quarterly dosing.”

The HELIOS-A study included 164 hATTR amyloidosis patients with polyneuropathy. At 9 months, vutrisiran met the primary and all secondary endpoints, with statistically significant improvements in neuropathy impairment, QoL, and gait speed, relative to external placebo. The subgroup analyses and exploratory efficacy data from HELIOS-A provide additional insights on the potential benefits of vutrisiran across important aspects of patients’ health and wellbeing, specifically:

• the modified Neuropathy Impairment Score (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy Score (Norfolk QOL-DN) were consistently improved with vutrisiran treatment compared with external placebo across all pre-specified patient subgroups at month 9, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline Familial Amyloid Polyneuropathy (FAP) stage, and in a pre-specified cardiac subpopulation
• improvements were observed in the Rasch-built Overall Disability Scale (R-ODS), a comprehensive patient-ranked 24-item scale which assesses activity and social participation limitations on a linearly weighted scale, compared with external placebo. Activity measures increase in intensity and include ability to perform activities of daily living and social engagement. [LS mean difference vs. placebo 4.3 (2.7, 6.0) p=3.26x10^-7]
• modified body mass index (mBMI) levels increased in patients receiving vutrisiran treatment compared with external placebo, indicating improvements in nutritional status over 9 months [LS mean difference vs. placebo 67.8 (43.0, 92.6) p=8.46×10⁻⁸]
• QoL (EuroQol Visual Analog Scale, EQ-VAS, self-rated health score) and neuropathy impairment (NIS), assessing patients’ muscle strength, sensation and reflexes, also improved in patients receiving vutrisiran versus external placebo at 9 months. [EQ-VAS LS mean difference vs. placebo 9.8 (4.8, 14.9) p=0.0001; NIS LS mean difference vs. placebo −13.7 (− 17.3, −10.1) p=1.08 x 10⁻¹³]
• improvement in the exploratory endpoint of the cardiac biomarker, NT-proBNP, a measure of cardiac stress, was observed in the vutrisiran arm in both the prespecified cardiac subpopulation [adjusted geometric fold change ratio: 0.60 (0.43, 0.82) p=0.0016] and the modified intent-to-treat (mITT) population [adjusted geometric fold change ratio: 0.63 (0.52, 0.75) p=9.2×10⁻⁷], relative to external placebo.

Patients with Prior TTR Stabilizer Use Receiving Vutrisiran

A second analysis presented from the HELIOS-A study showed that similar improvements in mNIS+7 and Norfolk QOL-DN were seen for vutrisiran-treated patients regardless of prior TTR stabilizer use. While TTR stabilizer use was not permitted at study entry, two-thirds of patients in HELIOS-A had previously used a TTR stabilizer. The most common reasons for discontinuing the stabilizer were to participate in the HELIOS-A study and disease progression. For improvements in mNIS+7 relative to external placebo, LS mean values were -14.49 (-22.69, -6.29) for patients with no previous stabilizer use and -18.96 (-24.77, -13.16) for patients with previous stabilizer use. In the case of Norfolk QOL-DN, the LS mean difference vs. external placebo was -23.0 (− 32.1, −14.0) for patients with no previous stabilizer use and -14.9 (-22.1, -7.6) for previous stabilizer use.

In the study, vutrisiran demonstrated an encouraging safety and tolerability profile relative to external placebo with 9 months of dosing regardless of prior stabilizer use. The majority of adverse events were mild to moderate in severity in all groups and there were no drug-related discontinuations or deaths.

The U.S. Food and Drug Administration (FDA) recently accepted the New Drug Application (NDA) submission for review for vutrisiran and has set an action date of April 14, 2022 under the Prescription Drug User Fee Act (PDUFA). Additionally, it was recently announced that based on discussions with the European Medicines Agency (EMA), the Company now plans to file, ahead of schedule, a Marketing Authorization Application (MAA) for vutrisiran based on 9-month results from the HELIOS-A study.

About Vutrisiran

Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary ATTR (hATTR) and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the European Medicines Agency, the U.S. Food and Drug Administration, or any other health authority.

About the HELIOS-A Phase 3 Study

HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 at nine months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at nine months. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they will receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

About hATTR Amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents 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.

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 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 potential 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.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam’s expectations, plans, aspirations, and goals, including those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with encouraging safety profile for a broad range of patients with hATTR amyloidosis, the timing of additional results from the ongoing HELIOS-A Phase 3 study of vutrisiran, the expected timing for FDA review of the NDA for vutrisiran and the accelerated timing for the filing of a MAA for vutrisiran with the EMA, Alnylam’s aspiration to become a leading biotech company, and the planned 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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