Alnylam Receives Positive CHMP Opinion for Vutrisiran for the Treatment of Hereditary Transthyretin-mediated (hATTR) Amyloidosis in Adult Patients with Stage 1 or Stage 2 Polyneuropathy

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of vutrisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. If approved by the European Commission (EC), vutrisiran will be commercialized under the brand name AMVUTTRA™ as the first and only treatment option to demonstrate reversal in neuropathy impairment with subcutaneous administration once every three months.

“Today’s decision by the CHMP is good news for patients living with hATTR amyloidosis with polyneuropathy, a rare, rapidly progressive and fatal condition for which there are few treatment options. We expect a European Commission (EC) decision on approval in September 2022. If approved, vutrisiran will become Alnylam’s second treatment for hATTR amyloidosis to be commercialized in Europe, delivering on our commitment to bring continued innovation to patients. We believe vutrisiran provides a compelling efficacy and safety profile, as well as the benefit of a quarterly subcutaneous dosing regimen, to help manage this debilitating condition,” said Kasha Witkos, SVP, Head International Region at Alnylam.

The CHMP decision was based on positive Month 18 results from HELIOS-A, a global, randomized, open-label, multicenter, Phase 3 study that evaluated the efficacy and safety of vutrisiran across a diverse group of patients with hATTR amyloidosis with stage 1 and stage 2 polyneuropathy. Vutrisiran met the primary and all secondary endpoints of the study at both 9 months and 18 months, demonstrating reversal in neuropathy impairment and an encouraging safety and tolerability profile. After 18 months of dosing, the frequently occurring adverse reactions in vutrisiran-treated patients were arthralgia (joint stiffness) and pain in extremity (pain in arms and legs). Other adverse reactions reported with vutrisiran were dyspnea (shortness of breath), injection site reaction and an increase in blood alkaline phosphatase (a liver enzyme).

Vutrisiran was previously granted Orphan Drug Designation in the European Union (EU) and U.S. for the treatment of ATTR amyloidosis. In June 2022, vutrisiran was approved by the U.S. Food and Drug Administration (FDA) for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Vutrisiran is under review by the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).

About Vutrisiran

Vutrisiran is an RNAi therapeutic approved in the United States for the treatment of the polyneuropathy of hATTR amyloidosis in adults. Vutrisiran is also 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. 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 to allow for quarterly, and potentially biannual, subcutaneous administration.

About the HELIOS-A Phase 3 Study

HELIOS-A (EudraCT 2018-002098-23; 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 (ONPATTRO^®) in a patient population comparable to that studied in HELIOS-A. The treatment period of the study was conducted over 18 months with two analyses at Month 9 and at Month 18. The primary endpoint was the change from baseline in mNIS+7 at 9 months. For the EU region, the primary endpoint was the change from baseline in mNIS+7 at 18 months. Secondary endpoints at 9 months were 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 9 months. Additional secondary endpoints at 18 months were evaluated in the HELIOS-A study, including change from baseline in 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 include 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 has developed RNAi therapeutic products which are licensed for the treatment of hATTR amyloidosis, acute hepatic porphyria, primary hyperoxaluria type 1 and primary hypercholesterolemia / mixed dyslipidemia. 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 future expectations, plans and prospects, including, without limitation, Alnylam’s views with respect to the safety and efficacy of vutrisiran, a quarterly subcutaneous injection, for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy, the potential of vutrisiran as the first and only treatment option to demonstrate reversal in neuropathy impairment the first and only treatment option to demonstrate reversal in neuropathy impairment with subcutaneous administration once every three months, continued regulatory review of vutrisiran in several jurisdictions, the continued evaluation of a biannual 50mg dosing regimen in the HELIOS-A trial, the ongoing evaluation of vutrisiran for the treatment of patients with ATTR amyloidosis, and 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; the potential impact of the recent leadership transition on Alnylam’s ability to attract and retain talent and 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 its product candidates; 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 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, AMVUTTRA or OXLUMO 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, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current and the risk of future 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.

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