Alnylam Receives Positive CHMP Opinion for Vutrisiran for the Treatment of ATTR Amyloidosis with Cardiomyopathy

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNA interference (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 its RNAi therapeutic vutrisiran for the treatment of wild type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM). ATTR-CM is a debilitating, rapidly progressive and potentially fatal disease for which there are limited treatment options. Vutrisiran is currently approved in the European Union (EU) under the brand name AMVUTTRA^® for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy.

ATTR-CM is caused by the deposition of misfolded transthyretin (TTR) fibrils, which drive progressive and irreversible cardiovascular damage and premature death. Vutrisiran is an RNAi therapeutic that works upstream to reduce the production of TTR at its source, resulting in sustained TTR knockdown. In Europe, it is administered as a subcutaneous injection once every three months, either by a healthcare professional, or self-administered by patients or their caregivers, offering flexibility in treatment delivery. Vutrisiran has the potential to be the first and only RNAi therapeutic to receive European Commission approval for ATTR-CM, offering a clinically differentiated approach to the treatment of this disease.

“This positive CHMP opinion marks another important milestone in our efforts to bring vutrisiran to people around the world living with ATTR amyloidosis with cardiomyopathy,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “In the HELIOS-B study, vutrisiran treatment resulted in rapid knockdown of TTR and led to improved survival, fewer hospitalizations and less disease progression in patients with ATTR-CM, nearly half of whom were on a TTR stabilizer. Combined with its quarterly dosing and well-established safety profile, we believe vutrisiran could offer an important new treatment option for patients in the EU.”

The CHMP opinion was based on positive results from the pivotal HELIOS-B Phase 3, randomized, double-blind, placebo-controlled multicenter global study, which met all 10 of its pre-specified primary and secondary endpoints across both the overall and monotherapy populations. The findings demonstrated the benefits of vutrisiran on outcomes of mortality and cardiovascular events, as well as functional capacity (6-minute walk test), health status and quality of life (Kansas City Cardiomyopathy Questionnaire), and heart failure symptoms and severity (NYHA class) in patients with ATTR-CM, with consistent effects across all patient subgroups, including those on a concomitant TTR stabilizer. In HELIOS-B, rates of adverse events (AEs), serious AEs, severe AEs and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. The safety profile of vutrisiran is characterized by injection site reactions and increase in blood alkaline phosphatase and alanine transaminase. Detailed results from the HELIOS-B study were published in The New England Journal of Medicine.¹

Vutrisiran was approved by the U.S. Food and Drug Administration (FDA) on 20 March 2025 and the Brazilian Health Regulatory Agency (ANVISA) on 31 March 2025 for the treatment of the cardiomyopathy of wild-type or hereditary ATTR-CM. It is currently under review by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Alnylam remains on track to proceed with additional global regulatory submissions for vutrisiran in 2025 and beyond.

AMVUTTRA^® (vutrisiran) INDICATION AND IMPORTANT SAFETY INFORMATION

Indication
In Europe and the UK, vutrisiran is indicated for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy.

Important Safety Information

Reduced Serum Vitamin A Levels and Recommended Supplementation

Vutrisiran treatment leads to a decrease in serum vitamin A levels. Supplementation of approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per day is advised for patients taking vutrisiran. 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 frequently occurring adverse reactions in patients treated with vutrisiran were pain in extremity and arthralgia. Other commonly reported adverse reactions with vutrisiran were dyspnoea, injection site reaction and increase in blood alkaline phosphatase.

For additional information about vutrisiran, please see the full Summary of Product Characteristics.

About AMVUTTRA^® (vutrisiran)
AMVUTTRA^® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of variant and wild-type transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection, vutrisiran is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. In Europe, it is administered as a subcutaneous injection once every three months, either by a healthcare professional, or self-administered by patients or their caregivers. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), which encompasses both wild-type and hereditary forms of the disease.

About ATTR
Transthyretin amyloidosis (ATTR) 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 – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000-300,000 people worldwide.^1-4

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.⁵ 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.⁶ 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.⁵ 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) 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 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.

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, Alnylam’s expectations regarding the safety and efficacy of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to be the first and only RNAi therapeutic to receive European Commission approval for ATTR-CM; the potential for vutrisiran to offer a clinically differentiated approach to treatment of ATTR-CM; the potential success of Alnylam’s efforts to bring vutrisiran to people around the world living with ATTR-CM; the potential for vutrisiran to offer an important new treatment option for patients in the EU; and the timing of global regulatory submissions for vutrisiran for ATTR-CM 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, risks and uncertainties relating to: Alnylam’s ability to successfully execute on its “Alnylam P⁵x25” strategy; Alnylam’s ability to 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 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; and any delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2024 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.

1 Fontana M., Berk J L, Gillmore, J D, et al. New England Journal of Medicine, 392(1), 33-44.

2 Hawkins PN, Ando Y, Dispenzeri A, et al. Ann Med. 2015;47(8):625-638.

3 Gertz MA. Am J Manag Care. 2017;23(7):S107-S112.

4 Conceicao I, Gonzalez-Duarte A, Obici L, et al. J Peripher Nerv Syst. 2016;21:5-9.

5 Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis. 2013;8:31.

6 Elbashir SM, Harborth J, Lendeckel W, et al. Nature. 2001;411(6836):494-498.

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