New Data From Landmark HELIOS-B Phase 3 Study Presented at ESC Congress 2025 Demonstrate Vutrisiran's Long-Term Cardiovascular Benefit in ATTR-CM

− Sustained Benefit of Vutrisiran Across Mortality, Cardiovascular Events, Quality of Life and Cardiac Biomarkers Observed Through Up to 48 Months, Including 12 Months from the Ongoing Open-Label Extension, Reinforce Potential as First-Line Treatment for ATTR-CM –

− Vutrisiran, which Delivers Rapid Knockdown of Transthyretin, Reduced the Risk of Composite of All-Cause Mortality or First Cardiovascular Event by 37% in the Overall Population and 42% in the Monotherapy Group During the Same Period –

Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced results of new analyses from the HELIOS-B Phase 3 study of AMVUTTRA^® (vutrisiran), an RNAi therapeutic approved for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults. Data from the 12-month follow-up of the ongoing open-label extension (OLE) period of HELIOS-B were presented during an oral session at the European Society of Cardiology (ESC) Congress 2025 held in Madrid, Spain. These data reflect outcomes of treatment through up to 48 months, including the initial double-blind period of 33-36 months, and highlight the ongoing clinical benefit of vutrisiran, which causes rapid knockdown of the disease-causing transthyretin (TTR) protein, including a 37% risk reduction in the composite endpoint of all-cause mortality (ACM) or first cardiovascular (CV) event in the overall population (p<0.001) and a 42% risk reduction in the monotherapy group (p<0.001), reinforcing vutrisiran's potential as a first-line treatment for patients with ATTR-CM. Vutrisiran also reduced the risk of ACM alone by 37% in the overall population (p<0.01) and 39% in the monotherapy group (p<0.01) during this same period.

The findings from the ongoing HELIOS-B study show that the clinical benefits seen during the double-blind period of 33-36 months across key clinical measures of disease progression, including quality of life (QoL) as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) and cardiac biomarkers, were maintained with continued vutrisiran treatment during the 12-month OLE period. The long-term safety and tolerability profile during the OLE period was consistent with the established profile of vutrisiran. Additionally, a post hoc analysis of the HELIOS-B trial presented during a poster session highlighted reductions in days lost to death and/or hospitalization (DLDH) and improvements in functional and QoL outcomes compared to placebo. Vutrisiran was associated with a reduction in mean DLDH of more than one month versus placebo over a three-year period, with a greater effect observed when accounting for impaired function and QoL.

"The HELIOS-B study continues to deliver robust evidence supporting the clinically differentiated profile of vutrisiran," said John Vest, M.D., Senior Vice President, TTR Global Clinical Lead, Alnylam. "These longer-term data demonstrate that, through up to 48 months, vutrisiran treatment conferred continued clinical benefit across key endpoints, including survival, cardiovascular events, and quality of life. These results reinforce the potential for vutrisiran, which provides rapid and sustained knockdown of TTR, to modify the course of disease over the long-term and to be a first-line therapy for ATTR-CM."

The landmark HELIOS-B Phase 3 clinical trial evaluated vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM) in a population representative of today's patients. Of the 654 patients who received treatment with vutrisiran in HELIOS-B, 466 entered the OLE period. At the data cutoff (April 9, 2025), vital status was ascertained for >99% of patients. Key findings from 12-month follow-up include:

Safety data for vutrisiran treatment through one year of the OLE period were consistent with that reported for the double-blind period. The rate of adverse events (AEs), including cardiac events, did not increase with longer treatment. Event rates for serious adverse events (SAEs) and severe AEs in the placebo/vutrisiran group were consistent with more advanced disease following placebo treatment during the double-blind period. No new safety concerns were identified.

"The open-label extension of HELIOS-B adds important long-term evidence to inform the management of ATTR-CM, a progressive and life-threatening condition that remains a significant clinical challenge," said Dr. Pablo Garcia-Pavia, Head of the Inherited Cardiac Diseases and Heart Failure Unit at the Department of Cardiology of Hospital Universitario Puerta de Hierro and group leader at the Spanish Cardiovascular Research Network (CIBERCV), in Madrid, Spain. "The irreversible nature of disease progression, taken together with the sustained clinical benefit seen in patients treated with vutrisiran through 48 months, collectively underscore the importance of early treatment initiation and further support the role of vutrisiran as a first-line treatment for ATTR-CM. The results were observed in a group of patients reflective of the contemporary ATTR-CM population, including those receiving substantial concurrent use of available standard-of-care therapies such as tafamidis and SGLT2 inhibitors."

A post hoc analysis from HELIOS-B further characterized the practical impact of vutrisiran treatment on all-cause mortality and recurrent CV events by assessing days lost to death and/or hospitalization (DLDH). This metric captures both the occurrence and burden of events over time and evaluated vutrisiran versus placebo on DLDH and days lost to death and/or cardiovascular hospitalization (DLDCVH) in both the overall and monotherapy populations. In the overall population, vutrisiran was associated with 32.2 fewer DLDH over 3 years compared to placebo. A similar benefit was seen for DLDCVH. Vutrisiran treatment was associated with a higher likelihood of patients experiencing no DLDH or DLDCVH and showed an even greater impact when factoring in days of impaired well-being. Results in the monotherapy group were consistent with the overall population. For more details, please visit Capella.

Data from the HELIOS-B study supported the recent approvals of AMVUTTRA for the treatment of the cardiomyopathy of wild-type or hereditary ATTR-CM in adults in the United States (US), Brazil, European Union (EU), Japan, United Arab Emirates (UAE) and United Kingdom (UK). Collectively, AMVUTTRA has more than 8,000 patient-years of experience worldwide and is the first RNAi therapeutic approved for the treatment of both the cardiomyopathy manifestations of ATTR amyloidosis and the polyneuropathy manifestations of hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

For additional information on Alnylam's presentations at the ESC 2025 Congress, please visit Capella.

AMVUTTRA^® (vutrisiran) INDICATIONS AND IMPORTANT SAFETY INFORMATION

Indications

In the EU, AMVUTTRA^® (vutrisiran) is indicated for the treatment of:

• hereditary transthyretin amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy (hATTR-PN).
• wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

Availability across the EU is subject to local reimbursement timelines.

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

Commonly reported adverse reactions with vutrisiran were injection site reactions and increase in blood alkaline phosphatase and alanine transaminase.

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 transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. It is marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults and it is also approved for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults in the US, Europe, Brazil, Japan, UAE and UK. Administered quarterly via subcutaneous injection, AMVUTTRA is the first and only RNAi therapeutic approved for the treatment of both the cardiomyopathy manifestations of ATTR amyloidosis and the polyneuropathy manifestations of hereditary transthyretin-mediated amyloidosis (hATTR).

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-CM; vutrisiran's sustained and long-term benefits in ATTR-CM; vutrisiran's potential as a first-line treatment for patients with ATTR-CM; the potential for vutrisiran to have continued clinical benefits and to modify the course of disease in ATTR-CM over the long term; and Alnylam's ability to execute 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 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" goals; 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; 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 Alnylam's approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam's product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; 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; Alnylam's ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products; the outcome of litigation; the potential risk of future government investigations; and unexpected expenditures; 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 other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing Alnylam's 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 Hawkins PN, Ando Y, Dispenzeri A, et al. Ann Med. 2015;47(8):625-638.

² Gertz MA. Am J Manag Care. 2017;23(7):S107-S112.

³ Conceicao I, Gonzalez-Duarte A, Obici L, et al. J Peripher Nerv Syst. 2016;21:5-9.

⁴ Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis. 2013;8:31.

⁵ Elbashir SM, Harborth J, Lendeckel W, et al. Nature. 2001;411(6836):494-498.

⁶ Zamore P. Cell. 2006;127(5):1083-1086.

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