Alnylam Announces Five-Year HELIOS-B Data Demonstrating Sustained Benefit of AMVUTTRA® (vutrisiran) in ATTR-CM

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced new data at the American Heart Association (AHA) Scientific Sessions 2026, adding to the robust body of evidence demonstrating the strength of RNAi-powered TTR silencing with AMVUTTRA^® (vutrisiran). The analyses, including data from the HELIOS-B Phase 3 two-year open-label extension (OLE) period, show that patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) treated continuously with AMVUTTRA had lower rates of the composite of all-cause mortality and recurrent cardiovascular events, better-preserved quality of life and greater stability of cardiac biomarkers through five years than patients who initiated treatment with AMVUTTRA approximately three years later. A separate post hoc analysis of HELIOS-B provides new physiologic insight into the effects of AMVUTTRA during exercise, demonstrating preserved exercise capacity and favorable effects across multiple components of the cardiopulmonary response to exercise compared with placebo.

“The sustained treatment effects observed with AMVUTTRA across multiple measures of cardiovascular health during the five years of HELIOS-B strengthen the evidence that early and continuous TTR silencing at the source can change the course of a rapidly progressive disease. Together with new insights into the effects of AMVUTTRA on the cardiopulmonary response to exercise, these findings underscore the importance of treating patients early, when preserving cardiac function and slowing disease progression may have the greatest impact,” said Pushkal Garg, M.D., Chief Research and Development Officer at Alnylam. “These data reinforce the strength of TTR silencing as a foundational approach to ATTR-CM care, and show the potential of RNAi therapeutics to translate deep, sustained target suppression into meaningful long-term outcomes for patients.”

Vutrisiran Demonstrated Significant Sustained Cardiovascular and Quality of Life Benefits through Five Years

In the HELIOS-B Phase 3 study, patients initially randomized to vutrisiran in the double-blind period were eligible to continue treatment during the OLE period, and patients initially randomized to placebo were eligible to transition to vutrisiran, enabling assessment of outcomes with continuous versus delayed treatment initiation through 60 months. Pre-specified analyses were conducted in both the monotherapy population not receiving tafamidis at baseline and the overall study population.

Across the monotherapy and overall populations, patients initially randomized to vutrisiran experienced more favorable long-term outcomes than patients who initiated vutrisiran during the OLE period, reinforcing the importance of initiating TTR silencing early in the course of disease. Continuous vutrisiran treatment was associated with significant and durable reductions in the composite of all-cause mortality (ACM) and recurrent cardiovascular (CV) events compared with those who initially received placebo and transitioned to vutrisiran during the OLE period, with a 48% lower risk in the monotherapy population and a 41% lower risk in the overall population. The risk of recurrent CV events was also significantly lower with continuous treatment with vutrisiran, decreasing by 50% in the monotherapy population and 41% in the overall population. Patients who initiated vutrisiran earlier also maintained better quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, and showed greater stability of cardiac biomarker levels, including NT-proBNP and troponin I, compared with delayed treatment initiation.

Among patients receiving tafamidis at baseline, continuous treatment with vutrisiran and tafamidis was associated with a 23% reduction in recurrent CV events (RR: 0.766; 95% CI: 0.597, 0.984; p=0.0366) relative to patients who initially received tafamidis alone and initiated vutrisiran during the OLE. The safety profile of vutrisiran through 60 months was consistent with its known safety profile, with no new safety signals identified.

“ATTR-CM is a progressive disease, making it critical to intervene before patients experience further irreversible decline. These long-term HELIOS-B data are particularly compelling because they demonstrate that patients treated continuously with vutrisiran experienced more favorable outcomes than those who initiated treatment later,” said Sarah Cuddy, M.D., Brigham and Women's Hospital and Harvard Medical School. “These findings reinforce the importance of considering TTR silencing early in the course of disease to preserve patients’ health and quality of life for as long as possible.”

HELIOS-B Post Hoc Analysis Provides New Insight into the Cardiopulmonary Response to Exercise

Exercise intolerance is a hallmark of ATTR-CM and can progressively limit patients’ daily function as the disease advances. A post hoc, single-center analysis of 48 patients enrolled in HELIOS-B who underwent cardiopulmonary exercise testing (CPET) with concurrent stress echocardiography at the National Amyloidosis Centre in London showed that vutrisiran preserved multiple components of the cardiopulmonary response to exercise over two years compared with placebo. Vutrisiran preserved exercise capacity, as measured by peak oxygen uptake (VO₂), with an LS mean difference of 1.57 mL/kg/min versus placebo (95% CI: 0.14 to 3.00; p=0.031). Vutrisiran also preserved chronotropic response and improved ventilatory efficiency, while stress echocardiography showed favorable changes in measures of right ventricular systolic reserve and left ventricular diastolic reserve. No patients received other ATTR-CM disease-modifying therapies during the study period. Together, these findings provide new physiologic insight into how TTR silencing with vutrisiran may help preserve the cardiovascular system’s ability to respond to the demands of exercise in patients with ATTR-CM.

To view Alnylam’s AHA Scientific Sessions 2026 presentations, please visit Capella.

Indications and Important Safety Information

Indications Approved by the U.S. FDA

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

• cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce CV mortality, CV hospitalizations and urgent heart failure visits.
• polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.

Important Safety Information

Reduced Serum Vitamin A Levels and Recommended Supplementation

AMVUTTRA 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 AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A 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

In a study of patients with hATTR-PN, the most common adverse reactions that occurred in patients treated with AMVUTTRA were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%).

In a study of patients with ATTR-CM, no new safety issues were identified.

For additional information about AMVUTTRA, please see the full U.S. Prescribing Information (revised March 2025).

About AMVUTTRA^® (vutrisiran)

AMVUTTRA^® (vutrisiran) demonstrates strength in RNAi-powered transthyretin (TTR) silencing, delivering rapid knockdown of TTR at the source of disease to address the underlying cause of transthyretin amyloidosis (ATTR). As ATTR is a rapidly progressive disease, even when patients may appear clinically stable, early treatment intervention is critical. In the HELIOS-B Phase 3 study, AMVUTTRA reduced the risk of all-cause mortality and recurrent CV events compared to placebo in the overall and monotherapy populations by 28.2% and 32.8%, respectively, through 36 months. It is the only TTR silencer approved for both the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) and cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in countries globally. More than 14,000 patients worldwide have been treated with AMVUTTRA, which is recommended by the European Society of Cardiology as a Class I, Level A treatment for patients with ATTR-CM. AMVUTTRA is administered once every three months via subcutaneous injection.

About Transthyretin Amyloidosis (ATTR)

Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating, and fatal disease caused by pathogenic 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 wild-type ATTR (wtATTR), which occurs without a TTR gene variant. It is estimated that more than 500,000 people worldwide live with ATTR, with ~80% remaining undiagnosed.

About RNAi Technology

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 (Nasdaq: ALNY) is a leading global biopharmaceutical company and the pioneer of the RNA interference (RNAi) revolution. The Company is focused on developing transformative therapies with the potential to prevent, halt, or reverse disease. For more than two decades, Alnylam has advanced the Nobel Prize-winning science of RNAi, delivering critical breakthroughs and six approved medicines. Alnylam has medicines available in more than 70 countries and a rapidly expanding and robust pipeline, in addition to consistently being recognized as an exceptional workplace and socially responsible organization. The Company is executing on its Alnylam 2030 strategy to accelerate innovation and scale impact to transform human health. For more information, please visit www.alnylam.com or follow Alnylam on X, LinkedIn, Facebook, Instagram, or YouTube.

Alnylam Forward-Looking Statements

This press release contains forward-looking statements. Forward-looking statements include statements regarding Alnylam’s expectations, beliefs, goals, plans or prospects, including, without limitation, statements regarding: the potential for early and continuous TTR silencing at the source to change the course of ATTR-CM; the potential of early treatment with AMVUTTRA, through preserving cardiac function and slowing disease progression, to have the greatest impact on ATTR-CM; the potential of RNAi therapeutics to translate deep, sustained target suppression into meaningful long-term outcomes for patients; the potential of TTR silencing early in the course of disease to preserve patients’ health and quality of life for as long as possible; the potential for TTR silencing with vutrisiran to help preserve the cardiovascular system’s ability to respond to the demands of exercise in patients with ATTR-CM; and Alnylam’s ability to achieve the goals in its Alnylam 2030 strategy. 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 2030 strategy; Alnylam’s ability to successfully launch, market and sell Alnylam’s approved products globally, including AMVUTTRA; 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; delays, interruptions or failures in the manufacture and supply of Alnylam’s marketed products or its product candidates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to manage its growth and operating expenses through disciplined investment in operations; 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 and government investigations; the risk of future litigation and government investigations; and unexpected expenditures; as well as those risks and uncertainties more fully discussed in the “Risk Factors” filed with Alnylam’s most recent periodic report (Quarterly Report on Form 10-Q or Annual Report on Form 10-K) filed with the SEC and in its other SEC filings. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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