–Late-Breaking Prespecified Subgroup Analysis of HELIOS-B Demonstrates that Vutrisiran Provided Consistent Clinical Benefit Across All-Cause Mortality and Recurrent Cardiovascular Events in Patients With or Without Tafamidis Use at Baseline –

–Additional Post Hoc Analyses Highlight Positive Impact of Vutrisiran in Addressing the Multisystemic Manifestations of ATTR-CM –

–Pooled Analysis Across Four Positive Phase 3 Studies of Vutrisiran and Patisiran Shows Consistent Treatment Effect Across Sexes –

–New Subgroup Analysis from KARDIA-3 Phase 2 Study of Zilebesiran Highlights Potential to Provide Enhanced Blood Pressure Control –

Company Website: https://www.alnylam.com
CAMBRIDGE, Mass. -- (Business Wire)

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced new data at the European Society of Cardiology (ESC) Congress 2026 demonstrating the strength of RNAi-powered silencing for cardiovascular disease. The findings further reinforce the clinical profile of AMVUTTRA^® (vutrisiran) across transthyretin amyloidosis (ATTR) patient populations, treatment settings, and manifestations of disease. Additionally, the data expand the potential application of RNAi to uncontrolled hypertension, the world’s leading cause of cardiovascular disease.

“With the power of our RNAi therapeutics platform, we have the potential to make a transformational impact on cardiovascular care,” said Pushkal Garg, M.D., Chief Research and Development Officer at Alnylam. “The data presented at ESC demonstrate the consistency of clinical outcomes achieved by RNAi-powered TTR silencing, reinforcing our conviction in AMVUTTRA as a first-line treatment option for ATTR-CM. With zilebesiran, we have the potential to extend the precision and durability of RNAi to uncontrolled hypertension. Together, these programs reflect our ambition to change the course of cardiovascular disease for patients with high unmet need.”

Vutrisiran Analyses

HELIOS-B Prespecified Subgroup Analysis Demonstrates Consistent Clinical Benefit with Vutrisiran Across Contemporary ATTR-CM Treatment Settings

A late-breaking oral presentation featured a prespecified subgroup analysis of the HELIOS-B Phase 3 clinical trial evaluating the treatment effect of vutrisiran according to baseline tafamidis use. The results were simultaneously published in the Journal of the American College of Cardiology.

Among 654 randomized and treated patients in HELIOS-B, 259 patients (40%) were receiving tafamidis at baseline. The treatment effect for vutrisiran on the primary composite endpoint of all-cause mortality and recurrent cardiovascular events through 33-36 months was consistent irrespective of baseline tafamidis use, suggesting clinical benefits across broad patient populations, including those receiving stabilizers.

All-cause mortality and additional cardiovascular outcomes showed a similar benefit among patients who were receiving tafamidis at baseline (“combination population”) and those who were not (“monotherapy population”). Across both groups, treatment with vutrisiran preserved functional capacity versus placebo, as measured by the Six-Minute Walk Test. Improvement in health status by vutrisiran versus placebo, as measured by the Kansas City Cardiomyopathy Questionnaire-overall summary score, was observed in both the monotherapy and combination populations with an attenuated effect seen among patients receiving tafamidis at baseline. Safety outcomes were generally similar between combination vutrisiran and tafamidis versus tafamidis alone, and between vutrisiran monotherapy versus placebo. HELIOS-B was not powered to establish the benefit of vutrisiran specifically in the population of patients receiving background tafamidis at baseline. These findings reinforce the impact of vutrisiran across contemporary ATTR-CM treatment settings and warrant further evaluation of TTR silencing and stabilization combination strategies.

Additional HELIOS-B Analyses Highlight the Potential Impact of Vutrisiran on the Multisystemic Burden of ATTR-CM

Additional analyses presented at ESC further underscore the multisystemic burden of ATTR-CM and the importance of evaluating measures beyond traditional cardiac endpoints. Real-world evidence from the French National Health Data System showed that patients with ATTR-CM had a significantly higher burden of extra-cardiac manifestations across multiple organ systems compared with matched controls, and multiple manifestations were recorded years before ATTR-CM identification and tended to accumulate over time, suggesting a prolonged pre-diagnostic phase with evolving multisystem involvement.

A post hoc analysis of HELIOS-B evaluated the impact of treatment with vutrisiran on intrinsic capacity, a composite measure encompassing locomotion, cognition, vitality, psychological well-being and sensory function aligned with the World Health Organization Integrated Care for Older People framework. In the overall study population, compared with placebo, patients treated with vutrisiran demonstrated 25% less decline from baseline intrinsic capacity score and a 52% reduction in the risk of decline, suggesting that treatment with vutrisiran may help preserve functional reserve and support healthy aging in patients with ATTR-CM.

A separate post hoc safety analysis of HELIOS-B showed that patients treated with vutrisiran had fewer adverse events overall compared with placebo across the overall study population, monotherapy population and combination population. Among the most frequent system organ classes in the overall population, the lowest adverse event rate ratios were observed for gastrointestinal disorders and nervous system disorders, with 42% and 41% lower adverse event rates, respectively, with vutrisiran compared with placebo; eye disorders showed a 46% lower event rate with vutrisiran compared with placebo.

Pooled Phase 3 Data Reinforce Consistent Treatment Effects of RNAi-Powered TTR Silencing Across Sexes

A pooled analysis of 1,402 patients (203 females, 1,199 males) across four Phase 3 studies of vutrisiran and patisiran further reinforces the clinical benefits of RNAi-mediated TTR silencing across sexes. Despite sex-specific baseline differences in disease presentation, treatment effects were consistent between females and males across both ATTR-CM and the polyneuropathy of hereditary ATTR (hATTR-PN), including clinical, biomarker, functional, health status and echocardiographic measures.

“These data add to the deep and consistent evidence base supporting RNAi-mediated TTR silencing in ATTR-CM,” said Teresa Trenkwalder, M.D., Senior Physician, TUM University Hospital German Heart Center. “Across patient populations, treatment settings, and manifestations of disease, the analyses of vutrisiran demonstrate the clinical benefit that can be achieved by reducing TTR production at its source.”

Zilebesiran Analysis

The KARDIA-3 Phase 2 study evaluated zilebesiran, an investigational RNAi therapeutic with the potential to provide continuous control of blood pressure (BP) with biannual dosing, in patients with uncontrolled hypertension with high cardiovascular (CV) risk treated with two or more background antihypertensives. In patients who were receiving a background diuretic with an office systolic BP (SBP) ≥140 mmHg at baseline, zilebesiran achieved greater reductions in mean office and 24-hour ambulatory SBP than in the overall study population. Furthermore, patients treated with zilebesiran experienced SBP reductions across the diurnal cycle, including at nighttime. Similar findings were observed in patients who had impaired nocturnal dipping at baseline. These findings are potentially important given the association between elevated nighttime BP and CV risk. The safety profile in this post hoc subgroup was consistent with the broader zilebesiran Phase 2 program. These findings further support the evaluation of zilebesiran in the ongoing global Phase 3 CV outcomes trial, ZENITH.

Zilebesiran will be featured as part of Alnylam's 10th “RNAi Roundtable” series on September 17, 2026, at 10:30 a.m. ET.

To view Alnylam’s ESC Congress 2026 presentations, please visit Capella. Alnylam may share additional data and information during the Congress through its Investors website and/or 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 can lower serum vitamin A levels, therefore supplementation of approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per day is advised for patients.

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.

ONPATTRO^® (patisiran) INDICATION AND IMPORTANT SAFETY INFORMATION

Indication

In the EU, ONPATTRO^® (patisiran) is indicated for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adults with stage 1 or stage 2 polyneuropathy.

Important Safety Information

Reduced Serum Vitamin A Levels and Recommended Supplementation

Patisiran treatment can lower serum vitamin A levels, therefore supplementation of approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per day is advised for patients.

Adverse Reactions

The most common adverse reactions that occurred in patients treated with patisiran were peripheral oedema (30%) and infusion-related reactions (19%).

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

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). 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. AMVUTTRA is administered once quarterly 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 Zilebesiran

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in development for cardiovascular (CV) risk reduction in hypertensive patients at high risk or with established CVD. Zilebesiran targets angiotensinogen (AGT), the most upstream precursor in the renin-angiotensin-aldosterone system (RAAS), which plays a role in blood pressure (BP) regulation and impacts CV and renal health. Clinical trial results have shown the potential for zilebesiran to provide continuous control of BP with biannual dosing in a broad population of patients with hypertension. Zilebesiran is being evaluated in a Phase 3 CV outcomes trial, ZENITH, which will assess its ability to reduce the risk of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure events in patients with hypertension and established or at high risk of CVD, despite the use of at least two or more antihypertensives. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA, or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.

About Cardiovascular Disease and Hypertension

Cardiovascular disease (CVD) is a global health crisis and a leading cause of death worldwide, responsible for approximately 20 million deaths annually. Hypertension is the primary cause of and number one modifiable risk factor for CVD. An estimated one in three adults worldwide have hypertension, and despite wide availability of antihypertensives, up to 80% of all patients, and up to one-third of treated patients, do not reach and maintain blood pressure (BP) targets. Even when BP appears well-managed, continuous control of BP may remain suboptimal, leading to variability in BP during the 24-hour period and in the long-term, putting patients at greater risk of cardiovascular events and end organ damage.

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 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. Alnylam routinely posts information that may be important to investors in the “Investors” section of its website at https://investors.alnylam.com/. Investors and potential investors are encouraged to consult the Alnylam website regularly.

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 efficacy or safety of vutrisiran for the treatment of ATTR CM, including in combination with a stabilizer; the potential clinical benefit that can be achieved by reducing TTR production at its source across patient populations, treatment settings and manifestations of disease; the potential for AMVUTTRA to be a first-line treatment for ATTR-CM; the potential for zilebesiran to extend the precision and durability of RNAi, and to provide continuous control of blood pressure with biannual dosing, in patients with uncontrolled hypertension; Alnylam’s ability to make a transformational impact on cardiovascular care and to change the course of cardiovascular disease for patients with high unmet need; and Alnylam’s ability to execute on its Alnylam 2030 strategy to accelerate innovation and scale impact to transform human health. 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 2025 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. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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Contacts:

Alnylam Pharmaceuticals, Inc.

Sarah D’Souza
(Media)
Media@alnylam.com

Josh Brodsky
(Investors)
Investors@alnylam.com

Source: Alnylam Pharmaceuticals, Inc.