Zilebesiran

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced new clinical and real-world data from its cardiovascular (CV) portfolio presented at the American College of Cardiology’s Annual Scientific Session and Expo (ACC.26), reinforcing the potential of RNAi to deliver fundamentally differentiated, effective, and durable impact for patients living with cardiovascular disease (CVD). New data continue to support the use of vutrisiran – the first and only transthyretin (TTR) silencer that delivers rapid knockdown of TTR at the source – as a first-line treatment for patients with the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR‑CM). The HELIOS-B analyses demonstrate that vutrisiran delivered meaningful improvements in how patients with ATTR-CM feel and function, with benefits sustained across disease severity, reinforcing how TTR silencing at its source translates into durable clinical and health-related quality-of-life (QoL) benefits for patients. Alnylam also presented pooled Phase 2 safety data for zilebesiran, an investigational RNAi therapeutic being evaluated for cardiovascular risk reduction in patients with hypertension, with the potential to provide continuous control of blood pressure. The results support continued evaluation of zilebesiran in patients with hypertension and high CV risk in ZENITH, a global Phase 3 Cardiovascular Outcomes Trial (CVOT) that was initiated in September 2025. Vutrisiran Analyses: New analyses expand the totality of HELIOS-B evidence demonstrating improvements in patients’ health-related QoL, consistent efficacy on CV outcomes across a range of patient subgroups, including those with advanced disease and diastolic dysfunction, and real-world data showing high treatment adherence with four healthcare professional (HCP)-administered doses per year. In addition to clinical studies, vutrisiran has more than 13,000 patient-years of experience for the treatment of ATTR-CM and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. HELIOS-B Analysis of QoL as Measured by KCCQ This analysis evaluated placebo-corrected mean score changes of vutrisiran-treated patients across the 23-item Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) from baseline to 30 Months. Compared to placebo, vutrisiran demonstrated improvements in nearly all components, most notably in physical limitations and QoL. Moreover, the magnitude of treatment effect in age-adjusted KCCQ-OSS favoring vutrisiran was comparable to the difference observed in patients 11 years (95% CI: 3-20 years) apart in age. These findings were simultaneously published in the European Journal of Heart Failure. HELIOS-B Post Hoc Analysis of Patients with Advanced Disease During the Double-Blind (DB) Period The analysis assessed the risk of patients developing advanced disease as defined by transitioning to New York Heart Association (NYHA) class III and National Amyloidosis Center (NAC) stage 3, or NYHA class IV, with vutrisiran versus placebo during the HELIOS-B DB period. In the overall population, fewer patients receiving vutrisiran developed advanced disease compared to patients receiving placebo (8.0% vs. 10.7%, respectively). The analysis also assessed the effect of vutrisiran on outcomes in patients with ATTR-CM who developed advanced disease. In these patients, treatment with vutrisiran reduced the risk of the composite of all-cause mortality (ACM) and recurrent CV events during the DB period by 40% in the overall population and 46% in the monotherapy population, versus placebo. Treatment with vutrisiran also reduced the risk of ACM during the DB period plus up to six months of open-label extension by 56% in the overall population and 77% in the monotherapy population, versus placebo. Vutrisiran had a favorable safety profile in patients with advanced disease, with a similar or fewer proportion of patients experiencing adverse events, compared to placebo. “These new data present further evidence of the meaningful impact vutrisiran offers patients with ATTR‑CM and provide deeper insight into its benefits for patients with more advanced disease,” said Ronald Witteles, M.D., HELIOS-B Investigator, Professor of Medicine at Stanford University School of Medicine and Co-Director of the Stanford Amyloid Center. “Vutrisiran not only meaningfully reduced the risk of progression to advanced disease, but among patients who did progress, it demonstrated compelling improvements in both cardiovascular outcomes and survival. These findings provide important evidence to help inform treatment decisions for the highest-risk ATTR‑CM patients.” Real-World Vutrisiran Adherence and Persistence Study A retrospective cohort study of real-world data in patients with amyloidosis indicated high adherence and persistence to vutrisiran treatment, with most patients still receiving treatment after 12 months. Patients were followed up for a mean of 613.8 days. Over the treatment period, 93.8% were adherent to vutrisiran, defined as PDC (proportion of days covered) ≥0.8. HELIOS-B Post Hoc Analysis of Diastolic Dysfunction Diastolic dysfunction is prognostic of poor outcomes in patients with ATTR-CM. To evaluate the effect of vutrisiran in patients across a range of diastolic dysfunction grades (DDGs) at baseline, a post hoc analysis of HELIOS-B assessed outcomes at Month 30 in patients who had evaluable DDG at baseline. Higher grade DDG at baseline corresponded with adverse outcomes in ATTR-CM. Vutrisiran was associated with a lower risk of worsening DDG, with a greater proportion of patients with baseline DDG III showing stable or improved NYHA class from baseline to Month 30 in the overall and monotherapy populations (70.8% and 70.8%, respectively), compared to patients receiving placebo (55.6% and 53.2%, respectively). Vutrisiran reduced the risk of ACM and CV events during the DB period, irrespective of baseline DDG. Zilebesiran Analysis Building on the efficacy and safety results of the KARDIA Phase 2 program, these data reinforce the rationale for evaluating zilebesiran in patients with hypertension and established or at high risk of CVD, despite the use of at least two or more antihypertensives, in ZENITH. By targeting liver-expressed angiotensinogen (AGT), the most upstream precursor in the renin-angiotensin-aldosterone system (RAAS), zilebesiran has the potential to provide continuous control of blood pressure with biannual dosing, offering a potentially differentiated approach to hypertension and CV risk management in patients with the highest unmet need. Pooled Safety Analysis from Phase 2 Studies A comprehensive analysis of safety across the Phase 2 KARDIA program demonstrated an acceptable safety profile for zilebesiran, both as monotherapy and in combination with standard-of-care antihypertensives, across patients with mild-to-moderate hypertension, those at high CV risk, or with lower eGFR at baseline. In the analysis, clinically relevant safety events, such as hypotension, hyperkalemia, and eGFR decline, were low across the patient populations, including those receiving zilebesiran in combination with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB). As previously reported, the majority of these events were transient and resolved without intervention. To view Alnylam’s ACC.26 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 cardiovascular mortality, cardiovascular 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) is a transthyretin (TTR) silencer that delivers rapid knockdown of TTR at the source to address the underlying cause of transthyretin amyloidosis (ATTR). In a clinical study, AMVUTTRA rapidly knocked down TTR in as early as six weeks and decreased TTR levels by 87% with two and a half years of treatment. It is approved as a treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults and for the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults in various countries, globally. Administered quarterly via subcutaneous injection, AMVUTTRA is the first and only silencer approved for the treatment of ATTR-CM and hATTR-PN. 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. About Zilebesiran Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in development for cardiovascular (CV) risk reduction in patients with hypertension. 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. 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. For more information, please visit www.alnylam.com and engage with us on X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram. 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, statements regarding the potential efficacy, safety or treatment effect of AMVUTTRA, zilebesiran or any of Alnylam’s other products or product candidates; the potential of RNAi to deliver fundamentally differentiated, effective, and durable impact for patients living with cardiovascular disease; the potential of AMVUTTRA to be a first line treatment for ATTR-CM, to provide treatment effects across the ATTR-CM disease spectrum, and to offer meaningful impact to patients with ATTR-CM; the potential for TTR silencing at the source to disease to translate into durable clinical benefit and health related quality of life benefits for patients; the potential of zilebesiran to provide continuous control of blood pressure with biannual dosing and to offer a potentially differentiated approach to hypertension and CV risk management in patients with highest unmet need; and Alnylam’s ability to achieve the goals in its “Alnylam 2030” strategy, 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 2030” strategy; Alnylam’s ability to successfully launch, market and sell Alnylam’s approved products globally, including AMVUTTRA and zilebesiran; 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, including Roche, Novartis, Sanofi, and Regeneron; 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 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 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.