New ACC.26 Data Strengthen Evidence for Vutrisiran in ATTR-CM and Highlight Zilebesiran’s Potential in Hypertension
Alnylam Pharmaceuticals, a leader in RNA interference (RNAi) therapeutics, announced new clinical and real-world findings from its cardiovascular portfolio at the American College of Cardiology’s Annual Scientific Session and Expo (ACC.26). The data reinforce the company’s commitment to advancing innovative RNAi-based therapies designed to deliver durable and differentiated outcomes for patients with cardiovascular disease (CVD).
The latest findings provide strong support for vutrisiran, a transthyretin (TTR) silencer, demonstrating consistent clinical benefits across a broad spectrum of patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). In parallel, pooled Phase 2 data for zilebesiran, an investigational therapy for hypertension, highlight its favorable safety profile and potential role in long-term cardiovascular risk reduction.
Vutrisiran Demonstrates Meaningful Quality-of-Life Improvements
Alnylam New analyses from the HELIOS-B clinical program underscore vutrisiran’s ability to improve health-related quality of life (QoL) in patients with ATTR-CM. As the first and only therapy designed to silence TTR production at its source, vutrisiran achieves rapid and sustained knockdown of the disease-causing protein.
A key analysis evaluated patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) over a 30-month period. Compared to placebo, patients treated with vutrisiran experienced significant improvements across nearly all domains, with particularly notable gains in physical limitations and overall quality of life.
Importantly, the magnitude of benefit was clinically meaningful. The improvement in QoL associated with vutrisiran treatment was comparable to the difference typically observed between patients more than a decade apart in age—an indicator of the therapy’s substantial impact on daily functioning and well-being.
These Alnylam findings further validate the mechanism of TTR silencing and its translation into tangible benefits for patients living with ATTR-CM, a progressive and often debilitating disease.
Consistent Benefits Across Disease Severity
Beyond QoL improvements, vutrisiran demonstrated consistent efficacy across varying levels of disease severity. Post hoc analyses from HELIOS-B examined outcomes in patients with advanced ATTR-CM, including those progressing to higher New York Heart Association (NYHA) classes and advanced National Amyloidosis Center (NAC) stages.
Results showed that fewer patients receiving vutrisiran progressed to advanced disease compared with those on placebo (8.0% vs. 10.7%). Among patients who did progress, vutrisiran treatment significantly improved outcomes. Specifically, the therapy reduced the risk of the composite endpoint of all-cause mortality (ACM) and recurrent cardiovascular events by 40% in the overall population and 46% in patients receiving monotherapy.
Further analysis revealed a substantial reduction in the risk of all-cause mortality when considering both the double-blind study period and an additional six months of open-label extension. In this Alnylam , vutrisiran reduced mortality risk by 56% in the overall population and by an impressive 77% among patients receiving it as monotherapy.
Notably, vutrisiran maintained a favorable safety profile even in patients with advanced disease, with adverse event rates comparable to or lower than those observed with placebo.
Positive Impact on Diastolic Dysfunction
Diastolic dysfunction is a key determinant of poor outcomes in patients with ATTR-CM. A dedicated analysis explored the effects of vutrisiran across different grades of diastolic dysfunction at baseline.
The findings demonstrated that Alnylam vutrisiran was associated with a reduced risk of worsening diastolic dysfunction over time. Among patients with the most severe baseline dysfunction (Grade III), a significantly higher proportion of those treated with vutrisiran maintained or improved their NYHA functional class compared with placebo.
Moreover, the therapy consistently reduced the risk of all-cause mortality and cardiovascular events regardless of baseline diastolic dysfunction grade, further emphasizing its broad applicability across patient subgroups.
Strong Real-World Adherence and Persistence
In addition to clinical trial data, real-world evidence highlights the practical advantages of vutrisiran’s dosing regimen. A retrospective cohort study in patients with amyloidosis demonstrated high levels of treatment adherence and persistence.
Patients were followed for an average of over 600 days, and nearly 94% met adherence criteria based on the proportion of days covered (PDC ≥0.8). Most patients remained on therapy after 12 months, reflecting both the tolerability of the treatment and the convenience of its quarterly administration by healthcare professionals.
This real-world performance supports vutrisiran’s potential as a sustainable long-term treatment option for ATTR-CM.
Extensive Clinical Experience
Vutrisiran’s growing body of evidence is complemented by substantial clinical experience. The therapy has accumulated more than 13,000 patient-years of data across indications, including both ATTR-CM and hereditary transthyretin-mediated amyloidosis with polyneuropathy (hATTR-PN).
Collectively, these data reinforce vutrisiran’s role as a foundational therapy capable of delivering durable clinical benefits, improving survival outcomes, and enhancing quality of life.
Zilebesiran Shows Promise in Hypertension Management
Alongside advances in ATTR-CM, Alnylam also presented new data on zilebesiran, an investigational RNAi therapeutic targeting angiotensinogen (AGT), a key upstream component of the renin-angiotensin-aldosterone system (RAAS).
Zilebesiran is designed to provide sustained blood pressure control through biannual dosing, offering a novel approach to hypertension management—particularly for patients at high cardiovascular risk who require multiple medications.
The newly presented pooled safety analysis from the Phase 2 KARDIA program supports zilebesiran’s favorable safety profile across a diverse patient population. This includes individuals with mild-to-moderate hypertension, those with elevated cardiovascular risk, and patients with reduced kidney function.
Favorable Safety Profile Across Patient Populations
The comprehensive safety analysis found that clinically relevant adverse events—such as hypotension, hyperkalemia, and declines in estimated glomerular filtration rate (eGFR)—occurred at low rates across treatment groups.
Importantly, these events were generally mild, transient, and resolved without intervention. The safety profile remained consistent whether zilebesiran was used as a standalone therapy or in combination with standard antihypertensive agents, including ACE inhibitors and angiotensin receptor blockers.
These findings further strengthen the rationale for continued development of zilebesiran in large-scale clinical trials.
Advancing to Phase 3 Evaluation
Building on encouraging Phase 2 results, zilebesiran is currently being evaluated in the ZENITH Phase 3 cardiovascular outcomes trial. Initiated in September 2025, the global study aims to assess the therapy’s ability to reduce cardiovascular events in patients with hypertension who are at high risk despite existing treatments.
By targeting the root cause of RAAS activation, zilebesiran has the potential to offer a differentiated therapeutic approach—delivering consistent and long-lasting blood pressure control while addressing unmet needs in high-risk populations.
Expanding the Potential of RNAi in Cardiovascular Disease
The data presented at ACC.26 highlight the growing impact of RNAi therapeutics in cardiovascular medicine. By targeting disease pathways at the genetic level, RNAi-based treatments such as vutrisiran and zilebesiran offer the potential for precise, durable, and transformative outcomes.
For patients with ATTR-CM, vutrisiran represents a significant advancement, addressing both disease progression and quality of life. Meanwhile, zilebesiran’s innovative mechanism and dosing profile position it as a promising candidate in the evolving landscape of hypertension management.
Conclusion
Alnylam’s latest findings reinforce the value of RNAi technology in addressing complex cardiovascular diseases. Vutrisiran continues to demonstrate robust and consistent benefits across clinical and real-world settings, supporting its role as a first-line therapy for ATTR-CM.
At the same time, zilebesiran’s encouraging safety data and ongoing Phase 3 evaluation signal its potential to redefine hypertension treatment.
Together, these advances underscore a broader shift toward innovative, mechanism-driven therapies capable of delivering long-lasting impact for patients living with cardiovascular disease.
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 isapproved 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.
