Alnylam Presents Detailed Results From the Positive HELIOS-B Phase 3 Study of Vutrisiran▼ in Patients With ATTR Amyloidosis with Cardiomyopathy

Alnylam Pharmaceuticals News

CAMBRIDGE, Mass.--Alnylam Pharmaceuticals, Inc., an RNAi therapeutics company, announced detailed results from the HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM).

The data were presented in a Hot Line session at the European Society of Cardiology (ESC) Congress 2024, taking place August 30-September 2 in London, United Kingdom. Results from the HELIOS-B study were also simultaneously published in The New England Journal of Medicine.

As previously reported, the HELIOS-B study met all 10 of its primary and secondary endpoints, across both the overall and monotherapy populations, with statistical significance.

Enrolled patients were predominantly New York Heart Association (NYHA) Class I or II with wild-type disease and had been diagnosed by non-invasive methods, with substantial concurrent treatment with available standard of care treatments such as tafamidis and SGLT2 inhibitors – reflecting the contemporary ATTR-CM patient population.

In the study, treatment with vutrisiran substantially reduced the risk of death and cardiovascular events relative to placebo (see table below for further details). In the overall population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28%, with similar reductions in both the mortality and cardiovascular events components of the endpoint. Mortality in this population was significantly reduced by 31% during the double-blind period and by 36% up to 42 months. In the monotherapy population, vutrisiran significantly reduced the risk of all-cause mortality and recurrent cardiovascular events by 33% and significantly reduced the risk of mortality by 35% up to 42 months. As a component of the primary endpoint, a non-significant reduction of 30% in mortality was observed (nominal p-value 0.1179) in the monotherapy population during the double-blind period.

Vutrisiran treatment was also associated with benefits versus placebo across multiple well-established clinical measures of disease progression, including 6-Minute Walk Test, Kansas City Cardiovascular Questionnaire, and NYHA Class, as well as the cardiac biomarker NT-proBNP.

Subgroup analyses demonstrated consistent benefits across all key patient segments, including patients receiving background tafamidis. Trends toward greater efficacy were seen in patients with earlier disease (i.e., younger patients and those with lower baseline NT-proBNP).

In HELIOS-B, the safety and tolerability profiles of vutrisiran were consistent with what had been established in the currently approved patient population, as well as earlier clinical studies.

“Results from the HELIOS-B study demonstrate a significant advance in the treatment of ATTR amyloidosis with cardiomyopathy, suggesting that knockdown of TTR production with vutrisiran can dramatically reduce all-cause mortality and cardiovascular events,” said Marianna Fontana, M.D., Ph.D., HELIOS-B investigator, Professor of Cardiology, University College London, National Amyloidosis Center, Royal Free Hospital, London. “Over the past decade, advances in ATTR-CM have led to more patients being diagnosed earlier in their disease, often with less severe symptoms and better prognosis, as well as receiving more robust background standards of care. In this contemporary setting, the bar was high to demonstrate benefit. These HELIOS-B data also suggest that, within this current patient population, vutrisiran may provide greater benefit to patients in earlier stages of the disease where, due to the progressive nature of ATTR-CM, early treatment can more effectively preserve functional capacity and quality of life.”

“We’re proud to share the detailed HELIOS-B data with the cardiology community at the ESC Congress 2024. With this study, we have demonstrated that the rapid knockdown of toxic TTR seen with vutrisiran improves survival, and reduces cardiovascular hospitalizations and disease progression versus placebo, with benefits consistently observed across populations and regardless of background stabilizer use,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “While the results have not yet been reviewed by a regulatory authority, the data we have shared today suggest that vutrisiran has the potential to become a new standard of care treatment for ATTR-CM, a progressive and ultimately fatal disease with limited treatment options. We want to thank everyone who contributed to the success of this study, including the patients, caregivers, investigators, study staff and my Alnylam colleagues. In light of these data, we are working with urgency to file these data with regulators and bring this medicine to patients around the world.”

Primary and Secondary Endpoints

The results of the prespecified primary and secondary endpoints in both the overall and monotherapy populations are detailed in the table below.

Subgroup analyses of the primary and secondary endpoints, which were not powered to show statistical significance, demonstrated generally consistent results across all key patient segments, including patients receiving tafamidis at baseline. In patients receiving baseline tafamidis, vutrisiran demonstrated a 22% reduction (HR 0.785, nominal p-value 0.2701, ARR 6.7) in the composite primary endpoint of ACM and recurrent CV events and a 41% reduction (HR 0.588, nominal p-value 0.0983, ARR 6.5) in ACM at 42 months versus placebo.

Trends toward greater than average benefit were seen in patients with baseline characteristics indicative of early disease. Patients with baseline NT-proBNP of ≤2000 experienced a 48% reduction (HR 0.525, nominal p-value 0.0019) in the composite primary endpoint, as well as a 65% reduction (HR 0.348, nominal p-value 0.0012) in ACM up to 42 months when treated with vutrisiran versus placebo. In patients younger than 75 years old, vutrisiran demonstrated a 46% reduction (HR 0.545, nominal p-value 0.0081) in the composite primary endpoint and a 45% reduction (HR 0.552, nominal p-value 0.0661) in ACM up to 42 months versus placebo.

Additionally, the study demonstrated evidence of benefit on NT-proBNP, an established cardiac biomarker that is prognostic of mortality in ATTR-CM. At Month 30, vutrisiran led to a 32% relative reduction in the fold change in NT-proBNP compared to placebo in the overall population (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.68; nominal p-value 3.440E-12) and a 43% relative reduction in the fold change in NT-proBNP compared to placebo in the vutrisiran monotherapy subgroup (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.57; nominal p-value 4.339E-12).

Safety

In the HELIOS-B study, vutrisiran demonstrated an encouraging safety and tolerability profile consistent with the established profile of the drug. Rates of adverse events (AEs), serious AEs, severe AEs and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. Cardiac AEs were similar or lower in the vutrisiran arm compared to placebo. AEs occurring in more than 15% of patients overall were similar or lower in the vutrisiran arm compared to placebo (cardiac failure, Covid-19, atrial fibrillation, gout, dypnoea and fall). No AEs were seen ≥3% more frequently in the vutrisiran arm compared to the placebo arm.

HELIOS-B (NCT: NCT04153149) was a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the efficacy and safety of vutrisiran on the reduction of all-cause mortality and recurrent cardiovascular events as a primary composite endpoint in patients with ATTR amyloidosis with cardiomyopathy. The study randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized 1:1 to receive vutrisiran 25mg or placebo subcutaneously once every three months during a double-blind treatment period of up to 36 months. After the double-blind period, all eligible patients remaining on the study were able receive vutrisiran in an open-label extension period of HELIOS-B.

The Company remains on track to proceed with global regulatory submissions for vutrisiran starting later this year, including filing a supplemental New Drug Application with the U.S. Food and Drug Administration using a Priority Review Voucher.

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.

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