Vutrisiran Reduces Mortality, CV Events in ATTR-CM in Phase 3 Trial

Pushkal Garg, MD

Credit: Alnylam Pharmaceuticals

Topline results from the Phase 3 HELIOS-B study demonstrate statistical significance on all primary and secondary endpoints for vutrisiran (AMVUTTRA) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM).¹

Announced by Alnylam Pharmaceuticals, Inc. on June 24, 2024, vutrisiran led to significant 28% and 33% reductions in the composite of all-cause mortality and recurrent cardiovascular events in both the overall and monotherapy populations, respectively, as well as benefits on key measures of disease progression.

“I’m thrilled by these overwhelmingly positive data from the HELIOS-B study, which suggest that vutrisiran has the potential to address the needs of patients with ATTR amyloidosis with cardiomyopathy, a steadily progressive, debilitating, and ultimately fatal disease,” said Pushkal Garg, MD, chief medical officer of Alnylam.¹

ATTR amyloidosis is caused by misfolded transthyretin proteins accumulating as amyloid deposits throughout the body, including in the nerves, heart, and gastrointestinal tract.² Patients present with polyneuropathy, cardiomyopathy, or a combination. Hereditary ATTR is caused by a TTR gene variant affecting ~50,000 people; wild-type ATTR is without a gene variant and impacts ~200,000–300,000 people globally.

Vutrisiran is an RNA interference (RNAi) therapeutic halting both mutant and wild-type TTR, addressing these underlying causes of ATTR amyloidosis. The therapy was previously approved by the US Food and Drug Administration (FDA) in June 2022 to treat the polyneuropathy of hereditary ATTR in adult patients.³

HELIOS-B is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed to measure the efficacy and safety of vutrisiran in reducing all-cause mortality and recurrent CV events as a primary composite endpoint in patients with ATTR-CM.¹

Adult participants (n = 655) with ATTR-CM were randomized 1:1 to receive vutrisiran 25 mg or placebo subcutaneously every three months, during a double-blind period of up to 36 months. After this period, all eligible patients remaining in the study could receive vutrisiran in an open-label extension period.

Achieving the primary endpoint in the double-blind period, vutrisiran showed a statistically significant reduction in the composite of all-cause mortality and recurrent CV events in the overall (hazard ratio [HR], 0.718; P = .0116) and monotherapy (HR, 0.672; P = .0162) population.

Vutrisiran also exhibited statistically significant improvements in all secondary endpoints of key disease progression measures, across both populations, including the 6-minute walk test, Kansas City Cardiomyopathy Questionnaire, and the New York Heart Association Class at Month 30 (P <.025 for all).

A pre-specified, intent-to-treat analysis with ≤6 months of data from the open-label extension revealed vutrisiran treatment reduced all-cause mortality in the overall population (HR, 0.645; P <.025) and the monotherapy population (HR, 0.655; P <.05) up to Month 42.

Alnylam indicated these effects remained consistent across all key patient subgroups, including baseline tafamidis use, ATTR disease type, and measures of disease severity.¹

Safety data from HELIOS-B showed consistent safety and tolerability with the established profile of vutrisiran. Rates of adverse events (AEs), serious AEs, and AEs leading to drug discontinuation were similar between study arms. No AEs were seen ≥3% more frequently in the vutrisiran arm compared with placebo.

Alnylam has announced plans to proceed with global regulatory submission later in 2024, including filing a supplemental New Drug Application (NDA) with the FDA using a Priority Review voucher.¹ Detailed findings from HELIOS-B have been submitted as a late-breaking abstract for presentation at the 2024 European Society of Cardiology meeting.

“Assuming favorable regulatory review, vutrisiran has the potential to become the new standard of care for the treatment of this disease, driving Alnylam’s next era of substantial growth,” said Yvonne Greenstreet, MBChB, chief executive officer of Alynylam.¹

References

1. _{Alnylam reports positive topline results from Helios-B Phase 3 study of VUTRISIRAN, achieving statistical sign. Investor Relations | Alnylam Pharmaceuticals, Inc. June 24, 2024. Accessed June 24, 2024. https://investors.alnylam.com/press-release?id=28231.}
2. _{Jain A, Zahra F. Transthyretin Amyloid Cardiomyopathy (ATTR-CM) [Updated 2023 Apr 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574531/}
3. _{Grossi G. FDA approves rnai therapeutic vutrisiran for Hattr Amyloidosis. HCP Live. June 14, 2022. Accessed June 24, 2024. https://www.hcplive.com/view/fda-approves-rnai-therapeutic-vutrisiran-for-hattr-amyloidosis.}