Vutrisiran Lowers Cardiovascular Events, Mortality in HELIOS-B Analysis

Analysis of the Phase 3 HELIOS-B study of vutrisiran (AMVUTTRA) for the treatment of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) supported the trial’s primary findings, with rapid knockdown of transthyretin and reduction of key cardiovascular events.

Announced by Alnylam Pharmaceuticals, Inc., on May 17, 2025, vutrisiran, compared with placebo, significantly reduced urgent heart failure visits and reinforced the RNAi therapeutic’s impact on all-cause and cardiovascular mortality across 42 months. These results were presented as a late-breaking session at the Heart Failure 2025 Congress and published in the Journal of the American College of Cardiology (JACC).

“These new data—including the impact on mortality, on cardiovascular events, and on urgent heart failure visits, the latter of which was reduced by nearly half—add to the story of consistency and magnitude of benefit,” said Pushkal Garg, MD, chief medical officer of Alnylam. “I remain impressed by the HELIOS-B results, which are noteworthy given the substantial use of heart failure treatments in the study population, and I believe they continue to reinforce [vutrisiran] as a clinically differentiated, first-line option for patients with ATTR-CM.”

Based on positive data from the Phase 3 HELIOS-B clinical trial, the US Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for vutrisiran for the treatment of adults with cardiomyopathy of wild-type or hereditary ATTR-CM in March 2025. Approval marked the first RNAi therapeutic targeted to reduce cardiovascular mortality, cardiovascular hospitalizations, and urgent heart failure visits in ATTR-CM.

HELIOS-B randomized 655 participants to vutrisiran 25 mg or placebo once every 3 months for up to 36 months, with an open-label extension following the double-blind period. Analyses of prespecified mortality and cardiovascular mortality used data up to 42 months of follow-up, with cardiovascular hospitalizations and heart failure events evaluated up to 36 months.

According to analysis, vutrisiran lowered the risk of all-cause mortality by 36% (95% CI, 0.46–0.88; P =.007) and cardiovascular mortality by 33% (95% CI, 0.47–0.96; P =.038) across 42 months in the overall population, compared with placebo. Vutrisiran also reduced urgent heart failure visits by 46% (95% CI, 0.30–0.98; P = .041) and heart failure hospitalizations by 33% (95% CI, 0.52–0.86; P = .002) in the overall population across 36 months.

Vital status across 42 months was collected for >99% of all randomized patients from HELIOS-B, with Alnylam confirming the robustness of the results. Patients in the trial received robust background therapy, including treatment with a TTR stabilizer and sodium-glucose cotransporter 2 (SGLT2) inhibitors.

In a recent episode of Don’t Miss a Beat, hosts Muthiah Vaduganathan, MD, MPH, a cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, and Steve Greene, MD, an advanced heart failure specialist at Duke University School of Medicine, were joined by Ahmad Masri, MD, who serves as the director of the HCM and Amyloid Program at Oregon Health & Science University, to discuss rapid therapeutic advances in ATTR-CM.

Masri reviewed the progression from a previously untreatable disease to one now managed with three FDA-approved disease-modifying agents: tafamidis (VYNDAMAX), acoramidis (Attruby), and vutrisiran (AMVUTTRA).

“Now, we have vutrisiran approved just in March 2025. It's a silencer knock-down agent, so it prevents secretion of TTR by about 80% or so from the liver, and in the HELIOS-B trial also showed improved survival and cardiovascular events,” Masri said. “We currently have three agents, and we view them as equivalent at this point in time.”

References

1. Witteles RM, Garcia-Pavia P, Damy T, et al. Vutrisiran Improves Survival and Reduces Cardiovascular Events in ATTR Amyloid Cardiomyopathy: HELIOS-B. J Am Coll Cardiol. Published online April 30, 2025. doi:10.1016/j.jacc.2025.04.008

2. AMVUTTRA® (vutrisiran) significantly reduces mortality and a range of important cardiovascular events in Pati. Investor Relations | Alnylam Pharmaceuticals, Inc. May 17, 2025. Accessed May 19, 2025. https://investors.alnylam.com/press-release?id=29051.

3. Iapoce C. FDA approves Vutrisiran (AMVUTTRA) for attr-cm. HCP Live. March 24, 2025. Accessed May 19, 2025. https://www.hcplive.com/view/fda-approves-vutrisiran-amvuttra-for-attr-cm.

4. Stephen Greene M, Muthiah Vaduganathan M, Ahmad Masri M. Don’t miss a beat: Navigating the attr-cm care landscape, with Ahmad Masri, MD. HCP Live. May 16, 2025. Accessed May 19, 2025. https://www.hcplive.com/view/don-t-miss-a-beat-navigating-the-attr-cm-care-landscape-with-ahmad-masri-md.