HELIOS-B: Open-Label Extension Proves Vutrisiran’s Long-Term Efficacy, With Ronald Witteles, MD

Vutrisiran has demonstrated significant clinical benefit in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) compared to placebo, based on 12-month data from an open-label extension of the HELIOS-B trial presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025.1

ATTR-CM is a progressive and frequently fatal disease, characterized by deposition of misfolded transthyretin protein in the heart. Vutrisiran inhibits hepatic transthyretin production, leading to rapid knockdown of the pathogenic protein. In the HELIOS-B trial, the subcutaneously administered RNA interface therapy was shown to lower the risk of the primary composite endpoint of all-cause mortality (ACM) and recurrent cardiovascular (CV) events compared to placebo.1

The editorial team at HCPLive sat down with Ronald Witteles, MD, co-director of the Stanford Amyloid Center and the Stanford Multidisciplinary Sarcoidosis Program at the Stanford University School of Medicine, to discuss the study and his thoughts on vutrisiran fitting into the broader ATTR-CM treatment landscape.

“We wanted to look at people who had followed for up to 12 months of open-label extension data,” Witteles told HCPLive. “The takeaway from all of that was that vutrisiran works, it works well, and the longer that patients are on it, you will have further separation of the curves. We can also see that patients who started on placebo and then switched to the open-label extension clearly had disease progression by several markers: quality of life, cardiac biomarkers, et cetera.”

HELIOS-B was a phase 3 interventional global trial, during which 655 patients were tested across 79 locations. The trial comprised a 33-36-month double-blind period, followed by a 2-year open-label extension. Investigators included 2 arms receiving vutrisiran; the first had been taking tafamidis on baseline, and the second had not. The latter was measured separately as the monotherapy population.1

To be included, patients were required to have a documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hereditary ATTR (hATTR) amyloidosis with cardiomyopathy or wild-type ATTR amyloidosis. Additionally, patients were required to exhibit a medical history of heart failure with ≥1 before hospitalization for heart failure or clinical evidence of heart failure.2

Patients were excluded from the study if they had known primary amyloidosis or leptomeningeal amyloidosis, if they had New York Heart Association Class IV heart failure or Class III heart failure and were at risk based on prespecified criteria, or had a polyneuropathy disability, among other conditions.2

Primary outcomes included a composite endpoint of ACM and recurrent CV events, as well as hospitalizations and urgent heart failure visits. Secondary outcomes included change from baseline in 6-minute walk test and change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary, among others.2

Patients receiving vutrisiran in the first phase of HELIOS-3 exhibited reduced risk of the primary composite endpoint in both the overall population and the monotherapy population. Patients who completed this period were eligible to enter the extension, which saw all patients receive vutrisiran 25mg Q3M. During this study, Witteles and colleagues measured mortality and CV events to determine the long-term efficacy of the drug.1

Ultimately, the 466 patients in the extension study exhibited sustained improvement across key measures of disease progression through the first 12 months of the study. The long-term safety and tolerability profile was also consistent with vutrisiran’s established profile.3

“If you look at the subjects who started and ended on vutrisiran, their average troponin level was a little lower all the way out at 48 months than it was at baseline. So that tells us something as well,” Witteles said. “The big take-home message is that you don’t want to wait to start therapy. That is lost functional status, it’s lost progression of disease.”

Editor's Note: Witteles reports disclosures with Alexion, Alnylam, AstraZeneca, BridgeBio, Novo Nordisk, and Pfizer.

References

1. Garcia-Pavia P, Witteles R, Morbach C, et al. HELIOS-B: 12-Month Results From the Open-Label Extension Period of Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy. Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.

2. Alnylam Pharmaceuticals. HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy. ClinicalTrials.gov identifier: NCT04153149. Updated May 13, 2025. Accessed October 16, 2025. https://clinicaltrials.gov/study/NCT04153149

3. Alnylam Pharmaceuticals. New Data from Landmark HELIOS-B Phase 3 Study Presented at ESC Congress 2025 Demonstrate Vutrisiran’s Long-Term Cardiovascular Benefit in ATTR-CM. August 31, 2025. Accessed October 16, 2025. https://investors.alnylam.com/press-release?id=29256