Vutrisiran in Transthyretin Amyloidosis: A Pooled Safety Analysis of HELIOS-A and HELIOS-B
Publication Details
JACC: Advances
August 2025
Author(s)
Ronald M Witteles1, Pablo Garcia-Pavia2, Caroline Morbach3, Julian D Gillmore4, Mark S Taylor5, Isabel Conceição6, William B White7, Cynthia Kwok8, Marianne T Sweetser8, Katherine L Boyle8, David Adams9
Affiliations
1Division of Cardiovascular Medicine and Stanford Amyloid Center, Stanford University School of Medicine, Stanford, California, USA; 2Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Health Research Institute of the Puerta de Hierro Majadahonda-Segovia, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBER-CV), and Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; 3Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, and the Department of Medicine I, University Hospital Würzburg, Würzburg, Germany; 4National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, United Kingdom; 5Department of Clinical Immunology, Liverpool Hospital and South West Sydney Clinical Campus, UNSW Medicine and Health, Sydney, New South Wales, Australia; 6Department of Neurosciences and Mental Health, ULS de Santa Maria, CAML, Faculty of Medicine, Centre of Studies Egas Moniz, University of Lisbon, Lisbon, Portugal; 7Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, USA; 8Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; 9Department of Neurology, CHU Bicêtre, APHP, INSERM U 1195, University Paris-Saclay, Le Kremlin Bicêtre, France
Abstract
Background:
Vutrisiran is an RNA interference therapeutic that has demonstrated efficacy for the treatment of patients with transthyretin amyloidosis (ATTR) with polyneuropathy and cardiomyopathy in the phase 3 HELIOS-A and HELIOS-B studies, respectively. During the initial randomized treatment periods of these studies, vutrisiran was well tolerated and had an acceptable safety profile.
Methods:
Data from patients who received at least one dose of vutrisiran at any time during the HELIOS-A or HELIOS-B studies were included in this pooled safety analysis. For reference, data from the external placebo arm of HELIOS-A (APOLLO placebo) and the placebo arm of HELIOS-B studies were included. Exposure-adjusted adverse event rates (AERs) and serious AERs were calculated per 100 patient-years.
Results:
The combined vutrisiran group comprised 707 patients (HELIOS-A vutrisiran group: n = 160; HELIOS-B vutrisiran group: n = 547) with a mean age at symptom onset of 68.5 years; 30.3% had hereditary ATTR. These patients had a median (range) treatment duration of 33.4 months (0.0-57.8) and a cumulative exposure of 1,518.9 patient-years. In the combined vutrisiran group, AERs and serious AERs for specific adverse events were comparable to those reported in either of the placebo reference groups and those previously reported during the initial randomized treatment periods of the HELIOS-A and HELIOS-B studies. AERs for cardiac failure, the most common adverse event in vutrisiran-treated patients excluding COVID-19, were lower in the HELIOS-A and HELIOS-B vutrisiran groups than in the corresponding placebo groups. Injection-site reactions were infrequent and mild or moderate in severity. There were no ocular, hepatic, or renal safety concerns with vutrisiran treatment.
Conclusions:
In a broad population of patients with ATTR who were treated for up to 58 months, vutrisiran was well tolerated and had an acceptable safety profile, consistent with that previously reported for the HELIOS-A and HELIOS-B studies.
PMID
40848527
DOI
10.1016/j.jacadv.2025.102066
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