Alnylam Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) for vutrisiran, an investigational RNAi therapeutic, for the treatment of transthyretin amyloidosis with cardiomyopathy (ATTR-CM). The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of March 23, 2025.
The sNDA is based on positive results from the HELIOS-B Phase 3 study, a randomized, double-blind, placebo-controlled, multicenter, global trial. The study demonstrated that vutrisiran had favorable effects on cardiovascular outcomes, survival, functional capacity, and quality of life in patients with ATTR-CM. These benefits were observed on top of substantial background standard of care treatments.
Clinical Efficacy and Safety
The HELIOS-B trial revealed a 28% relative risk reduction (HR, 0.72; 95% CI, 0.56 to 0.93; P = 0.01) in the composite outcome of all-cause mortality and recurrent cardiovascular events in the overall population. Vutrisiran also significantly improved functional capacity, as measured by the 6-minute walk test (least-squares mean difference, 26.5 meters; 95% CI, 13.4 to 39.6; P < .001), and quality of life, assessed by the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P < .001).
The safety profile of vutrisiran in the HELIOS-B study was consistent with its established profile. Common adverse reactions included pain in extremity (15%), arthralgia (11%), dyspnea (7%), and decreased vitamin A levels (7%). Alnylam recommends vitamin A supplementation at the recommended daily allowance (RDA) for patients taking vutrisiran.
Vutrisiran's Potential Impact
If approved, vutrisiran would become the first therapy approved in the U.S. to treat both the polyneuropathy manifestations of hATTR and the cardiomyopathy manifestations of ATTR amyloidosis. Vutrisiran (marketed as AMVUTTRA) is currently approved for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.
"We are pleased that the FDA has accepted our sNDA for vutrisiran for the treatment of ATTR with cardiomyopathy – a steadily progressing, debilitating and ultimately fatal disease," said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. "In HELIOS-B, treatment with vutrisiran improved cardiovascular outcomes, survival, disease progression and quality of life, as compared to placebo, in a population reflective of today’s patients on substantial background treatment. We look forward to working with the FDA to support their review of the application and bring vutrisiran to patients with ATTR-CM in the U.S. early next year."
About ATTR Amyloidosis
Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid deposits in various organs, including the nerves and heart. There are two main types of ATTR: hereditary ATTR (hATTR), caused by a TTR gene variant, and wild-type ATTR (wtATTR), which occurs without a gene variant. hATTR affects approximately 50,000 people worldwide, while wtATTR impacts an estimated 200,000 to 300,000 people worldwide.
Vutrisiran is an RNAi therapeutic that works by rapidly knocking down both mutant and wild-type transthyretin (TTR), addressing the underlying cause of ATTR. It is administered quarterly via subcutaneous injection.
