HELIOS-A: 9-month Results from the Phase 3 Study of Vutrisiran in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy
David Adams1, Ivailo L Tournev2,3, Mark S Taylor4, Teresa Coelho5, Violaine Planté-Bordeneuve6, John L Berk7, Alejandra González-Duarte8, Julian D Gillmore9, Soon-Chai Low10, Yoshiki Sekijima11, Laura Obici12, Rick Blakesley13, Seth Arum13, Rebecca Shilling13, John Vest13, Michael Polydefkis14
1Neurology Department, APHP, CHU Bicêtre, INSERM U1195, Université Paris-Saclay, 2Clinic of Nervous Diseases, University Hospital Aleksandrovska, Department of Neurology, Medical University – Sofia, 3Department of Cognitive Sciences, New Bulgarian University, 4Department of Clinical Immunology and Allergy, Westmead Hospital and Westmead Clinical School, University of Sydney, 5Hospital de Santo António, Centro Hospitalar do Porto, 6Neurology – Amyloid network, CHU Henri Mondor – Assistance Publique Hopitaux de Paris, 7Boston Medical Center, 8Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 9National Amyloidosis Centre, University College London, Royal Free Hospital, 10Division of Neurology, Department of Medicine, University of Malaya, 11Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, 12Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, 13Alnylam Pharmaceuticals, 14Department of Neurology, Johns Hopkins University School of Medicine
Objective:

Present 9-month efficacy and safety from the HELIOS-A Phase 3 study of vutrisiran, an investigational RNA interference (RNAi) therapeutic.

Background:
Hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, is an underdiagnosed, rapidly progressive, and fatal disease caused by misfolded transthyretin (TTR) that accumulates as amyloid fibrils in multiple tissues and organs. Vutrisiran is an RNAi therapeutic in development for the treatment of ATTR amyloidosis by targeting liver-expressed variant and wild type TTR. Vutrisiran utilizes the Enhanced Stabilization Chemistry (ESC)-GalNAc platform designed to provide increased potency and high metabolic stability. In a Phase 1 study of healthy volunteers, a single dose of vutrisiran 25 mg subcutaneously (SC) resulted in 80% mean maximum reduction in serum TTR maintained for 90 days.
Design/Methods:
HELIOS-A is a Phase 3, global, open-label study of vutrisiran 25 mg SC once every 3 months in patients with ATTRv amyloidosis with polyneuropathy (NCT03759379). Patients were randomized (3:1) to vutrisiran or patisiran, a reference comparator RNAi therapeutic approved for hATTR amyloidosis with polyneuropathy based on the APOLLO study. Randomization was stratified by TTR genotype (V30M vs. non-V30M) and baseline NIS score (<50 vs ≥50). The APOLLO placebo group (N=77) serves as an external control for the primary and most secondary endpoints. Month 9 efficacy analyses include change from baseline in mNIS+7 (primary endpoint), Norfolk QOL-DN (secondary), and 10-meter walk test (secondary), compared to APOLLO placebo group. 
Results:
HELIOS-A enrolled 164 patients (122 [74.4%] vutrisiran, 42 [25.6%] patisiran) across 57 sites in 22 countries. Baseline demographics, the 9-month primary endpoint, secondary endpoints, and safety results will be presented. 
Conclusions:
Vutrisiran has the potential to address a significant unmet need for patients with ATTRv amyloidosis with polyneuropathy by offering an additional treatment option. HELIOS-A will continue to investigate the efficacy and safety of vutrisiran through an 18-month treatment period and 18-month extension period.