HELIOS-A: Results from the Phase 3 Study of Vutrisiran in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy
David Adams1, Ivailo Tournev2, Mark Taylor3, Teresa Coelho4, Violaine Planté-Bordeneuve5, John Berk6, Alejandra González-Duarte7, Julian Gillmore8, Soon-Chai Low9, Yoshiki Sekijima10, Laura Obici11, Chongshu Chen12, Prajakta Badri12, Seth Arum12, John Vest12, Michael Polydefkis13
1Neurology Department, APHP, CHU Bicêtre, INSERM U1195, Université Paris-Saclay, 2University Hospital Aleksandrovska & New Bulgarian University, 3Westmead Hospital, 4Centro Hospitalar Universitário do Porto, 5CHU Henri Mondor – Assistance Publique Hopitaux de Paris, 6Boston Medical Center, Amyloidosis Center, Boston University, 7Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 8University College London, 9University Malaya Medical Centre, 10Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, 11Fondazione IRCCS Policlinico San Matteo, 12Alnylam Pharmaceuticals, 13Johns Hopkins University School of Medicine
Objective:
Present 18-month HELIOS-A efficacy and safety results.
Background:
Hereditary transthyretin-mediated (hATTR) amyloidosis (or ATTRv amyloidosis) is a progressive, life-threatening disease. Vutrisiran, an investigational RNA interference (RNAi) therapeutic, targets variant and wild-type TTR for the treatment of ATTR amyloidosis. 
Design/Methods:

HELIOS-A is an ongoing, 18-month, Phase 3 study in patients with ATTRv amyloidosis with polyneuropathy (NCT03759379). Patients were randomized (3:1) to vutrisiran (25 mg subcutaneous injection, every 3 months) or patisiran (0.3 mg/kg intravenous infusion, every 3 weeks), a reference comparator RNAi therapeutic approved for hATTR amyloidosis with polyneuropathy based on the APOLLO study. The APOLLO placebo group (n=77) is an external control. Primary endpoint: change from baseline in neuropathy impairment (modified Neuropathy Impairment Score +7 [mNIS+7]), vs. external placebo at Month 9. Primary analysis population: modified intention-to-treat (randomized patients receiving ≥1 dose of vutrisiran or placebo [mITT]).

Results:

HELIOS-A enrolled 164 patients (vutrisiran, n=122; patisiran, n=42), whose characteristics widely overlapped those of the external placebo group. At 9 months, vutrisiran achieved rapid, sustained reduction in serum TTR levels, similar to patisiran. Vutrisiran significantly improved mNIS+7 vs. external placebo (LS mean [±SE] change from baseline: −2.2±1.4 [vutrisiran]; +14.8±2.0 [placebo]; difference, −17.0; p=3.5×10−12). Vutrisiran also significantly improved quality of life (Norfolk QOL-DN), gait speed (10-meter walk test), nutritional status (modified body mass index), and disability (Rasch-built Overall Disability Scale [R-ODS]) vs. external placebo at Month 9. NT-proBNP levels improved vs. external placebo in the mITT population (adjusted geometric fold change ratio: 0.6; p=9.2×10−7) and a prespecified cardiac subpopulation. Most adverse events with vutrisiran were mild or moderate. There were no drug-related discontinuations or deaths.

Conclusions:

At 9 months, vutrisiran significantly improved multiple disease-relevant endpoints vs. external placebo, with an acceptable safety profile, indicating benefit across numerous important disease manifestations. Efficacy and safety results from the 18-month analysis will be presented at the meeting.