Impact of Baseline Polyneuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study
Dianna Quan1, Marco Luigetti2, John Berk3, Isabel Conceição4, Yohei Misumi5, Chi-Chao Chao6, Shaun Bender7, Emre Aldinc7, John Vest7, David Adams8
1Department of Neurology, University of Colorado Anschutz, 2Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, 3Boston Medical Center, 4Department of Neurology, CHULN, Hospital Santa Maria and Faculdade de Medicina, Universidade de Lisboa, 5Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 6Department of Neurology, National Taiwan University Hospital, 7Alnylam Pharmaceuticals, 8Neurology Department, CHU Bicêtre, APHP, Université Paris-Saclay
Objective:
This analysis evaluates the impact of baseline polyneuropathy severity on response to vutrisiran treatment in patients with hereditary transthyretin-mediated (ATTRv; v for variant) amyloidosis with polyneuropathy during the Phase 3 HELIOS-A study (NCT03759379).
Background:
ATTRv amyloidosis, also known as hATTR amyloidosis, is a rapidly progressive, multisystem disease. Vutrisiran, an RNAi therapeutic, improved neuropathy and quality of life (QOL) versus external placebo in HELIOS-A.
Design/Methods:
Patients were randomized (3:1) to vutrisiran (25 mg subcutaneous injection Q3M) or patisiran (0.3 mg/kg intravenous infusion Q3W; reference group). The primary endpoint was change from baseline in modified Neuropathy Impairment Score+7 (mNIS+7) at 9 months versus external placebo group from the APOLLO study (n=77). This post-hoc analysis divided patients into approximately equal quartiles of increasing baseline Neuropathy Impairment Score (NIS): Q1 ≥5.0─≤20.5; Q2 >20.5─≤44.1; Q3 >44.1─≤73.1; Q4 >73.1─≤127. Mean change from baseline to Month 18 was summarized by quartile for efficacy endpoints.
Results:
Across NIS quartiles, vutrisiran demonstrated benefit in mNIS+7 versus external placebo (mean change from baseline in mNIS+7 at Month 9/18: Q1 -3.3/-3.0 [vutrisiran] vs +13.8/+18.4 [external placebo]; Q2 -0.6/-3.1 vs +12.1/+24.5; Q3 -2.1/+6.2 vs +16.5/+33.1; Q4 +1.6/+3.2 vs +16.5/+30.7). Vutrisiran also demonstrated benefit versus external placebo across NIS quartiles for endpoints of QOL (Norfolk QOL-DN), disability (Rasch-built Overall Disability Scale), gait speed (10-meter walk test), and nutritional status (modified BMI). Overall, patients in lower NIS quartiles (less severe disease) at baseline maintained better scores at Month 18 than those in higher NIS quartiles. The external placebo group progressively worsened in all measures at Month 18.
Conclusions:
Vutrisiran demonstrated benefit in neurologic function and other key measures, versus external placebo, across all baseline polyneuropathy severities. Patients who initiated vutrisiran earlier in their disease course retained the highest level of neurologic function after 18 months, highlighting the importance of early diagnosis and treatment.