COMPARISON OF EFFICACY OUTCOMES WITH VUTRISIRAN VS. PATISIRAN IN HATTR AMYLOIDOSIS WITH POLYNEUROPATHY: POST-HOC ANALYSIS OF THE HELIOS-A STUDY

Background: hATTR amyloidosis is a progressive, life‐threatening disease caused by amyloid deposits derived from misfolded variant and wild‐type TTR protein. Vutrisiran and patisiran are approved RNAi therapeutics that reduce TTR protein production to treat hATTR amyloidosis with polyneuropathy. Objective: Assess the relative efficacy of RNAi therapeutics for hereditary transthyretin‐mediated (hATTR) amyloidosis with polyneuropathy. Design/Methods: In the Phase 3 HELIOS‐A study (NCT03759379), patients with hATTR amyloidosis with polyneuropathy were randomized (3:1) to vutrisiran (25 mg subcutaneously, Q3M) or patisiran (0.3 mg/kg intravenously, Q3W). Prespecified comparisons previously established the clinical efficacy of vutrisiran versus external placebo (from the Phase 3 APOLLO study of patisiran). The HELIOS‐A patisiran arm served as a reference group, and comparison of TTR reduction between vutrisiran and within‐study patisiran was included as a secondary endpoint. Here, additional post‐hoc analyses comparing the HELIOS‐A vutrisiran and patisiran arms on clinical outcomes are reported: neuropathy impairment (modified Neuropathy Impairment Score+7 [mNIS+7]), quality of life (Norfolk‐QOL‐DN), gait speed (10‐meter walk test [10‐MWT]), nutritional status (modified body mass index [mBMI]), and disability (Rasch‐built overall disability scale [R‐ODS]). Results: HELIOS‐A enrolled 164 patients (vutrisiran, n=122; patisiran, n=42). TTR reduction with vutrisiran was non‐inferior to that observed with patisiran (median difference [vutrisiran‐patisiran] [95% CI], 5.28% [1.17, 9.25], 95% CI lower limit >‐10%). In the current analysis, least‐squares mean (±SE) changes from baseline toMonth 18 for vutrisiran and patisiran, respectively, showed similar treatment effects: mNIS+7 (0.06±1.48 vs. 1.53±2.59; p=0.6248), Norfolk‐QOL‐DN (‐2.5±1.8 vs. ‐0.8±3.0; p=0.6472), 10‐MWT (‐0.019±0.025 vs. ‐0.053±0.043 m/s; p=0.4936), mBMI (21.8±9.2 vs. 7.6 ±15.8; p=0.4378), and R‐ODS (‐1.2±0.5 vs. ‐1.3±0.9; p=0.9266). Conclusions: At Month 18, vutrisiran and patisiran showed numerically and statistically similar efficacy for treating the polyneuropathy manifestations of hATTR amyloidosis. These post‐hoc findings demonstrate comparable efficacy between vutrisiran and patisiran, which both target the key pathogenic protein and have similar pharmacodynamic effects in terms of TTR lowering.