2023 American Academy of Neurology Abstract Website

Michael Polydefkis¹, Frank Birklein², Yoshiki Sekijima³, Davide Pareyson⁴, Marcia Waddington Cruz⁵, David Danese⁶, Kelley Capocelli⁶, Madeline Merkel⁶, Chongshu Chen⁶, John Vest⁶, David Adams⁷
¹Department of Neurology, Johns Hopkins University School of Medicine, ²Clinic and Polyclinic for Neurology, Johannes Gutenberg University of Mainz, ³Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, ⁴Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, ⁵Clementino Fraga Filho University Hospital, ⁶Alnylam Pharmaceuticals, ⁷Neurology Department, APHP

Objective:

Assess the relative efficacy of RNAi therapeutics for hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy.

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.

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 to Month 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.