Analyses of the Phase 3 Trial of Pridopidine’s Outcome on Function in Huntington Disease (PROOF-HD) Demonstrates Efficacy in Participants Without Antidopaminergic Medications
Michal Geva1, Ralf Reilmann2, Andrew Feigin3, Anne Rosser4, Sandra Kostyk5, Kelly Chen1, Munish Mehra6, Yael Cohen1, Paul Goldberg1, Michael Hayden1
1Prilenia Therapeutics, 2George-Huntington-Institute, 3NYU Langone Health, 4University of Cardiff, 5Ohio State University College of Medicine, 6Biometrics Department, Tigermed-BDM Inc
Objective:
The efficacy and safety of pridopidine was assessed for the treatment of Huntington Disease (HD) in the phase 3 trial, PROOF-HD.
Background:
Pridopidine is an orally available small molecule and potent sigma-1 receptor agonist.
Design/Methods:
PROOF-HD enrolled 499 adult-onset HD participants (Total Functional Capacity (TFC) ≥7). The primary endpoint was change from baseline to week 65 in TFC. The key secondary endpoint was change from baseline in the composite Unified Huntington Disease Rating Scale (cUHDRS), and additional endpoints included quantitative motor (Q-Motor), cognition (Stroop Word Reading (SWR)), and Quality of Life (HD-QoL). Prespecified analyses excluded participants on antidopaminergic medication (ADMs) (neuroleptics and anti-chorea medications) as their use may be associated with a worsening of disease progression.
Results:
Pridopidine was well tolerated with a safety profile comparable to placebo. The primary endpoint was not met. In analyses excluding participants on ADMs (placebo n=99, pridopidine n=79), pridopidine shows improvement from baseline in cUHDRS, a combined measure of motor function, cognition, and functional capacity up to week 52 and sustained benefit up to week 78. Q-Motor and SWR are improved from baseline at week 26 and sustained up to week 78. A trend for improvement in HD-QoL is also observed in this group. A responder analysis of participants excluding ADMs demonstrates that pridopidine enhances responder rates (5% improvement as threshold) across all visits for multiple key endpoints including cUHDRS, SWR, and Q-Motor.
Conclusions:
In analyses excluding participants on ADMs, pridopidine significantly improves or stabilizes all outcome measures for at least 1 year and was better than placebo up to week 78 for all endpoints. A responder analysis demonstrates consistent and clinically meaningful separation of pridopidine at all timepoints and for key outcome measures. PROOF-HD is the first trial to demonstrate benefit on multiple clinical measures of disease progression in HD.