The Phase 3 PROOF-HD Trial Demonstrates Meaningful Benefits of Pridopidine on Function, Cognition, and Motor Signs in Huntington Disease (HD)
Michal Geva1, Ralf Reilmann2, Andrew Feigin3, Anne Rosser4, Sandra Kostyk5, Kelly Chen1, Randal Hand1, Diderik Boot1, Yael Cohen1, Paul Goldberg1, Michael Hayden6
1Prilenia Therapeutics, 2George-Huntington-Institute, 3NYU Langone Health, 4University of Cardiff, 5Ohio State University College of Medicine, 6Prilenia Therapeutics and University of British Columbia
Objective:
Evaluate the safety and efficacy of pridopidine (45mg bid) in participants with HD (total functional capacity, TFC>7).
Background:
Pridopidine is a potent sigma-1 receptor agonist in development for HD. 

 

Design/Methods:

Key endpoints were change in TFC and progression (cUHDRS), at timepoints through 104 weeks. Additional endpoints included Q-Motor, cognition (SWR), and Quality-of-Life (QoL).

Prespecified subgroup analyses excluded participants on antidopaminergic medications  (ADMs; VMAT2 inhibitors and neuroleptics). 

Results:

Pridopidine was well tolerated with a safety profile comparable to placebo.

In participants off ADMs, pridopidine was superior to placebo across key measures (cUHDRS, TFC, SWR and Q-Motor) at all timepoints through 78 weeks. Pridopidine showed unprecedented significant improvements from baseline compared to placebo for at least 1 year in cUHDRS (wk52 Δ0.43, p=0.04); SWR (wk52 Δ4.22, p=0.02) and Q-Motor finger tapping (FT) inter-onset interval (IOI)(wk52 (Δ-22.84, p=0.04). Pridopidine preserved QoL through week 78. 

The benefits of pridopidine were maintained through the open-label extension portion of the study. Pridopidine demonstrated benefits through wk104 in cUHDRS (Δ1.48, p=0.0089), TFC (Δ1.01, p=0.051), SWR (Δ7.9, p=0.044), Q-Motor FT IOI (Δ-110.0ms, p=0.0001), and TMS (Δ-4.4, p=0.040) compared to a propensity score weighted control from the TRACK-HD observational study.

Pridopidine inhibits CYP2D6 and its concomitant use with certain ADMs (CYP2D6 metabolized) increases exposure of ADMs. In this trial, participants on lower doses of ADMs (per regulatory labels), maintain positive benefits of pridopidine. 
Conclusions:

Pridopidine shows consistent, sustained, and clinically meaningful benefits across multiple endpoints including function, clinical progression, cognition, motor and QoL in subjects off and on low doses of ADMs. 

10.1212/WNL.0000000000212224
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.