Updates from the ongoing PROOF-HD phase 3 study: PRidopidine’s Outcome On Function in Huntington Disease (PROOF)

Michal Geva1, Ralf Reilmann2, Andrew Feigin3, Sandra Kostyk4, Anne Rosser5, Noga Gershoni-Emek1, Yael Cohen1, Diderik Boot1, Y. Paul Goldberg1, and Michael R. Hayden1,6, and the Huntington Study Group Investigators and Coordinators

1 Prilenia Therapeutics
2 George-Huntington-Institut, Muenster, Germany,
3 NYU Langone Health, Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NY, USA,
4 The Ohio State University College of Medicine, Ohio, USA,
5 University of Cardiff, Wales, United Kingdom,
6 CMMT, University of British Columbia, Vancouver, Canada

Pridopidine is an oral, well-tolerated drug candidate currently being evaluated in the global PROOF-HD Ph3 trial for its effect on Total Functional Capacity (TFC) in early-stage HD. Human brain PET studies show that pridopidine 45 mg twice daily (bid), the dose evaluated in PROOF, selectively and robustly occupies the Sigma-1 receptor (S1R). The S1R is highly expressed in the basal ganglia and cortex, brain areas implicated in HD. S1R activation by pridopidine enhances cellular processes crucial for a neuron’s function and survival that are impaired in HD.

TFC is a validated, regulatory-accepted measure of HD clinical progression. In the PRIDE-HD trial, pridopidine 45 mg bid showed a beneficial effect vs. placebo on maintenance of TFC at week 52 (Δ0.87, p=0.0032), a pre-specified endpoint. Post-hoc analysis shows that this effect is driven by early HD patients (TFC 7-13) (Δ1.16, p=0.0003). Responder analysis shows that pridopidine reduces the probability of worsening in TFC by 80% in early HD (p=0.002). Exploratory analysis shows improvement in the combined assessment of total motor score (TMS), TFC, and the symbol digit modality test (SDMT) vs. placebo (Δ0.6, p=0.04). Q-Motor, a quantitative motor test, demonstrated improvement in the finger inter-tap interval vs. placebo at weeks 26 and 52 (Δ-0.034 sec, p=0.035 and Δ-0.044, p=0.03, respectively).

The primary endpoint in PROOF-HD is mean change in TFC from baseline to Week 65. Secondary endpoints include change from baseline in TMS, Q-Motor and cUHDRS (TFC, TMS, Stroop Word Reading and SDMT). Additionally, PROOF-HD will assess the effect of pridopidine on plasma NfL levels.

PROOF-HD is actively enrolling at 30 sites in the US and Canada and 29 sites in Europe. As of October 4, 2021, over 595 patients have been screened, and >440 patients randomized (over 91% of the total). Full recruitment expected ahead of schedule.