Aims

Background: Pridopidine is a well-tolerated, potent, selective sigma-1 receptor (S1R) agonist. The S1R regulates key cellular processes implicated in neurodegeneration including reducing ER stress and enhancing mitochondrial function. Pridopidine is the first drug to find a beneficial effect on TFC, a validated scale measuring functional capacity that is relevant to both patients and clinicians, in long-term HD trials. In post-hoc analysis of the PRIDE-HD trial, pridopidine 45mg bid had improved TFC scores vs placebo in early HD participants (HD 1+2) at 52 weeks (change from placebo 1.16, nominal p=0.0003). Responder analysis shows that pridopidine reduced the probability of TFC decline (1 or more points) by 80% (nominal p=0.02, week 52). Exploratory endpoints cUHDRS (combined score of cognitive, motor and function; nominal p=0.04) and Q-Motor assessment measuring motor function at 26 and 52 weeks (nominal p=0.02, p=0.195, respectively) also suggest beneficial effects.

Aim: To assess the effect of pridopidine 45mg bid on TFC in patients with early stage HD.

Methods

Design: PROOF-HD is a Phase 3, 65-week, randomized, double-blind, placebo-controlled trial. The primary endpoint is the mean change from baseline to week 65 in TFC. Secondary endpoints include change from baseline in Total Motor Score (TMS), cUHDRS, and Q-Motor to week 65.

Results

The target population is early HD (TFC≥7) participants with an expected TFC decline of -0.8 to -1 points/year.

Conclusions

We use data from prior trials where pridopidine has showed clinically meaningful and nominally significant benefit on endpoints to maximize likelihood of success in the design of the PROOF-HD trial.