Background Pridopidine is a safe, well-tolerated oral drug candidate, that potently activates the Sigma-1 Receptor (S1R). The S1R regulates many cellular processes.. Human brain PET studies show that pridopidine 45 mg bid, the dose evaluated in PROOF, selectively and robustly occupies the S1R.

Total Functional Capacity (TFC) is a validated, regulatory-accepted measure of disease stage and functional decline.

To date, no therapeutic agent has shown benefit on the rate of decline in TFC. Analysis of the pre-specified endpoint TFC in the PRIDE-HD trial shows a beneficial effect of pridopidine 45 mg bid vs. placebo on maintenance of TFC at wk52 (Δ 0.87, p=0.0032). Post-hoc analysis revealed that this effect is driven by early HD patients (TFC 7-13) (Δ 1.16, p=0.0003). The effect remains significant using a more conservative analysis (nominal p=0.016). Responder analysis shows that 45 mg bid reduces the probability of worsening in TFC by 80% (p=0.002,). Exploratory analysis also shows improvements in total motor score, TFC, and the symbol digit modality test vs. placebo (Δ0.6, p=0.04) when assessed in combination. Q-motor, a quantitative motor test, demonstrated improvement in the finger inter-tap interval vs. placebo at wk26 (Δ-0.034 sec, p=0.035) and 52 (Δ-0.044, p=0.03). P-values are nominal.

Aim Evaluate the efficacy and safety of pridopidine 45 mg bid on TFC in early HD.

Design PROOF-HD is a 65-week, double-blind, placebo-controlled, global Ph 3 trial.

PROOF assesses the effect of pridopidine 45 mg bid vs placebo on TFC in early HD patients. Primary endpoint is mean ΔTFC from baseline to Wk 65. Secondary endpoints are the proportion of patients with no TFC decline (TFC≥ 0) at Wk65 and changes from baseline to Wk65 in Q-motor, Total Motor Score (TMS) and cUHDRS.

Status As of July 4, 2021, 58/60 (97%) of sites have been activated and 235 patients have been randomized (48% of the total). There have been no dropouts from the trial, supporting the tolerability and safety of the drug.