Pridopidine Fails to Meet Primary Endpoint in Huntington’s Disease Trial

May 08, 2023

In a phase 3 study, pridopidine did not meet its primary endpoint in patients with Huntington’s disease, but analyses excluding some patients showed benefits.

Andrew Feign, MD, first explained why this trial was pursued, highlighting that pridopidine is a potent and specific signal-1-receptor (S1R) agonist. “Activation of the S1R by pridopidine positively influences multiple neuroprotective pathways that we think are relevant for multiple neurodegenerative diseases, specifically Huntington’s disease (HD). These pathways include enhancement of mitochondrial function, improvement of calcium homeostasis, and growth and maintenance of synaptic function, growth of dendritic spines, release of neurotrophic factor, and increase in autophagy.”

There is also significant preclinical and clinical data supporting the efficacy of pridopidine for HD, added Dr. Feign.

The current phase 3 trial PROOF-HD randomly assigned a total of 480 participants with manifest HD 1:1 to pridopidine 450 mg twice a day (N=240) or matching placebo (N=240). Patients had at least 36 CAG repeats and Unified Huntington’s Disease Rating Scale (UHDRS)-IS levels of no more than 90%. They were allowed antipsychotic, antidepressant, chorea, or other psychotropic medications. All participants were evaluated in person at baseline and at weeks 4, 26, 39, 52, and 65. The primary outcome was a change from baseline to week 65 in the UHDRS-Total Functional Capacity (TFC).

In total, 458 participants (91.8%) completed treatment up until week 65. Dr. Feign noted that more patients than anticipated and than seen in previous trials were on neuroleptics or chorea medication (60%). In the modified intention-to-treat population, pridopidine showed no benefit over placebo in a change of UHDRS-TFC.

When excluding patients using neuroleptics and/or chorea medications, there was a “suggestion of improvement” in the experimental group, but the differences did not reach statistical significance. Positive trends were observed on several Q-Motor pronation supination inter-tap-interval assessments. Also, prespecified analyses excluding patients using neuroleptics and/or chorea medications showed beneficial effects on multiple endpoints: overall progression, Q-Motor, and cognition. The safety and tolerability profile of pridopidine were similar to placebo. Additional analyses are ongoing.