Pridopidine for Huntington’s disease fails to meet the primary endpoint

Preliminary topline results of the phase 3 PROOF-HD study revealed that pridopidine did not meet its primary endpoint in patients with Huntington’s disease (HD). However, prespecified analyses, excluding patients using neuroleptics and/or chorea medications, showed beneficial effects on multiple endpoints.

Prof. Andrew Feigin (NYU Grossman School of Medicine, NY, USA) first explained: “Activation of the S1R by pridopidine positively influences multiple neuroprotective pathways that we think are relevant for multiple neurodegenerative diseases, specifically for HD. These pathways include enhancement of mitochondrial function, improvement of calcium homeostasis, growth, and maintenance of synaptic function, growth of dendritic spines, the release of neurotrophic factor, and increase in autophagy” [1]. Prof. Feigin added that significant preclinical and clinical data support the efficacy of pridopidine for HD.

The current phase 3 trial PROOF-HD (NCT04556656) randomised 480 participants with manifest HD 1:1 to pridopidine 450 mg twice daily (n=240) or matching placebo (n=240). Participants 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 in 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 (91.8%) participants completed treatment until week 65. Prof. Feigin noted that more participants than anticipated from previous trials took neuroleptics or chorea medication, namely 60%. In the modified intention-to-treat population, pridopidine showed no benefit over placebo in a change of UHDRS-TFC. When excluding participants 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 participants taking 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.

1. Feigin A. Pridopine outcome on function in HD: preliminary topline results. PL5.008, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.

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Posted on 26 June 2023