Home > Neurology > AAN 2023 > Pridopidine fails to meet the primary endpoint in Huntington’s Disease

Pridopidine fails to meet the primary endpoint in Huntington’s Disease

Presented By
Prof. Andrew Feign, NYU Grossman School of Medicine, USA
Conference
AAN 2023
Trial
Phase 3, PROOF-HD

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 Feign (NYU Grossman School of Medicine, NY, USA) first explained why this trial was pursued and highlighted 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 for Huntington’s Disease. 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 Prof. Feign.

The current phase 3 trial PROOF-HD (NCT04556656) randomised a total of 480 participants with manifest HD 1:1 to pridopidine 450 mg BID (n=240) or matching placebo (n=240) [1]. 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 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%) of participants completed treatment up until week 65. Prof. Reign noted that much more patients than anticipated and in previous trials were on 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 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.

 

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

 

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