Pridopidine in early-stage manifest Huntington’s disease: a phase 3 trial

Reilmann, Ralf, Feigin, Andrew, Rosser, Anne E. ORCID: https://orcid.org/0000-0002-4716-4753, Kostyk, Sandra K., Saft, Carsten, Cohen, Yael, Schuring, Henk, Hand, Randal, Tan, Andrew M., Chen, Kelly, Feng, Wei, Navon-Perry, Leehee, Cruz-Herranz, Andres, Syltevik, Christine, Boot, Diderik, Squitieri, Ferdinando, Kayson, Elise, Mehra, Munish, Goldberg, Y. Paul, Geva, Michal, Hayden, Michael R. and undefined, undefined 2025. Pridopidine in early-stage manifest Huntington’s disease: a phase 3 trial. Nature Medicine 10.1038/s41591-025-03920-3

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Abstract

Huntington’s disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington’s Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population. The TFC least-squares mean difference between pridopidine and placebo was −0.18 (95% confidence interval −0.49 to 0.14; P = 0.26). The cUHDRS least-squares mean difference between pridopidine and placebo was −0.11 (95% confidence interval −0.40 to 0.18; P = 0.45). Sensitivity analysis in a subgroup of participants not treated with antidopaminergic medications at any time demonstrated a consistent pattern favoring pridopidine across multiple measures, including TFC and cUHDRS. Notably, pridopidine 45 mg twice daily demonstrated a favorable safety and tolerability profile. Taken together, pridopidine has the potential to address a critical unmet need in HD. ClinicalTrials.gov identifier: NCT04556656.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Nature Research
ISSN:	1078-8956
Date of First Compliant Deposit:	15 September 2025
Date of Acceptance:	25 July 2025
Last Modified:	15 Sep 2025 14:30
URI:	https://orca.cardiff.ac.uk/id/eprint/181098

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