Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 5.
doi: 10.1038/s41591-025-03920-3. Online ahead of print.

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

Ralf Reilmann  1 , Andrew Feigin  2 , Anne E Rosser  3   4 , Sandra K Kostyk  5 , Carsten Saft  6 , Yael Cohen  7 , Henk Schuring  7 , Randal Hand  7 , Andrew M Tan  8   9 , Kelly Chen  7 , Wei Feng  7 , Leehee Navon-Perry  7 , Andres Cruz-Herranz  7 , Christine Syltevik  7 , Diderik Boot  7 , Ferdinando Squitieri  10 , Elise Kayson  11 , Munish Mehra  12 , Y Paul Goldberg  7 , Michal Geva  7 , Michael R Hayden  7   13 ; PROOF-HD study investigators
Affiliations

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

Ralf Reilmann et al. Nat Med. .

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 .

PubMed Disclaimer

Conflict of interest statement

Competing interests: A.C.-H., L.N.-P., A.M.T., M.G., Y.P.G., Y.C., R.H., K.C., W.F., C. Syltevik, D.B. and H.S. are employees of Prilenia Therapeutics B.V. and have stock options in the company. A.F. received grant support from Prilenia through NYU for his role as Principal Investigator for North American study sites. E.K. received grant support from Prilenia through the Huntington Study Group® for her role as PROOF-HD global study director. M.M. was a paid consultant for Prilenia Therapeutics. A.E.R. served as European co-lead for the PROOF-HD study. S.K.K. is the medical director of the Huntington Disease Society of America Center of Excellence at The Ohio State University, serves as the co-chair of the Huntington Study Group Executive Membership Committee and served as the North American co-Principal Investigator of the PROOF-HD trial. F.S. is co-founder and CSO of Fondazione LIRH (Lega Italiana Ricerca Huntington), a private Huntington’s disease-focused clinical research and care organization in Rome, Italy. He leads the Huntington Unit at Fondazione IRCCS Casa Sollievo della Sofferenza, a private research hospital. He has served on advisory boards, provided consultancy and coordinated Italian sites for the PROOF-HD, PRIDE-HD and MermaiHD studies evaluating pridopidine. C. Saft declares no conflicts of interest related to this study. M.R.H. is the CEO and scientific co-founder of Prilenia Neurotherapeutics B.V. He is also a physician scientist and University Killam Professor at the University of British Columbia. M.R.H. serves on the board of directors for Ionis Pharmaceuticals (San Diego), 89Bio (San Francisco) and AbCellera (Vancouver). R.R. is the founding director and owner of the George-Huntington-Institute (GHI), a private research institute focused on clinical and preclinical research in Huntington’s disease, and QuantiMedis, a clinical research organization providing Q-Motor (quantitative motor) services in clinical trials and research. He has provided consulting services, served on advisory boards, contributed to clinical trial operations and performed quantitative motor analyses for Prilenia. He was also the Principal Investigator for the European Sites for the PROOF-HD study, and the European coordinating investigator for the PRIDE-HD study evaluating pridopidine. The remaining authors declare no competing interests.

References

    1. Macdonald, M. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 (1993). - DOI
    1. Ross, C. A. et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 10, 204–216 (2014). - PubMed - DOI
    1. Achenbach, J., Stodt, B. & Saft, C. Factors influencing the total functional capacity score as a critical endpoint in Huntington’s disease research. Biomedicines 11, 3336 (2023). - PubMed - PMC - DOI
    1. Shoulson, I. Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs. Neurology 31, 1333–1335 (1981). - PubMed - DOI
    1. Huntington Study Group et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA 316, 40–50 (2016).

Associated data

LinkOut - more resources