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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\u2019s 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 \u22120.18 (95% confidence interval \u22120.49 to 0.14;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.26). The cUHDRS least-squares mean difference between pridopidine and placebo was \u22120.11 (95% confidence interval \u22120.40 to 0.18;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.45). 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\u2009mg 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:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03690193\" ext-link-type=\"uri\">NCT04556656<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-03920-3","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T09:04:00Z","timestamp":1757063040000},"page":"3780-3789","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Pridopidine in early-stage manifest Huntington\u2019s disease: a phase 3 trial"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5904-9517","authenticated-orcid":false,"given":"Ralf","family":"Reilmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Feigin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-4753","authenticated-orcid":false,"given":"Anne E.","family":"Rosser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra K.","family":"Kostyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Saft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"Schuring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randal","family":"Hand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0099-8814","authenticated-orcid":false,"given":"Andrew M.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leehee","family":"Navon-Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Cruz-Herranz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Syltevik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diderik","family":"Boot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7397-1727","authenticated-orcid":false,"given":"Ferdinando","family":"Squitieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Kayson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munish","family":"Mehra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. 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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\u00ae 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\u2019s 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\u2019s 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.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}