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The trial enrolled a total of 265\u2009HD gene expansion carriers with either early manifest (EM,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009179) or late prodromal (LP,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200986) HD, randomized (1:1) to receive 18\u2009monthly infusions of pepinemab (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200991 EM, 41\u2009LP) or placebo (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200988 EM, 45\u2009LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month\u200917 for OTS were\u2009\u22121.98 (\u22124.00, 0.05) (one-sided\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.028), and for PTAP\u20091.43 (\u22120.37, 3.23) (one-sided\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses\u2014including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose\u2013positron-emission tomography imaging assessments\u2014provide rationale and direction for the design of a phase\u20093 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.\n                  <\/jats:p>","DOI":"10.1038\/s41591-022-01919-8","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T12:05:36Z","timestamp":1659960336000},"page":"2183-2193","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Pepinemab antibody blockade of SEMA4D in early Huntington\u2019s disease: a randomized, placebo-controlled, phase 2 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