Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial

Author:

Feigin Andrew,Evans Elizabeth E.ORCID,Fisher Terrence L.ORCID,Leonard John E.ORCID,Smith Ernest S.,Reader Alisha,Mishra VikasORCID,Manber Richard,Walters Kimberly A.ORCID,Kowarski LisaORCID,Oakes David,Siemers Eric,Kieburtz Karl D.,Zauderer MauriceORCID,Kayson Elise,Goldstein Jody,Barbano Richard,Marder Karen,Dayalu Praveen,Rosas Herminia Diana,Kostyk Sandra,Kamholz John,Racette Brad,Bang Jee,Claassen Daniel,McDonell Katherine,Factor Stewart,Walker Francis,Goas Clarisse,Wojcieszek Joanne,Raymond Lynn A.,Corey-Bloom Jody,Sung Victor,Dean Marissa,Geshwind Michael,Nelson Alexandra,Frank Samuel,LaFaver Kathrin,Duker Andrew,Elmer Lawrence,Samii Ali,Lin Yi-Han,Chouinard Sylvain,Seeberger Lauren,Scott Burton,Boyd James,McFarland Nikolaus,Stimming Erin Furr,Suchowersky Oksana,Testa Claudia,Anderson Karen,

Abstract

AbstractSIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). 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 17 for OTS were −1.98 (−4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (−0.37, 3.23) (one-sided P = 0.06). 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—including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose–positron-emission tomography imaging assessments—provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

Funder

Vaccinex, Inc. Internal Research

Publisher

Springer Science and Business Media LLC

Subject

General Biochemistry, Genetics and Molecular Biology,General Medicine

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