Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial
Andrew Feigin, Elizabeth E. Evans, Terrence L. Fisher, John E. Leonard, Ernest Smith, Alisha Reader, Vikas Mishra, Richard Manber, Kimberly A. Walters, Lisa Kowarski, David Oakes, Eric Siemers, Karl Kieburtz, Maurice Zauderer, the Huntington Study Group SIGNAL investigators, Elise Kayson, Jody Goldstein, Richard L. Barbano, Karen Marder, Praveen Dayalu, H. Diana Rosas, Sandra K. Kostyk, John Kamholz, Brad A. Racette, Jee Bang, Daniel O. Claassen, Katherine E. McDonell, Stewart A. Factor, Francis O. Walker, Clarisse Goas, Joanne Wojcieszek, Lynn A. Raymond, Jody Corey‐Bloom, Victor Sung, Marissa Dean, Michael Geshwind, Alexandra Nelson, Samuel Frank, Kathrin LaFaver, Andrew P. Duker, Lawrence Elmer, Ali Samii, Yi‐Han Lin, Sylvain Chouinard, Lauren Seeberger, B.L. Scott, James Boyd, Nikolaus R. McFarland, Erin Furr Stimming, Oksana Suchowersky, Claudia Testa, Karen E. Anderson
Abstract
SIGNAL 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.