TY - JOUR
T1 - Pepinemab antibody blockade of SEMA4D in early Huntington’s disease
T2 - a randomized, placebo-controlled, phase 2 trial
AU - the Huntington Study Group SIGNAL investigators
AU - Feigin, Andrew
AU - Evans, Elizabeth E.
AU - Fisher, Terrence L.
AU - Leonard, John E.
AU - Smith, Ernest S.
AU - Reader, Alisha
AU - Mishra, Vikas
AU - Manber, Richard
AU - Walters, Kimberly A.
AU - Kowarski, Lisa
AU - Oakes, David
AU - Siemers, Eric
AU - Kieburtz, Karl D.
AU - Zauderer, Maurice
AU - Kayson, Elise
AU - Goldstein, Jody
AU - Barbano, Richard
AU - Marder, Karen
AU - Dayalu, Praveen
AU - Rosas, Herminia Diana
AU - Kostyk, Sandra
AU - Kamholz, John
AU - Racette, Brad
AU - Bang, Jee
AU - Claassen, Daniel
AU - McDonell, Katherine
AU - Factor, Stewart
AU - Walker, Francis
AU - Goas, Clarisse
AU - Wojcieszek, Joanne
AU - Raymond, Lynn A.
AU - Corey-Bloom, Jody
AU - Sung, Victor
AU - Dean, Marissa
AU - Geshwind, Michael
AU - Nelson, Alexandra
AU - Frank, Samuel
AU - LaFaver, Kathrin
AU - Duker, Andrew
AU - Elmer, Lawrence
AU - Samii, Ali
AU - Lin, Yi Han
AU - Chouinard, Sylvain
AU - Seeberger, Lauren
AU - Scott, Burton
AU - Boyd, James
AU - McFarland, Nikolaus
AU - Stimming, Erin Furr
AU - Suchowersky, Oksana
AU - Testa, Claudia
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135473877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135473877&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-01919-8
DO - 10.1038/s41591-022-01919-8
M3 - Article
C2 - 35941373
AN - SCOPUS:85135473877
SN - 1078-8956
VL - 28
SP - 2183
EP - 2193
JO - Nature medicine
JF - Nature medicine
IS - 10
ER -