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

Autor: Feigin A; New York University Langone Health and The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, New York, NY, USA., Evans EE; Vaccinex, Inc., Research, Rochester, NY, USA., Fisher TL; Vaccinex, Inc., Research, Rochester, NY, USA., Leonard JE; Vaccinex, Inc., Research, Rochester, NY, USA., Smith ES; Vaccinex, Inc., Research, Rochester, NY, USA., Reader A; Vaccinex, Inc., Research, Rochester, NY, USA., Mishra V; Vaccinex, Inc., Research, Rochester, NY, USA., Manber R; IXICO, London, UK., Walters KA; WCG Statistics Collaborative, Inc., Washington, DC, USA., Kowarski L; WCG Statistics Collaborative, Inc., Washington, DC, USA., Oakes D; University of Rochester Medical Center, Rochester, NY, USA., Siemers E; Siemers Integration LLC, Zionsville, IN, USA., Kieburtz KD; University of Rochester Medical Center, Rochester, NY, USA., Zauderer M; Vaccinex, Inc., Research, Rochester, NY, USA. mzauderer@vaccinex.com.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2022 Oct; Vol. 28 (10), pp. 2183-2193. Date of Electronic Publication: 2022 Aug 08.
DOI: 10.1038/s41591-022-01919-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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