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

Publication ,  Journal Article
Feigin, A; Evans, EE; Fisher, TL; Leonard, JE; Smith, ES; Reader, A; Mishra, V; Manber, R; Walters, KA; Kowarski, L; Oakes, D; Siemers, E ...
Published in: Nat Med
October 2022

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

October 2022

Volume

28

Issue

10

Start / End Page

2183 / 2193

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Semaphorins
  • Immunology
  • Huntington Disease
  • Humans
  • Double-Blind Method
  • Antineoplastic Agents
  • Antigens, CD
  • Antibodies, Monoclonal
  • 42 Health sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Feigin, A., Evans, E. E., Fisher, T. L., Leonard, J. E., Smith, E. S., Reader, A., … Huntington Study Group SIGNAL investigators, . (2022). Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med, 28(10), 2183–2193. https://doi.org/10.1038/s41591-022-01919-8
Feigin, Andrew, Elizabeth E. Evans, Terrence L. Fisher, John E. Leonard, Ernest S. Smith, Alisha Reader, Vikas Mishra, et al. “Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial.Nat Med 28, no. 10 (October 2022): 2183–93. https://doi.org/10.1038/s41591-022-01919-8.
Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, et al. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med. 2022 Oct;28(10):2183–93.
Feigin, Andrew, et al. “Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial.Nat Med, vol. 28, no. 10, Oct. 2022, pp. 2183–93. Pubmed, doi:10.1038/s41591-022-01919-8.
Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, Mishra V, Manber R, Walters KA, Kowarski L, Oakes D, Siemers E, Kieburtz KD, Zauderer M, Huntington Study Group SIGNAL investigators. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med. 2022 Oct;28(10):2183–2193.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

October 2022

Volume

28

Issue

10

Start / End Page

2183 / 2193

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Semaphorins
  • Immunology
  • Huntington Disease
  • Humans
  • Double-Blind Method
  • Antineoplastic Agents
  • Antigens, CD
  • Antibodies, Monoclonal
  • 42 Health sciences