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

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.

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

“…39,40 Indeed, SEMA4D plays a critical role in regulating the transition between homeostatic and reactive states of various types of glial cells. Antibody blockade of SEMA4D is being explored as a potential disease modifying strategy to slow cognitive decline in patients with early Huntington’s disease 41 and may be beneficial in other ACD. We have also identified a prominent signal near RBFOX1 , a gene that encodes the RNA binding fox-1 which has been shown to have a role in alternative splicing of the amyloid precursor protein.…”

Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity

“…Strategies that target these pathogenic processes have the potential to be broadly applicable to multiple devastating neurologic diseases. Clinical evaluation of the safety and efficacy of pepinemab (VX15/2503), a humanized anti-SEMA4D monoclonal antibody, has been initiated, including a completed Phase I trial in patients with multiple sclerosis (NCT01764737) [63], a Phase II trial in Huntington's disease (NCT02481674) that is complete and will be reported elsewhere [64], and an ongoing Phase I/II study of pepinemab in Alzheimer's disease (NCT04381468). Clinical and imaging outcomes including FDG-PET may provide further evidence of the biologic activity of astrocytes and their contribution to disease progression.…”

Huntington’s Disease Clinical Trials Corner: November 2022

“…In this edition, we highlight the ongoing PIVOT HD (NCT05358717) [1] and the recently completed SIGNAL (NCT05358717) [2] clinical trials. We tabulate all currently registered and ongoing clinical trials in Tables 2 to 4.…”

“…SEMA4D is a protein of the semaphorin family involved in immune regulation [11]. In the brain, it regulates the transition to reactive states in glial cells [2]. Blockade of SEMA4D with immunotherapy improved pathology and clinical phenotypes in the YAC128 mice [12].…”