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CTAD 2023 | SEMA4D as a therapeutic target: insights from SIGNAL-HD and implications for Alzheimer’s disease

Terrence Fisher, PhD, Vaccinex Inc., Rochester, NY, discusses semaphorin-4D (SEMA4D) as a therapeutic target in Alzheimer’s disease. SEMA4D is a protein upregulated on neurons in disease, which binds to plexin-B1/B2 receptors present on astrocytes, triggering astrocyte reactivity. This upregulation has been seen in Huntington’s disease (HD) and Alzheimer’s disease (AD), driving the hypothesis that SEMA4D blockade may ameliorate disease pathology by preserving normal astrocyte function. To this end, pepinemab was developed as a SEMA4D blocking antibody which is under clinical investigation in HD and AD. The SIGNAL-HD Phase II randomized, placebo-controlled trial (NCT02481674), involved 300 patients with late prodromal or early manifest HD. While the trial did not meet its co-primary clinical efficacy endpoints, findings indicated a favorable safety and tolerability profile, as well as a slowing of cognitive decline based on HD-CAB, compared to placebo. Exploratory analyses also revealed a reversal of brain hypometabolism, reduced brain atrophy, and decrease in GFAP in the pepinemab arm. Dr Fisher comments on how these data have informed the ongoing SIGNAL-AD study (NCT04381468). This interview took place at the Clinical Trials on Alzheimer’s Disease (CTAD) congress 2023 in Boston.

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