P3‐007: Vx15 Anti‐semaphorin 4d Antibody (pepinemab) Increases Fdg‐pet Signal and Is a Potential Treatment for Alzheimer's Disease
Year: 2019
Type: article
Abstract: Chronic inflammation is believed to play an important role in neuronal degeneration. Semaphorin 4D (SEMA4D) and its Plexin receptors (PLXNB1, PLXNB2) are expressed on brain neural, endothelial, and inflammatory cells. SEMA4D signaling through its cognate receptors triggers activation of inflammatory glial cells, inhibits migration and differentiation of glial progenitor cells that can replenish glia and repair damage to myelin, and disrupts endothelial tight junctions that are required for the integrity of the BBB. Antibody neutralization of SEMA4D ameliorates neurodegenerative processes in several preclinical models, including transgenic mouse models of Huntington's Disease (HD) and Alzheimer's Disease (AD). These data provided rationale for initiating SIGNAL, a randomized (1:1), double-blind, placebo-controlled phase 2 study of treatment with anti-SEMA4D antibody, pepinemab (VX15/2503), in subjects with HD. The SIGNAL study has an adaptive design in which the results of 36 subjects randomized in Cohort A informed group size and treatment duration in Cohort B. Preclinical studies suggested that SEMA4D plays an important role in inflammatory activation of astrocytes. Because of the important role astrocytes play in glucose transport and metabolism and data from several prior studies demonstrating that loss of FDG-PET signal correlates with cognitive decline in AD, FDG-PET imaging was included as a key endpoint related to the potential mechanism of action. Additional study endpoints include cognition (HD-CAB), quantitative motor assessments, UHDRS and patient-reported outcomes. Cohort A (n=36) is complete and Cohort B (n=265) is fully enrolled. No concerning safety signals were identified in Cohort A following up to 12 monthly IV administrations of pepinemab. FDG-PET imaging results consistently favored the pepinemab treatment group with median increase in FDG uptake from baseline of 8.6% (range: 0.5-20.4%) compared to placebo achieving significance (p<0.05) in a majority of frontal and parietal brain ROI (11/14). Initial results have shown pepinemab to be well tolerated in subjects with neurodegenerative disease. In addition, the demonstrated increase in FDG-PET signal in Cohort A together with preclinical data demonstrating beneficial effects on synaptic activity and improvement in behavioral deficits in a murine AD model suggest that pepinemab warrants clinical investigation in AD as well.
Source: Alzheimer s & Dementia
Institutions: Vaccinex (United States), NYU Langone Health
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980512277