Vaccinex, Inc. is set to present promising new efficacy and safety data from its Phase 1b/2 SIGNAL-AD study of pepinemab for Alzheimer's disease (AD) at the Clinical Trials on Alzheimer’s Disease (CTAD) Conference in Madrid on October 31, 2024. The presentation will be delivered by Elizabeth Evans, PhD, Chief Operating Officer and Senior VP Discovery and Translational Medicine of Vaccinex.
The SIGNAL-AD study is a randomized, double-blind trial evaluating the safety and efficacy of pepinemab, an anti-SEMA4D antibody, in patients with Mild Cognitive Impairment (MCI) and mild dementia due to AD. The study aims to assess whether pepinemab can block reactive astrogliosis and slow disease progression.
The Role of SEMA4D in Alzheimer's Disease
Vaccinex scientists discovered that Semaphorin 4D (SEMA4D), a molecule upregulated on stressed or damaged neurons during AD progression, binds to plexin-B1 receptors on astrocytes. This binding triggers changes in astrocytes, causing them to switch from supportive functions to neurotoxic inflammatory activity, which is believed to aggravate AD progression.
The company hypothesizes that pepinemab, by blocking SEMA4D signaling through astrocyte receptors, can slow or prevent the damaging consequences of astrocyte activation. Previous studies have shown that antibody blockade of SEMA4D appears to protect healthy astrocyte functions and slow disease progression in Huntington’s disease.
Key Outcomes and Biomarkers
The SIGNAL-AD study focuses on the impact of pepinemab treatment on cognitive decline and key biomarkers of disease progression. These biomarkers include levels of soluble astrocyte protein glial fibrillary acidic protein and phosphorylated tau peptide (p-tau 217), which are indicative of disease progression.
Amyloid-beta (Aβ) deposition is recognized as an early event in the pathological cascade leading to AD. Aβ aggregates trigger astrocyte reactivity and the formation of toxic tau tangles in neurons, driving neurodegeneration. Characterizing the expression of these biomarkers in relation to treatment effects is crucial.
Effects on Brain Vasculature
Some approved AD drugs have been reported to compromise brain vasculature integrity, leading to inflammation and microhemorrhages. Vaccinex will present evidence from new preclinical models suggesting beneficial effects of pepinemab treatment on brain vasculature, which could help avoid toxicity in AD patients.
About Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody designed to block SEMA4D, preventing it from binding to plexin-B1 receptors. This blockade aims to prevent the collapse of the actin cytoskeleton in cells and maintain the homeostatic functions of astrocytes and other glial cells in the brain. Pepinemab has shown a favorable safety profile in multiple clinical trials across different neurological and cancer indications.
The SIGNAL-AD study was funded in part by a grant from the Alzheimer’s Association and investments from the Alzheimer’s Drug Discovery Foundation (ADDF).
