Vaccinex, Inc. announced that the last patient completed their last visit in its randomized, placebo-controlled double-blind study of pepinemab treatment for Alzheimer?s disease. What can we expect to learn from this study? Vaccinex scientists discovered and published that SEMA4D, a molecule that binds to high affinity plexin-B1 receptors predominantly expressed on astrocytes in the brain, is highly upregulated on stressed or damaged neurons during progression of Alzheimer?s Disease (AD).

Astrocytes, which are key brain cells that support the health and function of neurons, undergo substantial changes in morphology and gene expression when SEMA4D binds to their plexin-B1 receptors. As a result, they switch from normal supportive functions to neurotoxic inflammatory activity that is believed to accelerate and aggravate progression of AD. The Company?s hypothesis, which is being tested in the SIGNAL-AD study, is that treating with pepinemab antibody can block signaling by SEMA4D and prevent some or all the damaging consequences of astrocyte activation.

The Company has previously reported that antibody blockade of SEMA4D appears to protect and restore healthy astrocyte functions and to slow or prevent disease progression in patients with Huntington?s disease by several different measures. Key outcomes of the SIGNAL-AD study will include safety and tolerability and the impact of pepinemab treatment on brain metabolic activity as detected by FDG-PET and astrocyte reactivity reflected in plasma levels of glial fibrillary acidic protein (GFAP), a molecule known to be released into blood by reactive astrocytes. Together, these are key biomarkers of disease progression.

Deposition of Aß amyloid in the brain is considered to be the earliest recognized event in the pathologic cascade leading to AD. Aggregates of Aß are believed to trigger a series of subsequent events, including astrocyte reactivity and formation of toxic tau tangles in neurons, which are believed to be key drivers of neurodegeneration. Accordingly, secondary endpoints will also include plasma levels of phosphorylated tau peptide (p-tau 217), a biomarker released into blood during formation of tau tangles in neurons.

In addition, several validated cognitive scales will be employed as exploratory endpoints to evaluate potential treatment effects on cognitive decline, the main clinical symptom of AD. The Company believes that the prevalence of AD (6 million people diagnosed with AD in the US alone) and current concerns about the limitations of treatment with anti-Aß amyloid antibodies such as Leqembi (Eisai and Biogen) and donanemab (Eli Lilly) could make pepinemab, if approved, attractive as a potential alternative treatment or possibly for use in combination with anti-Aß to enhance the benefit to patients. Pepinemab has, to date, been well-tolerated in clinical trials that enrolled a total of more than 600 patients.

The SIGNAL-AD study was funded in part by two investments from the Alzheimer?s Drug Discovery Foundation (ADDF) for a total of $4.75 million, and by an $0.75 million grant from the Alzheimer?s Association. Pepinemab is a humanized IgG4 monoclonal antibody designed to block SEMA4D, which can bind to plexin-B1 receptors to trigger collapse of the actin cytoskeleton in cells and lead to loss of homeostatic functions of astrocytes and other glial cells in the brain and of dendritic cells in immune tissue. Pepinemab appears to have been well-tolerated with a favorable safety profile in multiple clinical trials in different neurological and cancer indications.