Aims

Semaphorin 4D (SEMA4D) is upregulated in neurons and triggers activation of inflammatory glial cells in Huntington’s Disease (HD) and Alzheimer’s Disease (AD). Antibody neutralization of SEMA4D ameliorates neurodegenerative processes in preclinical models, and, in a Phase 2 HD trial, clinical benefit was evaluated.

Objectives: Blocking SEMA4D-induced inflammation to restore normal astrocytic and neuronal function and to delay cognitive deterioration and brain atrophy.

Methods

Preclinical studies investigate effects of SEMA4D on reactive transformation of astrocytes. A randomized placebo-controlled study (SIGNAL) of pepinemab (VX15/2503) in subjects with HD evaluated Clinical Global Impression of Change (CGIC), cognitive and imaging endpoints.

Results

Antibody blockade inhibited reactive astrocyte phenotype and showed beneficial effects on synaptic activity and behavior in a mouse AD model. While the SIGNAL trial did not meet pre-specified endpoints, exploratory analyses revealed a treatment benefit of pepinemab on the HD-Cognitive Assessment Battery Composite Score (p=0.007) in patients with early manifest (EM) disease and, among patients with more advanced disease (total functional capacity=11), treatment reduced deteriorating CGIC status (p=0.04). Finally, volumetric MRI and FDG-PET imaging analysis in EM patients demonstrated reduction in disease-associated atrophy and loss of brain metabolic activity in multiple brain regions.

Conclusions

The mechanism of action of pepinemab in slowing neurodegeneration is believed to be equally applicable to HD and AD. Based on mouse AD model data and exploratory clinical findings in SIGNAL-HD, initiation of a Phase 1b study of pepinemab in AD is planned with partial funding support from the Alzheimer’s Association and from the Alzheimer’s Drug Discovery Foundation.