Mechanistic Potential of Pepinemab, a SEMA4D-Blocking Antibody: Terrence L. Fisher, PhD


The senior vice president of clinical development at Vaccinex provided commentary on a presentation from CTAD 2023 highlighting the therapeutic potential of peptinemab, an agent that’s shown success in Huntington disease, in patients with Alzheimer disease. [WATCH TIME: 3 minutes]

WATCH TIME: 3 minutes

"Our mechanism of action is completely different from the toxic protein, we’re actually trying to work with the cells that support the neurons. Those are astrocytes. Our target, SEMA4D, is expressed on neurons and upregulated in diseases, not just HD (Huntington disease) and AD (Alzheimer disease), but other neurodegenerative diseases as well."

Even as antiamyloid therapies take the stage in the Alzheimer disease (AD) community, those who treat the disease understand that it will take a combination approach to truly slow, or even reverse, progression. At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting, held October 24-27, in Boston, Massachusetts, a session highlighted novel approaches to treating the neurodegenerative disorder, including the use of regenerative therapies, astrocyte reactivity biomarkers, and pepinemab (Vaccinex), a semaphoring-4D blocking antibody.

The talk, given by Terrence Fisher, PhD, senior vice president of clinical development at Vaccinex, highlighted the findings of SIGNAL-HD, a completed phase 2 trial (NCT02481674) of the agent in patients with Huntington disease (HD), and why it supports a phase 1/2a study in AD. SIGNAL-HD included 301 patients with late prodromal and early manifest HD who were evaluated for safety and a variety of clinical parameters including cognition, as well as imaging end points to assess brain atrophy and brain metabolism. Results from the study showed that a treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant treatment effect on HD-CAB composite score (P = .007).

Prior to the presentation, NeurologyLive® sat down with Fisher to discuss the results of the study and why they support further development of pepinemab. In the interview, Fisher provided context on the mechanism of action of pepinemab and why it holds advantages over other amyloid-based therapies, as well as its promising safety profile.

Feigin A, Evans EE, Fisher TL, et al. Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial. Nature. Published online August 8, 2022. Doi:10.1038/s41591-022-01919-8.
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