Top-line Data Show Potential Cognitive Benefit of Pepinemab in Early Huntington’s Patients

Vaccinex’s investigational antibody pepinemab showed good tolerability in a Phase 2 clinical trial of people with late prodromal (before clinical diagnosis) and early Huntington’s disease (HD), top-line data show.

The results also hint the treatment may improve cognition; however, those efficacy results did not reach statistical significance.

Pepinemab — also known as VX15/2503 — is designed to block the activity of semaphorin 4D (SEMA4D). This protein is elevated in the brains of people with Huntington’s and other neurodegenerative diseases. It is believed to promote inflammation and metabolic alterations, while preventing myelin repair and disrupting the blood-brain barrier (a membrane that protects the brain from the external environment).

By blocking SEMA4D, pepinemab was designed to limit inflammation, normalize metabolism, promote myelin repair and prevent blood-brain barrier disruption. The U.S. Food and Drug Administration has granted pepinemab fast track and orphan drug designations for the treatment of Huntington’s disease.

The investigational antibody was evaluated in people with Huntington’s in the Phase 2 clinical trial SIGNAL (NCT02481674), which was sponsored by Vaccinex. The trial enrolled 301 people with early manifest or late prodromal Huntington’s; participants were placed into two groups.

In the first group, which included 36 participants, participants were given either pepinemab (20 mg/kg) or a placebo intravenously (into-the-bloodstream) once per month for six months. Then, all participants were given pepinemab for an additional five months, followed by a three-month safety follow-up period.

Previously reported data from this initial group suggested that, relative to placebo, pepinemab treatment improved brain metabolism, halted brain atrophy (shrinkage), and eased motor and cognitive symptoms in people with early and late prodromal stage disease.

Results from the first group were used to inform the study design for the second group, which included 265 participants: 179 with early manifest disease and 86 with late prodromal disease. These participants were assigned randomly to be given pepinemab (20 mg/kg) or a placebo for 18 months, or up to three years in late prodromal patients, followed by a one-month follow-up period.

The COVID-19 pandemic prevented some participants from completing study visits, so statistical projections were used to “fill in” the missing data.

According to a Vaccinex press release, pepinemab was well-tolerated in the SIGNAL clinical trial, with “remarkably low treatment discontinuation and study drop-out rates over the extended 18 month treatment period.”

The study’s main measurement of efficacy was two cognitive assessments from the Huntington’s Disease Cognitive Assessment Battery and Clinical Global Impression of Change (CGIC), which assess changes in planning ability and memory associated with disease progression.

Based on these measurements, participants treated with pepinemab trended toward better cognitive scores compared to those given placebo; however, those differences did not reach statistical significance. In other words, although the two groups had numerically different scores, there is a not-negligible mathematical likelihood that the difference was due to random chance, rather than a true difference associated with treatment benefits.

“The results reported today strongly support a cognitive benefit to treatment with pepinemab and indicate that treatment with pepinemab antibody potentially targets cortical centers, including those that govern cognition. … We believe the data, therefore, suggest that patients at a somewhat more advanced stage of [Huntington’s disease] may derive the greatest benefit from pepinemab,” said Maurice Zauderer, PhD, president and CEO of Vaccinex.

“The insights gained from this study also suggest that pepinemab might be an important treatment option for Alzheimer’s and other neurodegenerative diseases known to primarily affect frontal cortex and to impact cognition,” Zauderer said.

Vaccinex also is sponsoring a clinical trial to evaluate pepinemab in people with Alzheimer’s (NCT04381468). The trial is currently recruiting in the U.S.; more information is available here.

Vaccinex also plans to present further detailed results from SIGNAL in the upcoming months, including detailed analyses of the effect of treatment on motor symptoms and in participants with prodromal disease.

“We are profoundly grateful to the patients and their families for their initiative and enthusiasm in participating in this study and their courage in confronting the burdens of this disease,” Zauderer added.