Vaccinex’s Pepinemab Halts Brain Shrinkage, Eases Symptoms in Early Huntington’s Patients, Results Shows

Vaccinex’s experimental therapy pepinemab (VX15/2503) improves brain metabolism, halts its atrophy, and eases motor and cognitive symptoms in people with late prodromal (before clinical diagnosis) and early Huntington’s disease, according to initial data from a Phase 2 clinical trial.

The findings were presented at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually April 2–5, in an oral presentation titled “Regulation of Glial Cell Activation and Neurodegeneration by Anti-Semaphorin 4D Antibody Pepinemab, Potential Treatment for Alzheimer’s and Huntington’s Disease.”

“The data, from Cohort A of our SIGNAL trial, suggest pepinemab has the potential to address both the brain [disease-associated events] and cognitive and motor symptoms characteristic of Huntington’s disease. The trial is ongoing, and we’re looking forward to building on these findings with data from Cohort B of the study,” Maurice Zauderer, Vaccinex’s president and CEO, said in a press release.

Pepinemab is an antibody designed to block the activity of semaphorin 4D (SEMA4D), a protein found at gradually increasing levels in patients’ brain nerve cells throughout the progression of Huntington’s disease.

SEMA4D regulates the migration and activation of microglia and astrocytes, the brain’s main inflammation-promoting cells whose chronic activation is thought to contribute to neurodegenerative processes.

Also, astrocytes’ activation toward an inflammatory state impairs their normal functions, such as those supporting a balance between energy metabolism and nerve cell activity. Notably, impaired brain metabolism is a feature of several neurodegenerative disorders, including Huntington’s.

Moreover, SEMA4D halts nerve cell development and repair of the loss of myelin (the protective sheath around nerve cell fibers), promotes nerve cell death, and disrupts the blood-brain barrier — a semipermeable membrane that protects the brain from the external environment — all of which can lead to further inflammation and nerve cell damage.

By blocking SEMA4D’s activity, pepinemab is thought to lessen brain inflammation, prevent blood-brain barrier disruption, promote myelin loss repair, and restore brain metabolism, potentially preventing further neurodegeneration.

Preclinical studies in a mouse model of the disease have shown that pepinemab can protect against the loss of brain volume (brain atrophy) — shrinkage that is a hallmark of Huntington’s disease. It also can prevent spatial memory loss and lessen anxiety-like behaviors.

The multi-center Phase 2 SIGNAL study (NCT02481674) is evaluating pepinemab’s safety, pharmacokinetics (uptake, distribution, and elimination in the body), and effectiveness in Huntington’s patients with late prodromal and early manifest disease.

The trial, which is the result of a collaboration between Vaccinex and the Huntington Study Group and the University of Rochester’s Clinical Trials Coordination Center, has enrolled 301 adult patients (older than 21) at more than 30 sites across the U.S. and Canada.

The study’s main goal is to assess pepinemab’s safety and tolerability. Secondary goals include changes in brain volume (assessed through magnetic resonance imaging), brain metabolic activity (as determined by FDG-positron emission tomography scans), and clinical features of the disease.

SIGNAL comprises two groups of patients. Group A involved 36 participants and was used to determine required sample size and treatment duration for group B, which intends to enroll 265 participants — 179 with early manifest disease and 86 with late prodromal.

In group A, participants were assigned randomly to receive either pepinemab (20 mg/kg) or a placebo intravenously (directly into the bloodstream) once a month for six months. After that, all of them received the therapy for an additional five months, followed by a three-month safety follow-up period.

Previously reported data showed that pepinemab was safe and preserved patients’ brain structure and metabolic activity.

Now, Vaccinex has presented detailed brain metabolism data from 19 patients in group A (11 initially assigned to pepinemab and eight to placebo).

Six-month data showed that pepinemab-treated patients had a significant increase in brain metabolic activity in several brain regions of interest, compared with those receiving a placebo. Afterward, the brain metabolic activity of patients switching from placebo to pepinemab reached similar levels to those continuing treatment for an additional five months.

Pepinemab treatment also protected against brain atrophy and improved motor and cognitive function. The selected dose of pepinemab was found to be enough to reach therapeutic levels of the compound in the brain (since it was shown to cross the blood-brain barrier) and peripheral tissues.

In group B, participants were assigned randomly to receive either 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.

Evaluation of this group is ongoing, and as of March 30, 200 participants had completed the trial, 38 had completed 16 months of treatment, and 16 had withdrawn.

Vaccinex emphasized that it is actively working to safely accelerate completion of the trial and that it will provide updates as warranted.

Pepinemab received fast track and orphan drug designations for the treatment of Huntington’s disease by the U.S. Food and Drug Administration. These designations are meant to provide regulatory support and financial benefits, accelerate pepinemab’s development and review, and ensure seven years of marketing exclusivity in the U.S. upon regulatory approval.

Since the brain’s metabolic impairment is common in other neurodegenerative diseases, such as Alzheimer’s, Vaccinex plans to initiate a clinical trial of pepinemab in Alzheimer’s patients later this year.

“Our presentation at this important meeting underscores the potential of pepinemab as a new therapeutic option for neurodegenerative diseases, notably Huntington’s and Alzheimer’s, two progressive and debilitating conditions with no effective treatments or known cures,” Zauderer said.