Pepinemab Clinical Trial Ongoing; Top-line Results Coming Later this Year

Vaccinex’s Phase 2 SIGNAL study, evaluating the investigational antibody pepinemab (VX15/2503) in Huntington’s disease patients with late prodromal and early disease, is ongoing and has tested pepinemab in all 265 patients enrolled in cohort B, the company announced.

As of March 31, only 37 patients in this group had not yet completed the planned 18 months of treatment, with most (32 individuals) completing 16 months of treatment.

Vaccinex also noted it is working closely with trial investigators to assure the safe completion of  remaining visits. Statistical projections will be used for the estimated 10% of patients who won’t be able to complete all trial visits as planned due to the COVID-19 pandemic.

Data from both study groups (A and B) will be announced during the second half of the year.

Pepinemab is designed to block the activity of semaphorin 4D (SEMA4D), a protein whose levels in brain nerve cells increase as Huntington’s disease progresses.

SEMA4D regulates the migration and activation of microglia and astrocytes, brain cells known for their role in promoting inflammation. Their chronic activation is thought to contribute to neurodegeneration.

Astrocytes’ overactivation also halts the cell’s normal function, which includes supporting a balance between energy metabolism and nerve cell activity. Impaired brain metabolism is seen in several neurodegenerative disorders, including Huntington’s.

SEMA4D also has been shown to halt nerve cell development and repair of the loss of myelin (the protective sheath around nerve cell fibers), promote the death of nerve cells, and disrupt the blood-brain barrier — a highly selective membrane that shields the central nervous system from systemic blood circulation.

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

Preclinical data in a mouse model of the disease has shown that pepinemab can protect against brain shrinkage, a hallmark of Huntington’s disease. The antibody also prevented spatial memory loss and lessened anxiety-like behaviors.

The Phase 2 SIGNAL study (NCT02481674) was designed to evaluate the safety, pharmacokinetics (uptake, distribution, and elimination in the body), and effectiveness of pepinemab in Huntington’s patients with late prodromal and early manifest disease.

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

The trial has enrolled 301 adult patients (older than 21) at more than 30 sites across the U.S. and Canada, who were divided into two groups: A and B.

Group A, which has 36 participants, determined sample size and treatment duration for group B, which included 265 participants: 179 with early manifest disease and 86 with late prodromal disease.

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

An initial analysis of brain metabolism data from 19 patients in group A (11 initially assigned to pepinemab and eight to placebo) showed that after six months of treatment, pepinemab improved brain metabolism, halted brain atrophy, and eased motor and cognitive symptoms when compared to placebo. This was seen in both early and late stage patients.

In group B, participants were assigned randomly to receive 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.

“While the COVID-19 pandemic has created unprecedented disruptions and uncertainty affecting clinical development timelines around the world, we continue to engage with our trial sites, […] and we do not currently anticipate that these trials will be materially impacted by the pandemic,” Maurice Zauderer, Vaccinex’s president and CEO, said in a press release.

“We continue to advance plans to leverage our work in Huntington’s disease and initiate a formal study of pepinemab in Alzheimer’s disease when trial sites are again permitted to safely enroll patients,” he added.

Vaccinex is planning to test pepinemab in Alzheimer’s patients later this year, a neurodegenerative disease also marked by metabolic impairments in the brain.

Pepinemab was given fast track and orphan drug designations for the treatment of Huntington’s disease by the U.S. Food and Drug Administration, two designations that provide regulatory support and financial benefits and accelerate pepinemab’s development and review.