VX15/2503 is a monoclonal antibody against the protein semaphorin 4D (SEMA4D) developed by the biotech company Vaccinex to slow down and prevent neurodegeneration in patients with Huntington’s disease (HD).

In 2015, Vaccinex, the Huntington Study Group and the University of Rochester’s Clinical Trials Coordination Center launched the first clinical trial to investigate a monoclonal antibody as a potential treatment for Huntington’s.

How does VX12/2503 work?

SEMA4D is implicated in several cellular processes that contribute to increased neuroinflammation and neurodegeneration common in diseases such as Huntington’s and multiple sclerosis (MS). SEMA4D plays different roles in different cells, contributing to an arrest in neural development and an increase in cell death.

VX15/2503 blocks the activity of SEMA4D, thereby preventing the activation of microglia and astrocytes, which are the main inflammatory cells in the brain. Their chronic activation is believed to contribute to neurodegenerative processes. In addition, VX15/2503 allows the differentiation of oligodendrocyte cells, which have the potential to remyelinate damaged nerve cells.

In animal models of Huntington’s disease, treatment with VX15/2503 showed protection against loss of brain volume — a characteristic of this disease — as well as prevention of spatial memory loss and suppression of anxiety-like behaviors.

Clinical studies with VX15/2503

The Phase 2 SIGNAL placebo-controlled study (NCT02481674) testing VX15/2503 started in 2015 with an expected completion date of March 2020. The trial will assess the safety, tolerability, pharmacokinetics, and effectiveness of VX15/2503 in patients with late prodromal (before a doctor actually diagnoses the disease) and early manifest Huntington’s.

In April 2017, Vaccinex announced an initial set of results from the SIGNAL trial. No severe safety signals were identified and the treatment seemed to be effective in preserving brain structure and metabolic activity.

During the trial, 36 participants received monthly infusions of either VX15/2503 or placebo for six months and were followed for 11 months after the start of treatment. Afterward, all participants received  VX15/2503 infusions (open-label) for another five months and were followed for three months.

Brain imaging measures were performed in all participants to assess changes in brain structure and metabolic activity. Analysis of the results showed that VX15/2503 reduced the decrease in brain volume and metabolic activity in cortical regions of the brain, which decreased at an annual rate of 2 to 3 percent in the placebo control group.

Other details about VX15/2503

Besides the potential use of VX15/2503 for the treatment of Huntington’s, the antibody was also tested in Phase 1 clinical trials for the treatment of advanced solid tumors (NCT01313065) and MS (NCT01764737).

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