SAN DIEGO—Patients with relapsing-remitting multiple sclerosis (MS) who received high doses of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase II trial had evidence of remyelination at week 24, according to research described at the ACTRIMS 2018 Forum. The treatment did not meet the primary end point of reduction in the number of active lesions seen on MRI, however.
GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4 (TLR4), said study author Robert Glanzman, MD. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination.
“Because we are not directly suppressing the immune system, what we think we are doing is taking away a driver of autoimmunity,” explained Dr. Glanzman, Chief Medical Officer of GeNeuro, a Geneva-based company that is developing GNbAC1.
In a study known as CHANGE-MS, 270 patients with relapsing-remitting MS were randomized to one of three doses of GNbAC1 (6 mg/kg, 12 mg/kg, or 18 mg/kg) or to placebo via monthly IV infusion over six months. The study was conducted at 70 centers in 13 European countries over three years. It had a 24-week, double-blind, placebo-controlled period, followed by a 24-week, dose-blind, active-only treatment period. During the latter period, controls were randomized to the three doses of GNbAC1. Brain MRI scans were performed at weeks 12, 16, 20, 24, and 48 to look for evidence of remyelination.
The mean age of patients was 38, and 65% of the population was female. The researchers observed no safety concerns and no significant effect on inflammatory measures during weeks 12 to 24, even though the absolute number of lesions was reduced by about 50%.
Although the primary end point of the cumulative number of gadolinium-enhancing lesions seen on brain MRI scans every four weeks during weeks 12 to 24 was not met, post hoc analyses suggest a decrease in neuroinflammation in the 18 mg/kg GNbAC1 group at week 24, compared with placebo. “We gained about a quarter or half of percent in normal-appearing white matter at the cerebral cortex at the high dose,” said Dr. Glanzman. “Normally, MS patients lose white matter over time, both in the cortex and in gray matter. We are actually showing evidence of remyelination, which is really exciting. If these data are replicated and confirmed at week 48, we think we really have an exciting compound.”
GeNeuro sponsored the study.