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Masitinib, an orally administered tyrosine kinase inhibitor targeting the innate immune system, showed positive signs in treating progressive forms of multiple sclerosis (MS) in the .

The drug, which specifically downregulates mast cells and microglia, appeared to slow disability progression in people with primary progressive multiple sclerosis (PPMS) and non-active secondary progressive MS (SPMS) over 2 years, reported Patrick Vermersch, PhD, of University of Lille in France, at MS Virtual 2020, the joint ACTRIMS-ECTRIMS meeting.

Point estimates consistently supported efficacy, but not all were significant.

This is the first time that a drug targeting innate immune cells -- as opposed to targeting adaptive immune cells like B cells and T cells -- has shown positive results in PPMS and non-active SPMS, Vermersch noted. "Despite some atypical endpoints evaluation, the data showed significant difference versus placebo for disability progression using EDSS," he said.

"Over time, we have accumulated data telling us that to control the progressive forms, we need to control innate immunity," Vermersch told 番茄社区. "The data obtained with other products in progressive forms -- siponimod [Mayzent] in SPMS and ocrelizumab [Ocrevus] in PPMS -- showed significant but modest results, and the positive results were driven by patients with baseline characteristics of clinical and MRI activity," he said.

"Masitinib may provide a new option for physicians with progressive patients," he added. "We have no therapeutic option for patients without superimposed clinical or MRI activity and it is an urgent need."

This trial is of substantial interest for several reasons, noted Jeffrey Cohen, MD, of the Cleveland Clinic in Ohio, who wasn't involved with the study.

"Masitinib has a novel mechanism of action, postulated to target innate immune mechanisms which are postulated to play a role in progressive MS," he told 番茄社区.

"Though not all analyses demonstrated significant results, overall, the trial showed benefit on slowing disability worsening in progressive MS, potentially addressing a big unmet need," Cohen added.

The MS study tested two doses of masitinib independently, each with its own placebo group. In the first group, 300 patients with PPMS and non-active SPMS were randomized 2:1 to 4.5 mg/kg/day or placebo. In the second group, another 300 PPMS and non-active SPMS patients were randomized to a masitinib titration up to 6.0 mg/kg/day or placebo.

Patients with PPMS or non-active SPMS were defined as having no relapse within 2 years measured by (EDSS) progression, not by imaging. Participants were required to have baseline EDSS scores of 2.0-6.0; a score of 6.0 means a patient needs intermittent or unilateral constant assistance, like a cane, to walk.

The primary endpoint was the change from baseline in absolute EDSS value averaged over the 2-year study, using the mean of all changes from baseline in EDSS. These changes were measured at eight time points, every 12 weeks, for each patient from week 12 through week 96.

The primary analysis was calculated using generalized estimated equations to allow repeated measures to be analyzed and correlations across variables and time to be adjusted. "The primary analysis is not a one-time ANCOVA test of the last EDSS value measured at week 96," Vermersch emphasized. To support the findings, sensitivity analyses included change in ordinal EDSS score (+1 improvement; 0 stable; -1 worsening) from baseline, averaged over the 2-year study.

In the 4.5 mg/kg/day group, median EDSS was 5.5 at baseline, and about half of participants had an EDSS score of 6.0. Mean and median ages were near 50, and about 54% were female.

Patients taking 4.5 mg/kg/day showed a statistically significant reduction in disability progression on EDSS on the primary analysis. Means of absolute EDSS changes from baseline were 0.001 for the masitinib group and 0.098 for the placebo group (with positive values indicating worsening). The between-group difference was -0.097 (P=0.0256), favoring masitinib.

Ordinal analysis showed a 39% relative probability of either reduction in EDSS progression or increase in EDSS improvement (HR 0.61, 95% CI 0.37-0.99, P=0.0446) with masitinib.

Masitinib reduced the risk of first disability progression by 42% (HR 0.58, 95% CI 0.35-0.96, P=0.034). Kaplan-Meier analysis indicated that a first disability progression was identified in 38% of the placebo group versus 28% of those on masitinib.

The risk of confirmed 12-week disability progression was reduced by 37% (HR 0.63, 95% CI 0.33-1.20, P=0.159), which was not statistically significant, but "is relevant from a medical standpoint," Vermersch said.

The proportion of patients with at least one adverse event over 96 weeks was 94.5% in the masitinib group and 87.1% for placebo. Serious, non-fatal adverse events were 21.1% in the masitinib group and 12.9% for placebo. Relapse occurred in 2% of the masitinib group and 1% of placebo; maculopapular rash occurred in 1.5% of patients treated with masitinib.

"The safety data are reassuring: some skin reactions, gastrointestinal, and neutropenia, but considered mild to moderate in most cases, reversible, and manageable," Vermersch said.

In the high-dose group (titrated to 6.0 mg/kg/day), the placebo arm "unusually showed an improvement relative to baseline after 96 weeks," Vermersch noted.

"Numerically, masitinib 6.0 mg/kg/day titration change in EDSS was comparable to the masitinib 4.5 mg/kg/day result. Therefore, only the masitinib 4.5 mg/kg/d dose will be pursued further in MS," he said. No new safety signal was observed in the high-dose group.

A confirmatory study of masitinib in progressive MS patients is planned by the drugmaker, AD Science, Vermersch told 番茄社区. The drug also is being studied in , amyotrophic lateral sclerosis (), , certain , and infection.

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