#MSVirtual2020 – Masitinib Delays Disability Progression in PPMS, Non-active SPMS

AB Science’s lead candidate masitinib safely and effectively delays disability progression in people with primary progressive multiple sclerosis (PPMS) and non-active secondary progressive MS (SPMS), according to top-line data from a clinical trial.

The therapy was found to significantly lower the risk of first and confirmed (three-month) disability progression, and to reduce the risk of becoming wheelchair-bound in a broad population of progressive MS patients, compared with a placebo.

“These results are the start of a possible revolution in the treatment of multiple sclerosis, as it is the first time a treatment has shown efficacy in both progressive forms of this [disease],” Patrick Vermersch, MD, PhD, the trial’s main coordinator, said in a press release.

“With this conclusive study, AB Science is now on the verge of becoming the first biotech company in the world to propose a new approach for the treatment of progressive forms of multiple sclerosis,” said Olivier Hermine, MD, PhD, AB Science’s co-founder and president of the scientific committee, and a member of the French Academy of Sciences.

“We will … as soon as possible initiate the process to start a confirmatory study, a necessary step to definitively validate the therapeutic potential of masitinib in a broader population,” Hermine added.

The data were presented by Vermersch, who also is a professor at University of Lille, in France, at the MSVirtual2020 conference, held online Sept. 11–13. This was the 8th joint meeting of the American (ACTRIMS) and European (ECTRIMS) Committees for Treatment and Research in MS.

Vermersch’s oral presentation was titled “Masitinib in primary progressive (PPMS) and non-active secondary progressive (nSPMS) multiple sclerosis: Results from phase 3 study AB07002” (abstract #FC04.01).

Masitinib (formerly known as AB1010) is an oral, selective tyrosine kinase inhibitor that works by blocking the activity of mast cells, microglia, and macrophages — immune cells people are born with that are believed to play important roles in progressive MS. By suppressing these cells, the therapy is expected to limit neurodegeneration in progressive forms of the disease.

“Targeting innate immunity-related MS disease progression via modulation of mast cells and activated macrophage/microglia may slow or prevent worsening of disability in progressive MS,” Vermersch said in his presentation.

A previous proof-of-concept Phase 2 trial (NCT01450488) of masitinib in 35 progressive MS patients showed promising results, justifying its continued testing.

Now, a multicenter, Phase 2b/3 clinical trial — called AB07002 (NCT01433497) — evaluated masitinib’s safety and effectiveness in 656 adults with primary or non-active secondary forms of progressive MS.

Participants, recruited at several centers across seven European countries, were randomly assigned to receive either one of two doses of masitinib or a placebo, twice a day, for 96 weeks (about two years).

One masitinib group (the low-dose group) received 4.5 mg/kg per day for the study’s duration, while the other, high-dose group, escalated to 6 mg/kg per day after three months of treatment; each treatment group had its own placebo group.

The trial’s main goal was to assess changes in patients’ disability levels, measured through the expanded disability status scale (EDSS) score, from the study’s start (baseline) and every 12 weeks (about three months) up to two years.

The researchers also analyzed the risk of disability progression (as first onset and three-month confirmed) and of reaching an EDSS score of 7.0 — reflecting a level of disability severe enough that the patient is restricted to a wheelchair.

Final data from the study’s low-dose arm included 199 patients (79 with PPMS and 120 with SPMS) who received masitinib and 101 patients (45 with PPMS and 56 with SPMS) given a placebo. In both groups, the participants had a median age of 50, with advanced disease; about half of the patients were women.

The results showed the trial met its main goal, with the patients treated with the low-dose therapy showing significantly slower disability progression than those in the placebo group, irrespective of their type of progressive MS.

In addition, those receiving masitinib’s low dose were 39% more likely to have either reduced disability or fewer disability worsening events than those given a placebo.

These masitinib-treated patients also showed a significantly lower risk of first disability progression — by 42% — and of confirmed (3-month) disability progression by 37% over a timeframe of 96 weeks — which, Vermersch noted, is clinically relevant.

The patients who received masitinib also had a 98% lower risk of reaching an EDSS score of 7.0 for the first time, and a 100% lower risk of reaching EDSS 7.0 for three months, compared with those in the placebo group.

Masitinib’s safety profile was consistent with that reported in previous studies, with no new safety concerns identified. The most common treatment-related adverse events were diarrhea, nausea, rash, and various blood assessments.

Results from the high-dose treatment group showed that the effects on patients’ disability progression were comparable to those found with the lower dose. But “unexpectedly the placebo group … showed an improvement relative to baseline,” Vermersch said, making it “very difficult to show any clinical impact on efficacy of this high dose of masitinib.”

Therefore, only the 4.5 mg/kg dose of masitinib per day will be evaluated in future MS studies.

In conclusion, the trial’s results showed that the low dose of masitinib had a sustained and significant benefit in disability progression in a broad population of progressive MS patients over two years, suggesting that the therapy “may provide a new treatment option for PPMS and non-active SPMS,” Vermersch said.

The researcher also noted that masitinib’s safety profile “is suitable for long-term administration.”

In AB Science’s release, Vermersch noted: “Masitinib can be administered on a long-term basis as it is not an immunosuppressive treatment, which is particularly important in patients who are to receive long-term treatment and who, for some, have already an immune system weakened by previous treatments or because of their age.”

“I am looking forward to continuing the development of this product and to seeing the realization of new therapeutic hope for these patients,” he added.

AB Sciences also is testing the therapeutic potential of masitinib in other neurological diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, and certain inflammatory diseases and cancers.