Masitinib Slows Disability Progression in PPMS, Non-active SPMS

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Masitinib, AB Science’s experimental oral therapy, significantly slows disability progression in adults with primary progressive multiple sclerosis (PPMS) and non-active secondary progressive MS (SPMS), according to final data from the AB07002 Phase 2b/3 clinical trial.

These findings, indicating that the trial met its main goal, support AB Science’s current plans to launch a larger Phase 3 trial, dubbed AB20009 (2021-000639-30), to confirm the therapy’s benefits in this patient population.

The upcoming study has been cleared so far by French and Swedish health authorities, and is expected to involve 75 sites in Europe, the U.S., Canada, Israel, and South Africa.

“The results of study AB07002 demonstrate, for the first time, the efficacy of a therapeutic product in the treatment of MS patients who were progressing but not clinically active, which includes non-active primary progressive and secondary progressive MS,” Patrick Vermersch, MD, PhD, said in a press release. Vermersch is the study’s first author and the upcoming trial’s principal investigator.

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“There is currently no approved therapy that encompasses this particular population of progressive MS,” added Vermersch, who is a professor of neurology at the University of Lille, France.

“I am therefore excited to continuing the development of masitinib in its confirmatory Phase 3 study (AB20009), with the anticipation that it could be a new therapeutic hope for these patients,” he said.

AB07002’s results were detailed in the study, “Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial,” and published in the journal Neurology: Neuroimmunology & NeuroInflammation.

Masitinib is an orally available small molecule that blocks tyrosine kinase, an enzyme essential for the activity of mast cells, microglia, and macrophages — immune cells that “are increasingly implicated in the [underlying mechanisms] of progressive MS,” said Olivier Hermine, MD, PhD, AB Science’s president of the scientific committee.

These cells are part of the innate immune system, the body’s first line of defense that is comprised of cells people are born with. In turn, the adaptive immune system, acquired through exposure to a given microbe or molecule, is thought to be the main contributor to relapsing forms of MS.

By suppressing innate immune cells, masitinib is expected to slow disease progression in people with progressive forms of MS.

Promising results from a previous proof-of-concept Phase 2 trial (NCT01450488) testing the therapy in 35 progressive MS patients supported the launch of the AB07002 Phase 2/3 trial (NCT01433497).

The study evaluated masitinib’s safety and effectiveness against a placebo in 611 adults with PPMS and non-active SPMS who had experienced no disease relapse in the two years prior, but who had evidence of disability accumulation.

Participants, recruited at sites across 20 countries, were assigned randomly to receive either one of two doses of masitinib (403 patients) or a placebo (208 patients), twice a day, for 96 weeks (about two years).

One masitinib group (the low-dose group) received 4.5 milligrams per kilogram (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.

At study’s start (baseline), patients’ average age was approximately 50 years, about half needed a walking aid, and there were no significant feature differences between the PPMS and non-active SPMS subgroups.

Newly published, final data showed that the trial met its main goal, with masitinib’s low dose being superior to a placebo at significantly slowing disability progression, as assessed with the expanded disability status scale (EDSS). Notably, this superiority was observed in both PPMS and non-active SPMS patients.

The high dose resulted in comparable effects in EDSS scores, but the corresponding placebo group showed an “atypical pattern of EDSS improvement relative to baseline during the early phase of the study,” preventing the detection of significant group differences, the researchers wrote.

Also, compared with a placebo, the low dose of masitinib was associated with a 47% greater likelihood of having either disability reduction or absence of disability progression.

Patients treated with this dose were also at significantly lower risk of first disability progression (by 42%), confirmed three-month disability progression (by 37%), and of reaching an EDSS score of 7.0 — reflecting a level of disability severe enough that the patient is wheelchair-bound.

While most of the trial’s secondary goals were not attained, the 4.5 mg/kg dose of masitinib significantly improved arm and hand function (as measured with the 9-hole peg test) in the entire group and improved overall health (as assessed via the patient-reported health state visual analogue scale) in only adults with non-active SPMS.

The rates of adverse events, serious adverse events, and adverse events leading to treatment discontinuation were higher in the masitinib groups relative to the placebo groups, and generally higher in the high-dose group.

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Still, the therapy’s safety profile was consistent with that reported in previous trials, with no new safety concerns identified. The most common adverse events included diarrhea, rash, nausea/vomiting, swelling in the lower legs, upper arms, or hands, and itchy skin.

Also, “there was no evidence of increased risk of infection with masitinib, which could prove advantageous compared with other MS drugs, many of which are associated with an increased risk of infectious complications,” the researchers wrote.

“Validation of these findings via a confirmatory phase 3 study will be necessary, in part because neuroimaging data were not collected during the current study and also due to an absence of signal on secondary [measures],” they added.

The upcoming AB20009 trial will test 4.5 mg/kg of masitinib against a placebo for two years in up to 800 adults, 18–65 years, with PPMS or non-active SPMS.

Eligible participants must have moderate to severe disability, as defined by EDSS scores of 3-6, and no T1 gadolinium-enhancing brain lesions on MRI scans — a marker of MS lesions with active inflammation.

The study’s main goal is to determine if the therapy is superior to a placebo at delaying three-month confirmed disability progression. Secondary goals will include time to six-month confirmed disability progression, changes in EDSS scores over two years, and time to becoming wheelchair-bound.

Changes in motor and cognitive function, brain volume and lesions, and relapses also will be assessed, as well as in quality of life, fatigue, and depression. An additional goal is to measure changes in the levels of nerve damage biomarkers in a subgroup of 200 patients of pre-selected trial sites.