Confirmed: Mast Cell Drug Curbs ALS Mortality

BOSTON -- When phase II/III trial results were published in 2019 for a novel approach to treating amyotrophic lateral sclerosis (ALS), the 48-week data left an important question unanswered: did the treatment extend survival? Now, a follow-up study reported here provides an answer.

With mean follow-up of 75 months, patients with moderate-severe (but not very severe) ALS receiving the investigational drug masitinib in addition to riluzole (Rilutek) lived an average of 10 months longer than did patients receiving placebo and riluzole in the study, according to Albert C. Ludolph, MD, of Ulm University in Germany.

Patients with moderate disease only showed even better survival with the drug, extended by 25 months on average relative to placebo, Ludolph told attendees at the American Academy of Neurology annual meeting.

Put another way, he said, the addition of masitinib to riluzole cut mortality risk by 44% (P<0.05). He explained that, at the 48-week mark in the original analysis, nearly all patients were still alive and thus it was not possible to assess impacts on mortality.

Ludolph is now heading the steering committee for a new phase III trial aimed at confirming the benefit.

Masitinib is a tyrosine kinase inhibitor that inhibits microglia proliferation and activation and also blocks mast cell degranulation, a process that releases damaging cytokines. It has something of a checkered history. The drug's French developer, AB Science, initially positioned it as a veterinary drug to treat mast cell tumors in dogs, gaining approvals in the U.S. and Europe. It's still sold for that purpose in Europe, but the FDA withdrew authorization in 2015 when AB Science missed a deadline to supply additional data that the agency had required.

Since then, the company has turned to human applications. Preclinical data indicated that its mechanism of action might make it helpful in certain neurodegenerative conditions. Subsequent clinical trials have yielded positive results not only in ALS, but also for progressive multiple sclerosis and Alzheimer's disease, as well as certain malignancies, asthma, and other conditions. AB Science hit a pothole in June 2021 with these programs, voluntarily halting enrollment in various trials after seeing a potential cardiac safety issue. But that concern was resolved and recruitment resumed a few months later.

One of the takeaways from the ALS study first reported in 2019 was that patients with the most severe manifestations did less well than those with better function. Thus, part of the new analysis involved excluding patients with scores of 0 (indicating complete loss of function) on any domain in the ALS Functional Rating Scale assessment. The ongoing confirmatory trial uses the same exclusion. Ludolph said a substantial benefit in patients with such advanced ALS would not be expected with masitinib, given that its mechanism of action would protect intact neurons but not reverse existing nerve damage.

The long-term data were also analyzed for outcomes besides survival. Among 220 patients in the original study with available data -- which included 30 with extreme disabilities -- masitinib delayed risk of meaningful progression by 27%. When the analysis was restricted to participants without any total disabilities, however, risk of progression was decreased by 42%. Progression-free survival time was extended 13 months in that group, compared with a meager 4-month prolongation in the overall sample.

Even without the ongoing confirmatory trial, AB Science felt confident enough about the data in hand that, last August, it filed a European marketing application for the ALS indication.

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