Phase 3 Trial of Masitinib as Add-on ALS Treatment Cleared by FDA

AB Science plans to launch a Phase 3 clinical trial testing the safety and effectiveness of its tyrosine kinase inhibitor masitinib as an add-on treatment for people with amyotrophic lateral sclerosis (ALS).

Its announcement follows U.S. Food and Drug Administration (FDA) approval of the company’s investigational new drug application, requesting the right to initiate this study.

The start of patient enrollment, however, awaits a resolution to the ongoing COVID-19 health crisis and a return to stability at U.S health centers.

FDA agreement “is really a good news for all of us and in particular for the patients, and we aim to initiate the Phase 3 confirmatory trial in ALS as soon as conditions at U.S. clinical sites stabilize post-the coronavirus pandemic,” Alain Moussy, co-founder and CEO of AB Science, said in a press release.

Masitinib is an experimental oral treatment designed to block the activity of multiple cell types — including macrophages, neutrophils, mast cells, and Schwann cells — involved in the inflammatory and neurodegenerative processes marking ALS. It does so through the activity of proteins called tyrosine kinases.

Masitinib was recently evaluated in a Phase 2/3 clinical trial (NCT02588677) that compared its safety and efficacy against a placebo, both given in combination with riluzole (brand name Rilutek, marketed by Sanofi), an approved ALS medication.

This earlier trial, known as Study AB10015, enrolled 394 people diagnosed in the past three years, but regardless of their ALS functional rating scale-revised (ALSFRS-R) at the study’s start (baseline). This scale measures a patient’s ability to perform daily life tasks, like speaking, swallowing, and dressing.

Study AB10015’s inclusion data, in other words, was broad, with enrolled patients able to range from those who had lost certain physical abilities to those with severely affected physical function.

Participants were randomly assigned masitinib — at a daily dose of 4.5 or 3.0 mg per kg  — or a placebo for up to 48 weeks (11 months). All continued receiving a stable dose of riluzole.

Results showed that patients on 4.5 mg/kg masitinib experienced a significantly slower decline (by 27%) in their ability to perform everyday activities at 48 weeks compared to those on placebo.

But these benefits were only observed in patients with a typical disease progression — those who lost fewer than 1.1 ALSFRS-R points per month before entering the trial. Patients with a faster disease worsening did not benefit as much from adding masitinib to standard treatment.

A subgroup analysis, however, suggested that if masitinib’s use started at less severe disease stages, then it could significantly delay progression in patients with fast progressing disease, too.

The upcoming Phase 3 trial (NCT03127267) — called Study AB19001 — aims to confirm these findings. It will include up to 495 ALS patients diagnosed within the last two years, and whose disease is progressing at a normal or at a fast pace — defined as a 0.3, or greater, ALSFRS-R point decline each month.

Participants must also have an overall ALSFRS-R score of at least 26 (out of 48 total points).

People in the trial will be randomly assigned to one of three groups. A first group will be treated with masitinib as a daily add-on therapy starting at 3.0 mg/kg, and escalating to 4.5 mg/kg after four weeks. The second will follow a similar escalating line of treatment, but after four weeks on the 4.5 mg/kg dose will move to a higher, 6 mg/kg dose. The third group will be given a placebo.

As in Study AB10015, all in the new trial (including the placebo group) will continue on stable doses of riluzole.

The trial’s main goal is to determine if masitinib plus riluzole slows the decline in ALSFR-S scores compared to a placebo. Secondary assessments include changes in measures of limb strength, lung function, quality of life, and survival.

“I am extremely pleased with this FDA clearance, which represents a significant milestone for the development of masitinib in ALS,” said Albert Ludolph, MD, chairman of the department of neurology at the University Hospital and Medical Faculty of Ulm, in Germany, and international coordinator for the upcoming trial.

“Masitinib is the first drug that targets both microglia and mast cells to be evaluated in ALS. I am convinced that this approach represents a promising potential addition to our currently limited therapeutic options for patients with ALS,” Ludolph said.

Trial sites are yet to be announced, but those interested in learning more can contact the study coordinator.

The trial was designed with scientific assistance from the Committee for Medicinal Products for Human Use (CHMP), an advisor committee of the European Medicines Agency (EMA). This assistance was among the development benefits offered to masitinib once it was awarded orphan drug status.

Trial results are expected to support a new request for approval to the EMA,  after CHMP rejected an application in 2018 citing low reliability and robustness of the data, and possible bias in the earlier trial’s primary analysis.