Masitinib, Given Early in ALS Course, Extends Life, Trial Data Show

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by Marisa Wexler MS |

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Treatment with the investigational oral therapy masitinib can extend lifespan when given early in the course of amyotrophic lateral sclerosis (ALS), according to a new study.

“These long-term survival data, with an average follow-up of 75 months since diagnosis, suggest that masitinib can offer a substantial survival benefit when treatment is initiated before severe loss of functionality,” Albert Ludolph, chairman of the department of neurology at University Hospital and Medical Faculty of Ulm and a study co-author, said in a press release.

Masitinib-treated ALS patients in a clinical trial’s higher-dose group lived about two years longer than did those in a placebo group, researchers found.

The study, “Long-term survival analysis of masitinib in amyotrophic lateral sclerosis,” was published in
Therapeutic Advances in Neurological Disorders and was funded by AB Science, the developer of masitinib.

Scientists at AB Science and other institutions reported the results of a new analysis of data from the Phase 2/3 clinical trial AB10015 (NCT02588677). In that study, 394 adults with ALS were given either masitinib at daily doses of 3 or 4.5 mg/kg, or a placebo, for 48 weeks (about a year). All enrolled also were given Rilutek (riluzole), an approved ALS treatment.

Final trial data, reported in 2019, showed that masitinib at the 4.5 mg/kg dose significantly slowed the rate of disease progression, as assessed with the ALS Functional Rating Scale-revised (ALSFRS-R). Survival data were not yet available.

In the new study, researchers reported on survival outcomes for 378 (96%) of trial participants after an average follow-up of about 6.25 years (75 months).

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An initial analysis, including all trial participants, showed no significant difference between the masitinib and placebo groups in terms of overall survival.  Median overall survival was 33 months for masitinib-treated patients and 37 months for those on placebo.

Earlier results had also shown that, in terms of disease progression, masitinib tended to be most effective in individuals with relatively mild disease (reflected as higher scores on the ALSFRS-R). So in new analyses, researchers looked only at patients with scores of two points or higher on every item on the ALSFRS-R at the study’s start (called a baseline measure), corresponding to mild or moderate disease.

Here, treatment with masitinib at a dose of 4.5 mg/kg led to significantly longer median overall survival (69 months vs. 44 months in the placebo group). This corresponds to a median difference of 25 months — a bit over two years — in favor of masitinib. Further statistical analyses indicated that masitinib’s reduced the risk of death by 44% among these participants compared with placebo.

“Findings from this long-term OS [overall survival] analysis, with an average follow-up of 75 months since diagnosis, indicate that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years and reduces risk of death by at least 44% as compared with placebo, provided that treatment starts early in disease (i.e., prior to severe impairment of functionality),” the researchers wrote.

A similar benefit in favor of masitinib was found in analyses that included only individuals with scores of two points or more for every ALSFRS-R item, and a relatively low rate of disease progression (a change of less than 1.1 points in ALSFRS-R from disease onset to the study’s start). In this group, a significant median overall survival difference of 25 months was seen compared with placebo, and a significant 47% reduced risk of death.

Additional analyses using data from an early access patient program also showed a significant survival improvement with masitinib’s use relative to placebo.

Notably, patients with both mild disease and slow ALS progression in this trial is similar to the patient group enrolled in AB19001 (NCT03127267), an ongoing Phase 3 trial further evaluating masitinib’s safety and efficacy. Enrollment here and in other masitinib trials is expected to soon resume in France following a suspension earlier this year. It was stopped after data showed a potentially higher risk of ischemic heart disease, a condition of recurring chest pain or discomfort, with masitinib’s use.

“The current confirmatory phase 3 study (AB19001) in ALS patients with mild or moderate impairment of functionality at baseline, is very well-aligned with this population [that showed the greatest survival benefit in AB10015],” Ludolph said.

“The magnitude of this observed survival signal for masitinib … is very encouraging and data from study AB10015 have now demonstrated a consistently significant treatment effect in terms of overall survival, hazard ratio, slowed rate of functional decline, and slowed deterioration in respiratory function and quality-of-life,” added Jesús S. Mora, MD, director of the ALS Unit at Hospital San Rafael in Madrid, Spain, and a study co-author.

Masitinib, an oral therapy, is designed to inhibit certain enzymes called tyrosine kinases, thereby blocking the activity of several immune cells involved in inflammatory and neurodegenerative processes. In addition to ALS, the therapy is being evaluated as a potential treatment for multiple sclerosis, Alzheimer’s disease, asthma, COVID-19, and some types of cancer.