Investigational Treatment Masitinib May Help Slow ALS Progression, Preclinical Data Show

Masitinib, the lead experimental medicine being developed by AB Science, can modulate the activity of different cell types known to be involved in inflammation and nerve degeneration in amyotrophic lateral sclerosis (ALS), according to results from a preclinical study.

The findings were discussed in a presentation, titled “Post-paralysis treatment with masitinib ameliorates peripheral nerve pathology driven by macrophages, mast cells and neutrophils in an inherited model of ALS,” by Emiliano Trías, PhD, a researcher at the Institut Pasteur de Montevideo in Uruguay, during the 2019 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, which took place April 13–17 in Orlando.

Masitinib is an orally administered therapy that was designed to target and block the activity of immune system cells, such as mast cells and macrophages, which are responsible for triggering inflammatory processes known to contribute to the development and progression of several neurological diseases.

Prior studies have shown that mast cells can infiltrate into the skeletal muscles of ALS patients to a significantly greater degree than in healthy individuals, suggesting that these immune cells may contribute to the disease’s underlying inflammatory process. Supported by these findings, researchers believe that inhibiting these inflammatory processes with therapies such as masitinib may reduce symptoms associated with ALS and other central nervous system diseases.

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More recent studies have demonstrated that masitinib can efficiently target the mechanisms leading to neurological inflammation in a model of inherited ALS.

Masitinib was found to specifically target the CSF1-IL34/CSF1R and SCF/c-Kit signaling pathways, which are important for the normal activity of different types of cells, including macrophages, neutrophils, Schwann cells, and mast cells. These four subtypes are involved in neurological inflammation and nerve cell damage in ALS. Also, masitinib was found to have a significant neuroprotective effect on the peripheral nervous system by reducing the accumulation of the inflammatory mast cells and macrophages in SOD1-driven ALS.

“These findings provide a new and complementary mechanism of action for masitinib that may explain its beneficial effects in ALS,” Luis Barbeito, PhD, head of the Neurodegeneration Laboratory at the Institut Pasteur in Montevideo and senior author of the study, said in a press release. “For the first time we have revealed the underlying cellular interplay and mechanism that masitinib targets in the peripheral nervous system.”

In previous studies, masitinib was shown to significantly prevent the accumulation of mast cells and neutrophils in the muscles of rats that had ALS due to SOD1 mutations — muscles already paralyzed from peripheral nerve damage. This was accompanied by significantly slower progression of nerve damage and motor deficits. Also, masitinib treatment prevented structural changes in Schwann cells —  which are responsible for producing the protective myelin sheath around nerve cells — and significantly prolonged the rats’ survival.

Collectively, the preclinical data indicate that masitinib can effectively target and prevent independent mechanisms in the brain and spinal cord which are known to promote ALS progression.

Results from a previous Phase 3 clinical study (NCT02588677) have shown promising therapeutic effects of masitinib in many patients with ALS, including a reduction in the deterioration rate of motor functions.

AB Science is now preparing to launch a new Phase 3 clinical trial (NCT03127267) to explore the safety and efficacy of this experimental therapy when used in combination with Rilutek (riluzole) in approximately 495 patients with familial or sporadic ALS. Find more information about the trial here.