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Managing mast cells with masitinib
PARIS—AB Science SA is rounding out the third quarter of 2016 with encouraging preclinical study results for masitinib, its orally administered tyrosine kinase inhibitor. The compound was found to have a neuroprotective effect in rat models of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), slowing disease progression and prolonging survival.
The results of this work were published in the paper “Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis,” which appeared in the Journal of Neuroinflammation.
Masitinib is an orally administered tyrosine kinase inhibitor that targets mast cells and macrophages by inhibiting a limited number of kinases. The compound has applications in a variety of cancers, inflammatory diseases and even some central nervous system conditions. In cancer, the immunotherapy effect of masitinib, alone or in combination with chemotherapy, can affect survival. In terms of inflammatory and central nervous system diseases, the compound’s activity on mast cells and microglia—and by extension inhibition of the activation of the inflammatory process—can impact the symptoms and degeneration associated with such diseases. Masitinib treatment has also resulted in positive interim results in an ongoing Phase 2/3 study comparing the efficacy and safety of masitinib in combination with riluzole versus placebo in combination with riluzole in ALS patients.
Olivier Hermine, president of the Scientific Committee of AB Science, said, “The positioning of masitinib in ALS is based on a novel mechanism of action inhibiting microglial cells without depleting them. It was the first time that a drug was tested in clinical trial aimed at this novel target, and this may explain why the interim analysis was positive whereas previous studies failed in this indication.”
Research has shown that in animal models of ALS, the proliferation and accumulation of microglial cells (microgliosis), particularly the emergence of aberrant glial cells, is a major neuropathological feature. The CSF1/CSF1R signaling pathway is responsible for regulating this disease mechanism.
Masitinib is a potent inhibitor of CSF1R-dependent cell proliferation (IC50 90 nM). By targeting the CSF1/CSF1R signaling pathway, masitinib can inhibit glial cell proliferation, including aberrant microglial cells strongly associated with motor neuron degeneration, and also retard microglia cell migration. Treatment with masitinib, initiated 7 days after paralysis onset, was found to prolong post-paralysis survival by 40 percent, with respect to the control group.
As noted in the paper, “In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.”
“These findings demonstrate an unprecedented protective effect for masitinib in ALS rat models with respect to other studies found in the scientific literature,” Prof. Luis Barbeito, head of the Neurodegeneration Laboratory at the Institut Pasteur, said in a press release. “In particular, masitinib was protective when administered after onset of overt paralysis, a model that closely simulates the clinical condition of ALS patients and therefore better represents their therapeutic needs.”
AB Science plans to file a registration dossier regarding masitinib in ALS as it moves to secure marketing authorization.
In related news, the company announced on July 11 that the U.S. Food and Drug Administration has granted a Single Patient IND for Compassionate Use of masitinib for a patient with ALS. The request for single compassionate use was accepted based on a briefing document from AB Science detailing the interim results of its ongoing Phase 2/3 study of masitinib in ALS. AB Science noted in the press release that the company “has indicated that it is willing to accommodate as many such requests as possible with masitinib in ALS until a clinical study can be initiated with masitinib in the USA or until masitinib is registered in amyotrophic lateral sclerosis.”