Indolent systemic mastocytosis (ISM) is a hematological disease characterized by an abnormal number and activation of mast cells in the bone marrow and other organs. The disease if characterized by multiple symptoms that are disabling and can in some cases be life-threatening. Symptoms associated ISM are predominantly associated with neurological disorders (depression, fatigue, cognitive impairment, headache), skin disorders (pruritus, skin lesions), flushing and gastro-intestinal disorders.
Masitinib’s anti-mast cell properties appear particularly well-adapted to the treatment of indolent systemic mastocytosis. A reduction of mast cell activity is generated via its inhibitory action on wild-type c-Kit, Lyn and Fyn tyrosine kinases. It is through this multifaceted mechanism of action, a feature not seen in other c-Kit inhibitors, that masitinib can elicit a response in patients of both positive and negative D816V c-Kit mutation status.
In mast cell activation syndrome (MCAS), since masitinib has been designed to be a potent inhibitor of mast cell activation (through its action against wild-type c-Kit, Lyn and Fyn tyrosine kinases), it is uniquely well-suited for the treatment of severe MCAS, unlike other c-Kit tyrosine kinase inhibitors that typically target specific c-Kit mutations that are associated with systemic mastocytosis.
Severe asthma that remains uncontrolled despite daily treatment with high dose oral corticosteroid represents the most severe form of asthma. The quality of life of these patients is severely impacted, with major reduction in lung function, restrictions on activities of daily living, and high risk of asthma exacerbation.
There is a growing body of evidence that strongly implicates mast cell activity in the pathophysiology of severe asthma. Mast cells are a persistent presence in the airway epithelium of asthma patients and their presence correlates with disease severity, asthma phenotype, and airway hyperresponsiveness. Proinflammatory cytokines and other mediators secreted by mast cells affect airway smooth muscle function, bronchoconstriction, inflammation, and airway remodeling.
Masitinib is a first in class oral drug in severe asthma, selectively targeting mast cells through inhibition of tyrosine kinases c-Kit, LYN and FYN. Masitinib is also a potent inhibitor of PDGFR signaling, which is associated with pathologic airway smooth muscle cell proliferation and airway remodeling.
In preclinical models of asthma, masitinib significantly decreased airway hyper-responsiveness and pulmonary eosinophil recruitment in mice, and improved airway inflammation and lung mechanics in cats1.
Through targeting both mast cell-related asthma pathophysiology and PDGFR-related airway remodeling, masitinib’s dual action seems particularly well-adapted to the treatment of severe uncontrolled asthma.