Chronic inflammatory disorders are linked to a deregulation of the immune system, leading to organ infiltration of many inflammatory cells (e.g. mast cell, macrophage, lymphocyte, granulocytes, dendritic cells). It has been widely demonstrated that kinases such as c-Kit, Lyn and PDGFR, all key targets of masitinib, are strongly implicated in the activation of inflammatory cells and fibrous tissue remodeling.

It has been shown that mast cells play a key role in the organization and activation of the inflammatory cascade, not only by participating directly in the tissue destruction but also by recruiting and activating other immune cells such as macrophages and lymphocytes. The kinases of c-Kit, Lyn and Fyn are critical kinases for mast cell function. Therefore, therapeutic agents able to inhibit these kinases can modulate the activity of mast cells, subsequently leading to a reduction in tissue inflammation and consequently clinical benefits. In-vitro and animal studies have now largely demonstrated that masitinib is a potent inhibitor of these kinases, which makes masitinib a promising drug candidate in diseases where chronic inflammation plays a central role.

Masitinib mechanism of action in systemic mastocytosis and mast cell activation syndrome

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.