Masitinib in Inflammatory Diseases

The severity of asthma can be graded from mild intermittent disease, with little impact on everyday life, through to severe disease with permanent symptoms and serious limitation of normal activities.

Data suggests that mast cells are involved in allergic and anaphylactic reactions, playing an important role in hypersensitivity and inflammatory processes of the disease and also tissue remodeling of the airways.

Masitinib is currently investigated both in severe asthma uncontrolled by oral corticosteroids (OCS) and severe asthma uncontrolled by high dose inhaled corticosteroids (ICS).

Asthma uncontrolled by oral corticosteroid is the most severe form of asthma (step 5 of the GINA guidelines for asthma management) and represents a high unmet medical need. Quality-of-life for such patients is severely affected, with major reduction in lung function, restrictions on activities of daily living, frequent asthma exacerbations and greater risk of life-threatening asthma exacerbations.

The ability and effect of masitinib to inhibit mast cell function in asthma was explored in a classical murine model of allergic airway inflammation. The results showed a dose response effect of masitinib on mast cells recruitment in lung tissue.

Mast cells appear to play a central role in the pathogenesis and persistence of asthma, and thus in severe asthma uncontrolled by oral corticosteroids. There is a growing consensus that airway inflammation is a critical element in the pathogenesis of asthma, and that asthma is in fact a chronic inflammatory syndrome in which inflammation promotes airway hyperresponsiveness and airway obstruction. The growing awareness that these common features are important resulted in the current NAEP definition of asthma (National Asthma Education Program, 1991), which emphasizes that asthma is characterized by reversible obstruction and hyper- responsiveness of the airways with both of these physiological abnormalities occurring on a background of airway inflammation.

A classical view of the pathogenesis of the asthmatic inflammation is that, following the immunization phase and the development of an immune response, allergens initiate the inflammatory process by triggering IgE-bearing pulmonary mast cells. Mast cell activation leads to the release of multiple mediators which produce a localized allergic response, and subsequently, secrete various cytokines which then participate in the local recruitment and activation of other inflammatory cells such as eosinophils, basophils, T lymphocytes and mononuclear phagocytes. These recruited cells, in turn, contribute to the development of an inflammatory response, which may then become persistent, and thereby perpetuate the asthmatic symptoms.

Masitinib, by inhibiting mast cells activation is expected to show clinical benefits in patients with moderate to severe asthma and to be an alternative to ineffective corticosteroid therapy.

Summary of severe asthma clinical program with masitinib

Phase	Design	Population	Primary Target	Patient Target	IDMC recommandation	Study Status	Related publications
2a	Double-blind, placebo-controlled, parallel-group study	Patients with severe corticosteroid dependent asthma	Change from baseline in corticosteroids doses, after 4 months of treatment	44	NA	Study completed	Humbert, 2009
2/3	Prospective, double-blind, placebo-controlled, 2-parallel groups study	Patients with severe asthma uncontrolled with oral corticosteroids	Severe Asthma exacerbation rate adjusted on the available person-time (time to end of treatment)	420	Continuation of the study without resampling option (based on interim analysis and safety data)	Recruitment completed	–
3	Prospective, double-blind, placebo-controlled, 2-parallel groups study	Patients with severe asthma uncontrolled with high dose of inhaled corticosteroids and with elevated eosinophil levels	Severe Asthma exacerbation rate adjusted on the available person-time (time to end of treatment)	350	Continuation of the study (based on safety data)	Recruitment completed

Phase

Design

Population

Primary Target

Patient Target

IDMC recommandation

Study Status

Related publications

Double-blind, placebo-controlled, parallel-group study

Patients with severe corticosteroid dependent asthma

Change from baseline in corticosteroids doses, after

4 months of treatment

Study completed

Humbert, 2009

2/3

Prospective, double-blind, placebo-controlled, 2-parallel groups study

Patients with severe asthma uncontrolled with oral corticosteroids

Severe Asthma exacerbation rate adjusted on the available person-time (time to end of treatment)

420

Continuation of the study without resampling option (based on interim analysis and safety data)

Recruitment completed

–

Prospective, double-blind, placebo-controlled, 2-parallel groups study

Patients with severe asthma uncontrolled with high dose of inhaled corticosteroids and with elevated eosinophil levels

Severe Asthma exacerbation rate adjusted on the available person-time (time to end of treatment)

350

Continuation of the study (based on safety data)

Recruitment completed

Phase 2a proof of concept

Clinical phase 2a proof of concept with masitinib in asthma supported the development of masitinib in severe asthma uncontrolled with corticosteroids. In this phase 2a study, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo at 16 weeks of treatment (median reduction of 78% and 57% in the masitinib and placebo arms, respectively). However, when focusing on the truly dependent corticosteroids asthma patients, meaning patients receiving > 15mg equivalent prednisone per day, a significant difference was observed. In this subgroup of patients, doses of corticosteroids were reduced by 52% in masitinib treated patients compared to 28% in placebo treated patients. In parallel, the number of patients experiencing at least one exacerbation during the study period was 42.4% and 54.5% in the masitinib-treated and placebo groups, respectively. Additionally, an improved asthma control was observed in masitinib- treated patients, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 vs 0.43 unit in the placebo arm.

Phase 3 studies

First phase 3 study

AB Science launched a phase 3 study to assess the safety and efficacy of masitinib in severe asthma uncontrolled by oral corticosteroids.

The Independent Data Safety and Monitoring Committee (IDMC) has, on each occasion, recommended the continuation of this phase 3 study based on the analysis of the safety data.

In February 2017, an interim analysis was performed and the IDMC did not request implementation of the protocol resampling option.

Recruitment was completed with 420 enrolled patients.

Second phase 3 study

AB Science has initiated a second pivotal phase 3 study in asthma uncontrolled by high-dose inhaled corticosteroid and with elevated eosinophil levels.

This second study has been launched on the basis of preclinical data from mice and cats that showed masitinib can reduce eosinophil levels in the context of asthma

[Lee-Fowler, 2012].This effect in eosinophil levels coupled with the existing clinical data of masitinib in severe asthma justifies investigation of the therapeutic use of masitinib in this subpopulation.

The IDMC has, on each occasion, recommended the continuation of this phase 3 study based on the analysis of the safety data.

Recruitment was completed with 347 enrolled patients.

Asthma uncontrolled by oral corticosteroid represents the most severe form of asthma and represents a high unmet medical need. The quality of life of these patients is severely impacted, with major reduction in lung function, restrictions on activities of daily living, work absenteeism, night-time awakening several times a week, frequent exacerbations and greater risk of life-threatening asthma exacerbations. The target population in adult patients is estimated at 70,000 in the USA and in the EU.

The patient population in asthma uncontrolled by high-dose inhaled corticosteroid plus long-acting beta-agonists (LABAs) and with elevated eosinophil level is much broader and is estimated to affect 1,500,000 adults in the USA and Europe.

Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics.
Humbert M, de Blay F, Garcia G, Prud’homme A, Leroyer C, Magnan A, Tunon-de-Lara JM, Pison C, Aubier M, Charpin D, Vachier I, Purohit A, Gineste P, Bader T, Moussy A, Hermine O, Chanez P.
Allergy. 2009 Aug;64(8):1194-201. doi: 10.1111/j.1398-9995.2009.02122.x.

The tyrosine kinase inhibitor masitinib blunts airway inflammation and improves associated lung mechanics in a feline model of chronic allergic asthma.
Lee-Fowler TM, Guntur V, Dodam J, Cohn LA, DeClue AE, Reinero CR. Int Arch Allergy Immunol. 2012;158(4):369-74.

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Masitinib in Inflammatory Diseases

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