Journal of Asthma and Allergy (Jun 2022)
Efficacy and Safety of Masitinib in Corticosteroid-Dependent Severe Asthma: A Randomized Placebo-Controlled Trial
Abstract
Lavinia Davidescu,1 Grigoriy Ursol,2 Oleksii Korzh,3 Vikranth Deshmukh,4 Lesia Kuryk,5 Monja-Marie Nortje,6 Olga Godlevska,3 Gilles Devouassoux,7 Eduard Khodosh,8 Elliot Israel,9,10 Alain Moussy,11 Colin D Mansfield,11 Olivier Hermine,11– 13 Pascal Chanez14 1Department of Pulmonology, University of Oradea, Oradea, Romania; 2Medical and Diagnostic Center of Private Enterprise of Private Production Company “Acinus”, Kropyvnytskyi, Ukraine; 3Department of General Practice - Family Medicine, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine; 4Department of Pulmonary Medicine, Respira Hospital, Nagpur, Maharashtra, India; 5National Institute of Phthisiology and Pulmonology Named After F.G. Yanovsky of National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine; 6Moriana Clinical Research, Brandfort, South Africa; 7Department of Pulmonology, Hôpital de la Croix Rousse, GHN, HCL and Université Claude Bernard Lyon 1, Lyon, France; 8Department of Pulmonology, Municipal Nonprofit Enterprise, City Clinical Hospital #13, Kharkiv, Ukraine; 9Harvard Medical School, Boston, MA, USA; 10Division of Pulmonary and Critical Care Medicine and Allergy and Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 11AB Science, Paris, France; 12Imagine Institute, INSERM UMR 1163 and CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France; 13Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 14Clinique des Bronches, Allergie et Sommeil, APHM Hôpital Nord, C2VN Center INSERM INRAE UMR1062, Aix-Marseille Université, Marseille, FranceCorrespondence: Pascal Chanez, Clinique des Bronches, Allergie et Sommeil, APHM Hôpital Nord, C2VN Center INSERM INRAE UMR1062, Aix-Marseille Université, Marseille, France, Tel +33 6 50 71 07 05, Email [email protected]: Masitinib is an oral tyrosine kinase inhibitor that selectively targets mast cell activity and platelet-derived growth factor receptor (PDGFR) signaling, both of which are implicated in various mechanisms of asthma pathogenesis.Objective: Assessment of masitinib as an add-on to standard maintenance therapy as compared with placebo in the treatment of oral corticosteroid-dependent severe asthma.Methods: We conducted a randomized (2:1), placebo-controlled study of masitinib (6 mg/kg/d) in adults with severe asthma uncontrolled by high dose inhaled corticosteroids and long-acting beta-adrenoreceptor agonists plus oral corticosteroids (OCS) (≥ 7.5 mg/d). No minimum baseline blood eosinophil count was specified. Following a protocol amendment, the primary endpoint was reduction of annualized severe asthma exacerbation rate adjusted for the overall time on treatment (SAER). Subgroup analysis according to yearly cumulative OCS intake was also performed, a higher OCS dose indicating more severe asthma that is harder to control.Results: Following an average exposure of approximately 13 months, masitinib (n = 240) reduced the SAER by 35% relative to placebo (n = 115) (rate ratio (RR) 0.65 (95% CI [0.47– 0.90]; P = 0.010)). For patients with eosinophil ≥ 150 cell/μL, masitinib (n = 181) reduced SAER by 38% relative to placebo (n = 87); RR 0.62 (95% CI [0.42– 0.91]; P = 0.016). Benefit of masitinib was shown to increase in the most severely affected patients (OCS intake of > 1000 mg/year), with a significant (P < 0.01) reduction in SAER of 50%– 70%. Safety was consistent with the known masitinib profile.Conclusion: Orally administered masitinib reduces the risk of asthma exacerbations in severe asthma patients, with an acceptable safety profile. Masitinib may potentially provide a new treatment option for oral corticosteroid-dependent severe asthma.Keywords: asthma clinical trials, asthma medication, mast cells, tyrosine kinases, severe asthma
