Efficacy and Safety of Masitinib in Corticosteroid-Dependent Severe Asthma: A Randomized Placebo-Controlled Trial

Abstract

Background

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

Abbreviations

ACQ-7, 7-question version of the Asthma Control Questionnaire; AE, adverse event; AQLQ, Asthma Quality of Life Questionnaire score; EudraCT, European Clinical Trials Database; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GCP, Good Clinical Practice; ICS, inhaled corticosteroids; IL, interleukin; ITT, intention-to-treat; LABA, long-acting beta-adrenoreceptor agonists; MMRM, multivariate mixed model of repeated measures; OCS, oral corticosteroids; SAE, serious non-fatal adverse event; SAER, severe asthma exacerbation rate (annualized rate adjusted for the overall time on treatment).

Clinical Trial Registration

Study AB07015 was registered to the European Clinical Trials Database (EudraCT #2010-020803-63) prior to enrollment of the first patient on 26 January, 2011. For example, the record for the Bulgarian national competent authority (Bulgarian Drug Agency) was first entered in the EudraCT database on 20th January 2011, and the record for the Hungary national competent authority (National Institute of Pharmacy) was first entered in the EudraCT database on 6th December 2010, at least 2 months before the first participant was randomized to the study (9th February 2011). Registration to the ClinicalTrials.gov database (#NCT01449162) occurred about 8 months later, following recruitment of 6% (27/419) of the study population.

Data Sharing Statement

Masitinib is under clinical investigation and has not yet been approved in any sought-after indication by any health authority worldwide. As such, there is no plan for data-sharing at this point in time.

Ethics Approval and Informed Consent

Study AB07015 was conducted according to the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and national regulations. An independent data monitoring committee periodically reviewed blinded patient safety and efficacy data. Trial conduct was overseen by local ethics committees, who approved the study protocol and amendments. All patients provided written informed consent before trial participation.

Consent for Publication

All authors have read and approved the manuscript, which they have collectively written in its entirety.

Acknowledgements

We are grateful to the study participants and thank the AB07015 Study Group investigators (Supplementary Table 1).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

AM, OH and CDM are employees and shareholders of AB Science. AM reports patents WO2004/014903 issued to AB Science, PCT/EP2020/084251 pending to AB Science, US9078894B2 issued to AB Science, WO2003002106A2 issued to AB Science. PC reports grants/research support from Almirall, Boston Scientific, Boehringer Ingelheim, Centocor, GlaxoSmithKline, AstraZeneca, Novartis, and Teva; honoraria or consultation fees from Almirall, Boehringer Ingelheim, Johnson & Johnson, GlaxoSmithKline, Merck Sharp & Dohme, AstraZeneca, Novartis, Teva, Chiesi, Sanofi, AMU, SNCF, Centocor, Boston Scientific and ALK; served on advisory committees for Almirall, Boehringer Ingelheim, Johnson & Johnson, GlaxoSmithKline, AstraZeneca, Novartis, Teva, Chiesi, Schering Plough, and Sanofi. EI reports personal fees, non-financial support from AB Science, during the conduct of the study; and grants from AstraZeneca (Destination), Avillion - Mandala/Denali, Circassia, Gossamer Bio, NIH-SARP4, Novartis, PCORI; Personal fees for royalties or licenses from Wolters Kluwer; Consulting fees from Allergy and Asthma Network, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Avillion, Biometry, Equillium, Genentech, GlaxoSmithKline, Merck, NHLBI (CONNECTS), Novartis, Pneuma Respiratory, PPS Health, Regeneron, Sanofi Genzyme, Sienna Biopharmaceuticals, TEVA, Cowen; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for Westchester Medical Center, Yale School of Medicine. Payment for expert testimony: Cambridge Medical Experts, Danaher Lagnese, SettlePou; Non-financial supports from Circassia (Equipment for PCORI-PREPARE Study), Genentech (Study Drug for NIH-Funded Study (PARK)), TEVA (Study Drug for PCORI-PREPARE Study), GSK (Background study medication for NIH PrecISE Trial); Data Safety Monitoring Board or Advisory Board for Novartis; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for NAEPP: National Asthma Education Prevention Program (Member, Coordinating Committee; Unpaid) Stock or stock options: Vorso (Stock Options; Unpaid). All remaining authors have no competing interests in this work.

Additional information

Funding

AB Science, Paris, France. Masitinib is under clinical development by the study funder, AB Science.