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Open Access Highly Accessed Research article

Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study

Jacques Tebib1*, Xavier Mariette2, Pierre Bourgeois3, René-Marc Flipo4, Philippe Gaudin5, Xavier Le Loët6, Paul Gineste7, Laurent Guy7, Colin D Mansfield7, Alain Moussy7, Patrice Dubreuil789, Olivier Hermine107* and Jean Sibilia11

Author Affiliations

1 Service de Rhumatologie, Centre Hospitalier Lyon-Sud, 765 chemin du Grand-Revoyet, 69495 Pierre-Bénite, France

2 Service de Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France

3 Service de Rhumatologie, Groupe Hospitalier Pitié Salpétrière, 83 bd de l'Hôpital, 75013 Paris, France

4 Service de Rhumatologie, Hôpital Roger Salengro, Rue du Professeur Emile Laine, 59037 Lille cedex, France

5 Service de Rhumatologie, CHU Hôpital Sud – GREPI-TIMC-IMAG UMR CNRS 5525, Avenue de Kimberley, 38434 Échirolles, France

6 Service de Rhumatologie, CHU Hôpitaux de Rouen, 1 rue de Germont, 76230 Rouen, France

7 AB Science, S.A., 3 avenue Georges V, 75008 Paris, France

8 Inserm U891, Centre de Recherche en Cancérologie de Marseille, Molecular and Functional Hematopoiesis, Centre de référence des mastocytoses, 27 Bd Leï roure, 13009 Marseille, France

9 Institut Paoli-Calmettes, Marseille, France; Université Méditerranée, 27 Bd Leï roure, 13009 Marseille, France

10 CNRS UMR 8147, Service d'hématologie et centre de référence des mastocytoses, Hôpital Necker, 149 Rue de Sèvres, 75743 Paris, France

11 Service de Rhumatologie, Hôpital de Hautepierre, Avenue Molière – BP 49 – 67098 Strasbourg, France

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Arthritis Research & Therapy 2009, 11:R95  doi:10.1186/ar2740


See related editorial by Walker, http://arthritis-research.com/content/11/4/120

Published: 23 June 2009

Abstract

Introduction

Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.

Methods

This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.

Results

Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.

Conclusions

Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.

Trial registration

ClinicalTrials.gov NCT00831922.