title: Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00831922.
authors: Service de Rhumatologie, Centre Hospitalier Lyon-Sud, 765 chemin du Grand-Revoyet, 69495 Pierre-Bénite, France. jacques.tebib@chu-lyon.fr.
authors: Jacques
authors: J
authors: Tebib
authors: Xavier
authors: X
authors: Mariette
authors: Pierre
authors: P
authors: Bourgeois
authors: René-Marc
authors: RM
authors: Flipo
authors: Philippe
authors: P
authors: Gaudin
authors: Xavier
authors: X
authors: Le Loët
authors: Paul
authors: P
authors: Gineste
authors: Laurent
authors: L
authors: Guy
authors: Colin D
authors: CD
authors: Mansfield
authors: Alain
authors: A
authors: Moussy
authors: Patrice
authors: P
authors: Dubreuil
authors: Olivier
authors: O
authors: Hermine
authors: Jean
authors: J
authors: Sibilia
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011446:Prospective Studies; D011725:Pyridines; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles; C526575:masitinib