RESEARCH - Masitinib in the treatment of active RA: results of a multicenter, open-label, dose-ranging, Phase IIa study

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Arthritis Research & Therapy 2009, 11:R95doi:10.1186/ar2740

Published: 23 June 2009

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 , Gineste7 , t

Guy7 , Colin D Mansfield7 , Alain Moussy7 , Patrice Dubreuil7,8,9 ,

Olivier Hermine7,10 and Sibilia11

1Service de Rhumatologie, Centre Hospitalier Lyon-Sud, 765 chemin du

Grand-Revoyet, 69495 Pierre-Bénite, France

2Service de Rhumatologie, Hôpital Bicêtre, Assistance

Publique-Hôpitaux de Paris, 78 rue du Général Leclerc, 94275 Le

Kremlin-Bicêtre Cedex, France

3Service de Rhumatologie, Groupe Hospitalier Pitié Salpétrière, 83 bd

de l'Hôpital, 75013 Paris, France

4Service de Rhumatologie, Hôpital Salengro, Rue du Professeur

Emile Laine, 59037 Lille cedex, France

5Service de Rhumatologie, CHU Hôpital Sud – GREPI-TIMC-IMAG UMR CNRS

5525, Avenue de Kimberley, 38434 Échirolles, France

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

76230 Rouen, France

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

8Inserm U891, Centre de Recherche en Cancérologie de Marseille,

Molecular and Functional Hematopoiesis, Centre de référence des

mastocytoses, 27 Bd Leï roure, 13009 Marseille, France

9Institut Paoli-Calmettes, Marseille, France; Université Méditerranée,

27 Bd Leï roure, 13009 Marseille, France

10CNRS UMR 8147, Service d'hématologie et centre de référence des

mastocytoses, Hôpital Necker, 149 Rue de Sèvres, 75743 Paris, France

11Service de Rhumatologie, Hôpital de Hautepierre, Avenue Molière – BP

49 – 67098 Strasbourg, France

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.

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http://arthritis-research.com/content/11/3/R95

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