Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.
Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study.
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DOI：
10.1186/ar2740
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发表时间：
2009
影响因子：
4.9
通讯作者：
Sibilia J
中科院分区：
文献类型：
--
作者：
Tebib J;Mariette X;Bourgeois P;Flipo RM;Gaudin P;Le Loët X;Gineste P;Guy L;Mansfield CD;Moussy A;Dubreuil P;Hermine O;Sibilia J
由于目前对患有活动性类风湿关节炎（RA）的患者的治疗选择仍然不足，特别是对于那些对疾病缓解抗风湿药物（DMARD）无反应的患者，需要新的和改进的药物。本研究评价了马赛替尼（AB 1010），一种有效的和选择性的c-KIT蛋白酪氨酸激酶抑制剂，在DMARD难治性RA的单药治疗中的安全性和有效性。这是一项多中心、非对照、开放标签、随机化、剂量范围探索、IIa期试验。马赛替尼口服给药43例患者谁没有充分的反应DMARD，在初始随机剂量水平为3和6毫克/公斤每天超过12周的时间。允许根据耐受性和缓解标准调整剂量。通过美国风湿病学会20%/50%/70%改善标准（ACR 20/50/70）反应、使用28个关节计数的疾病活动评分（DAS 28）、RA改善指数（ACRn）和C-反应蛋白（CRP）改善（相对于第12周基线）评估疗效。所有疗效终点均观察到改善，包括ACR 20/50/70评分分别为54%、26%和8%，约一半人群的CRP水平降低超过50%。这种改善在整个扩展期（> 84周）是可持续的，并且也独立于初始DMARD抗性（抗肿瘤坏死因子-α和/或甲氨蝶呤）。相对较高的患者退出率（37%）需要使用末次观察值结转（LOCF）数据插补。不良事件的发生率很高（95%），尽管大多数为轻度或中度严重程度，治疗12周后观察到频率显著下降。报告了2起非致死性严重不良事件。剂量反应分析初步表明，基于效价和耐受性趋势，每日两次经口给药的初始剂量水平为6.0 mg/kg/天是最合适的。马赛替尼治疗改善了DMARD难治性活动性RA。在治疗的前12周期间，大多数轻度至中度副作用的初始高发生率之后，马赛替尼似乎通常耐受良好。这与可持续疗效反应的证据一起表明马赛替尼适合于长期治疗方案。由于这是马赛替尼在非肿瘤病理学中的第一项研究，因此观察到的相对较高的患者退出率可以部分归因于对不良事件的高度谨慎反应。有足够的令人信服的证据证明需要进一步进行安慰剂对照研究。ClinicalTrials.gov NCT 00831922。
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. 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. 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. 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. ClinicalTrials.gov NCT00831922.
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