Department of Medical and Molecular Genetics, 8th Floor Tower Wing, Guy's Hospital, King's College London, Great Maze Pond, London, SE1 9RT, UK.
Drugs. 2014 Mar;74(4):415-22. doi: 10.1007/s40265-014-0193-9.
The development of small-molecule inhibitors of inflammatory cascade signaling kinases offers a potential approach to treating rheumatoid arthritis (RA). Spleen tyrosine kinase is one such tyrosine kinase. Recent research efforts have focussed on the development and testing of a spleen tyrosine kinase inhibitor, fostamatinib. We reviewed the results of the clinical trials of fostamatinib in RA with the aim of outlining its clinical efficacy and the nature and frequency of its main adverse events. To date, this drug has been evaluated in over 3,200 RA patients enrolled in three phase II, one phase IIb and three phase III trials. These studies showed fostamatinib was effective. In four trials in which patients received 100 mg twice daily, fostamatinib reduced inflammatory synovitis; the relative risks of achieving American College of Rheumatology Responder rates compared with placebo in the combined studies ranged from 1.6 for 20 % of responders to 3.7 for 70 % of responders. There was a similar relative risk of achieving a clinically meaningful reduction in disability of 1.6 for the chance of patients achieving a reduction in health assessment questionnaire scores of 0.22 or more. Three of the trials examined the impact of fostamatinib on erosive radiographic damage using changes in the modified total Sharp score. None of them provided any evidence for a significant effect of fostamatinib on erosive damage over 6 months. All the trials included descriptions of adverse events. Hypertension was common, involving over 40 % of patients treated. Other common adverse events included diarrhoea, neutropenia and increases in hepatic enzyme levels. Some patients developed infections. On the conclusion of the phase III trials, one of the main pharmaceutical sponsors decided not to further develop fostamatinib for RA.
小分子抑制剂炎症级联信号激酶的开发为治疗类风湿关节炎（RA）提供了一种潜在的方法。脾酪氨酸激酶就是这样一种酪氨酸激酶。最近的研究重点是开发和测试脾酪氨酸激酶抑制剂福他替尼。我们综述了福他替尼治疗 RA 的临床试验结果，旨在概述其临床疗效及其主要不良事件的性质和频率。迄今为止，该药物已在超过 3200 名 RA 患者中进行了评估，这些患者参加了三项 II 期、一项 IIb 期和三项 III 期试验。这些研究表明福他替尼是有效的。在四项接受 100mg 每日两次治疗的患者试验中，福他替尼减轻了炎症性滑膜炎；与安慰剂相比，联合研究中达到美国风湿病学会应答率的相对风险范围为 1.6（应答率为 20%）至 3.7（应答率为 70%）。在机会上，患者达到健康评估问卷评分降低 0.22 或更多的临床意义上的残疾减少的相对风险也相似，为 1.6。三项试验检查了福他替尼对使用改良总 Sharp 评分变化的侵蚀性放射学损害的影响。它们都没有提供任何证据表明福他替尼对侵蚀性损害有显著影响超过 6 个月。所有试验均包括不良事件描述。高血压很常见，涉及超过 40%的治疗患者。其他常见的不良事件包括腹泻、中性粒细胞减少症和肝酶水平升高。一些患者发生了感染。在 III 期试验结束时，主要制药赞助商之一决定不再进一步开发福他替尼治疗 RA。
