Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis
Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis
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DOI：
10.1056/nejmoa1112168
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发表时间：
2012-08-16
影响因子：
158.5
通讯作者：
Niezychowski, Wojciech
中科院分区：
文献类型：
--
作者：
Sandborn, William J.;Ghosh, Subrata;Niezychowski, Wojciech
溃疡性结肠炎是一种慢性结肠炎性疾病，目前的治疗方法并不普遍有效。另一种治疗方法可能是托法替尼(Tofacitinib，CP-690,550)，这是一种口服Janus激酶1、2和3的抑制剂，在体外对激酶1和3具有功能特异性，有望阻断涉及包含伽马链的细胞因子的信号转导，包括白细胞介素2、4、7、9、15和21。这些细胞因子对淋巴细胞的激活、功能和增殖是不可或缺的。方法在一项双盲、安慰剂对照的2期试验中，我们评估了托法替尼对194例成人中重度活动期溃疡性结肠炎的疗效。患者被随机分配接受托法替尼0.5毫克、3毫克、10毫克或15毫克的剂量或安慰剂，每天两次，持续8周。主要结果是8周时的临床反应，定义为溃疡性结肠炎活动度的Mayo评分系统(可能的分数从0到12，分数越高，表示病情越严重)的评分比基线绝对下降3分或更多，相对下降30%或更多，同时直肠出血评分下降1分或更多，或绝对直肠出血评分0或1。结果8周时的主要临床反应发生在32%，48%，61%，78%的患者服用托法替尼0.5 mg(P=0.39)，3 mg(P=0.55)、10 mg(P=0.10)和15 mg(P<；0.001)，而接受安慰剂的患者中这一比例为42%。服用托法替尼0.5 mg(P=0.76)、3 mg(P=0.001)、10 mg(P<；0.001)和15 mg(P<；0.001)的患者在8周后临床缓解率分别为13%、33%、48%和41%，而安慰剂组为10%。低密度脂蛋白胆固醇和高密度脂蛋白胆固醇均呈剂量依赖性增加。3例接受托法替尼治疗的患者中性粒细胞绝对值低于1500。结论托法替尼治疗中重度活动期溃疡性结肠炎的患者比接受安慰剂治疗的患者更有可能出现临床反应和缓解。(资金由辉瑞提供；ClinicalTrials.gov编号，NCT00787202。)
BackgroundUlcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.MethodsIn a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.ResultsThe primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.39), 3 mg (P = 0.55), 10 mg (P = 0.10), and 15 mg (P < 0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score 1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.76), 3 mg (P = 0.01), 10 mg (P < 0.001), and 15 mg (P < 0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.ConclusionsPatients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.)