Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes no), baseline corticosteroid use (yes no), and baseline disease activity (modified Mayo score [MMS]; 4–6 7–9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with , and , respectively. Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. Arena Pharmaceuticals.

中文翻译：

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艾曲莫德作为溃疡性结肠炎的诱导和维持治疗 (ELEVATE)：两项随机、双盲、安慰剂对照 3 期研究

Etrasimod 是一种每日一次、口服的 1-磷酸鞘氨醇 (S1P) 受体调节剂，可选择性激活 S1P 受体亚型 1、4 和 5，且对 S1P 没有可检测到的活性，目前正在开发用于治疗免疫介导的疾病。包括溃疡性结肠炎。在这两项 3 期试验中，我们旨在评估 etrasimod 对中度至重度活动性溃疡性结肠炎成年患者的安全性和有效性。在两项独立随机、多中心、双盲、安慰剂对照 3 期试验中，ELEVATE UC 52 和 ELEVATE UC 12 患者患有活动性中度至重度溃疡性结肠炎，并且对至少一种药物反应不足或丧失反应或不耐受批准的溃疡性结肠炎治疗被随机分配 (2:1) 至每日一次口服依曲莫德 2 mg 或安慰剂。ELEVATE UC 52 的患者来自 40 个国家的 315 个中心。ELEVATE UC 12 的患者来自 37 个国家的 407 个中心。随机分组根据之前接受过生物制品或 Janus 激酶抑制剂治疗（是否）、基线皮质类固醇使用情况（是否）和基线疾病活动度（改良 Mayo 评分 [MMS]；4-6 7-9）进行分层。ELEVATE UC 52 包括 12 周的诱导期和随后的 40 周的维持期，采用治疗贯穿设计。ELEVATE UC 12 在第 12 周独立评估诱导。主要疗效终点是 ELEVATE UC 52 中第 12 周和第 52 周以及 ELEVATE UC 12 中第 12 周临床缓解的患者比例。两项试验均评估了安全性。ELEVATE UC 52 和 ELEVATE UC 12 分别注册为 、 和 。ELEVATE UC 52 患者于2019年6月13日至2021年1月28日期间入组。ELEVATE UC 12 患者于2020年9月15日至2021年8月12日期间入组。ELEVATE UC 52 和 ELEVATE UC 12 筛选了821名患者和606名患者分别有 433 名和 354 名患者随后接受随机分配。ELEVATE UC 52 的完整分析集包括 289 名分配至 etrasimod 的患者和 144 名分配至安慰剂的患者。在 ELEVATE UC 12 中，238 名患者被分配至依曲莫德组，116 名患者被分配至安慰剂组。在 ELEVATE UC 52 中，在 12 周诱导期结束时，与安慰剂组患者相比，依曲莫德组中获得临床缓解的患者比例显着更高（274 名患者中的 74 名 [27%]，135 名患者中的 10 名 [7%]）患者；p<0·0001）和第52周（274名患者中的88名[32%]，135名患者中的9名[7%]；p<0·0001）。在 ELEVATE UC 12 中，在 12 周诱导期结束时，依曲莫德组 222 名患者中有 55 名 (25%) 获得临床缓解，而安慰剂组 112 名患者中有 17 名 (15%) 出现临床缓解 (p=0·026 ）。在 ELEVATE UC 52 中，etrasimod 组 289 名患者中有 206 名患者（71%）报告了不良事件，安慰剂组 144 名患者中有 81 名患者（56%）报告了不良事件，etrasimod 组 238 名患者中有 112 名患者（47%）报告了不良事件，安慰剂组 54 名患者报告了不良事件。 ELEVATE UC 12 安慰剂组的 116 名患者中，有 47% 的患者出现这种情况。没有报告死亡或恶性肿瘤。艾曲莫德作为中度至重度活动性溃疡性结肠炎患者的诱导和维持治疗是有效且耐受性良好的。Etrasimod 是一种具有独特属性组合的治疗选择，可能会解决溃疡性结肠炎患者持续未得到满足的需求。竞技场制药公司。