美国加州大学圣地亚哥分校William J Sandborn团队研究了Etrasimod对中重度溃疡性结肠炎的诱导和维持治疗效果。相关论文发表在2023年3月2日出版的《柳叶刀》杂志上。

Etrasimod是一种每日一次的口服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，对S1P2、3没有可检测的活性，目前正开发用于治疗免疫介导疾病，包括溃疡性结肠炎等。在这两项3期试验中，研究组旨在评估etrasimod在中度至重度活动性溃疡性结肠炎成年患者中的安全性和有效性。

在两项独立的随机、多中心、双盲、安慰剂对照的3期临床试验ELEVATE UC 52和ELEVATE UC12中，患有活动性中度至重度溃疡性结肠炎且对至少一种经批准的溃疡性结肠炎治疗反应不足或丧失或不耐受的成年人被随机分配（2:1），每天口服一次etrasimod 2mg或安慰剂。ELEVATE UC 52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触生物制剂或Janus激酶抑制剂治疗（是vs否）、基线皮质类固醇使用（是vs无）和基线疾病活动（修正梅奥评分[MMS]；4-6 vs 7-9）进行分层。ELEVATE UC 52包括12周的诱导期，随后是40周的维持期，采用贯穿治疗设计。ELEVATE UC 12在第12周独立评估诱导。主要疗效终点是ELEVATE UC 52患者第12周和第52周以及ELEVATE UC12患者第12周有临床缓解的患者比例。两项试验均评估了安全性。

ELEVATE UC 52患者于2019年6月13日至2021年1月28日登记。ELEVATE UC 12患者于2020年9月15日至2021年8月12日登记。ELEVATE UC 52和ELEVATE UC12分别筛选了821名患者和606名患者，433名和354名患者随后接受了随机分配。ELEVATE UC 52的完整分析集包括289名患者被分配到etrasimod组，144名患者被分配到安慰剂组。在ELEVATE UC 12中，238名患者被分配到etrasimod组，116名患者被分到安慰剂组。在ELEVATE UC 52中，与安慰剂组相比，在12周诱导期结束时（274名患者中74名[27%]对135名患者10名[7%]；p<0.0001）和第52周时（274位患者中88名[32%]对135位患者9名[7%]；p<0.0001），etrasimod组获得临床缓解的患者比例明显更高。

在ELEVATE UC 12中，在12周诱导期结束时，etrasimod组222名患者中有55名（25%）获得了临床缓解，而安慰剂组112名患者中只有17名（15%）。ELEVATE UC 52中，etrasimod组289名患者中206名（71%）和安慰剂组144名患者中81名（56%）报告了不良事件，ELEVATE UC12中，etrasimod组238名患者中112名（47%）以及安慰剂组116名患者中54名（47%）报告不良事件。无死亡或恶性肿瘤报告。

研究结果表明，对于中度至重度活动性溃疡性结肠炎患者，etrasimod作为诱导和维持治疗有效且耐受性良好。Etrasimod是一种具有独特属性组合的治疗方案，可解决溃疡性结肠炎患者持续未满足的需求。

附：英文原文

Title: Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

Author: William J Sandborn, Séverine Vermeire, Laurent Peyrin-Biroulet, Marla C Dubinsky, Julian Panes, Andres Yarur, Timothy Ritter, Filip Baert, Stefan Schreiber, Sheldon Sloan, Fabio Cataldi, Kevin Shan, Christopher J Rabbat, Michael Chiorean, Douglas C Wolf, Bruce E Sands, Geert DHaens, Silvio Danese, Martina Goetsch, Brian G Feagan

Issue&Volume: 2023-03-02

Abstract:

Background

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 S1P2,3, 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.

Methods

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 vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4–6 vs 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 ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively.

Findings

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 vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs 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.

Interpretation

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.

DOI: 10.1016/S0140-6736(23)00061-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00061-2/fulltext