Etrasimod as induction and maintenance treatment for patients with moderately to severely active ulcerative colitis in East Asia (ENLIGHT UC): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.

In the randomised, placebo-controlled, double-blindphase 3 ENLIGHT UC study, also known as the ES101002 study, we aimed to evaluate the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis in East Asia.

在随机、安慰剂对照、双盲的第三阶段 ENLIGHT UC 研究中，也被称为 ES101002 研究，我们的目标是评估 etrasimod 在东亚地区中度至重度活动性溃疡性结肠炎患者中的疗效和安全性。

Methods

Using a central interactive web response system, in the 12-week induction period, adults (aged 18-75 years, inclusive) with moderately to severely active ulcerative colitis (modified Mayo score [MMS] 4-9 with an endoscopic subscore ≥2 and a rectal bleeding subscore ≥1) and an inadequate response, loss of response, or intolerance to at least one ulcerative colitis treatment were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo.

使用中心互动网络响应系统，在12周的诱导期内，将年龄在18至75岁之间，患有中度至重度活动性溃疡性结肠炎（改良Mayo评分[MMMS]为4-9，内镜下评分≥2，直肠出血评分≥1）且对至少一种溃疡性结肠炎治疗反应不足、失去反应或不耐受的成人随机分配（2:1）至每日一次口服etrasimod 2 mg或安慰剂。

Patients and study staff were masked to treatment assignment.

患者和研究工作人员对治疗分配情况是不知情的。

Patients were enrolled from 52 hospitals across China, Taiwan, and Souh Korea.

患者来自中国、台湾和韩国的52家医院。

Randomisation was stratified by previous treatment status and baseline disease activity.

随机分组根据先前治疗状态和基线疾病活动性进行分层。

Patients who had an MMS clinical response at induction period week 12 were re-randomly assigned (1:1) to once-daily oral etrasimod 2 mg or placebo for the 40-week maintenance period.

在诱导期第12周时具有MMS临床反应的患者被重新随机分配（1:1），在接下来的40周维持期中，每天一次口服etrasimod 2 mg或安慰剂。

Randomisation was stratified by induction period treatment, previous exposure to biologicals or JAK inhibitors, and concomitant use of oral corticosteroids at induction period baseline.

随机化是根据诱导期治疗、之前是否接触过生物制剂或JAK抑制剂，以及诱导期基线时是否同时使用口服皮质类固醇进行分层的。

The primary efficacy outcome was MMS clinical remission (stool frequency subscore=0 [or stool frequency subscore=1 with a ≥1 point decrease from induction period baseline], rectal bleeding subscore=0, and endoscopic subscore ≤1 [excluding friability]), assessed in the induction and maintenance periods separately (at induction period week 12 and maintenance period week 40).

主要疗效结果是MMS临床缓解（排便频率子评分=0[或排便频率子评分=1且较诱导期基线下降≥1分]，直肠出血子评分=0，内镜子评分≤1[排除易碎性]），分别在诱导期和维持期进行评估（在诱导期第12周和维持期第40周）。

The primary efficacy analyses used the full analysis set (FAS), which included all patients who were randomly assigned and received at least one dose of study treatment for the induction period, and all re-randomly assigned patients who showed clinical response at induction period week 12 and received at least one dose of study treatment for the maintenance period.

主要疗效分析使用了全分析集（FAS），包括所有被随机分配并至少接受一次诱导期研究治疗的患者，以及所有在诱导期第12周显示出临床反应并至少接受一次维持期研究治疗的重新随机分配患者。

The safety analyses for each treatment period used the safety analysis set (SAF), which included all patients who received any amount of study drug in the corresponding treatment period.

每个治疗期间的安全性分析使用了安全性分析集(SAF)，该集包括在相应治疗期间接受任何数量研究药物的所有患者。

ENLIGHT UC is registered with ClinicalTrials.gov (NCT04176588) and the study is complete.

ENLIGHT UC已在ClinicalTrials.gov注册（NCT04176588），研究已完成。

Results

606 patients were screened between Sept 25, 2019, and April 27, 2023, and 340 were randomly assigned for the induction period and treated (FAS: 228 patients [88 female and 140 male] assigned to etrasimod and 112 patients [44 female and 68 male] assigned to placebo). 157 patients who showed clinical response in the induction period were re-randomly assigned and treated in the maintenance period (FAS: 77 patients [35 female and 42 male] assigned to etrasimod and 80 patients [32 female and 48 male] assigned to placebo).

在2019年9月25日至2023年4月27日期间，共有606名患者接受了筛查，其中340名患者在诱导期间被随机分配接受治疗（意向治疗分析集：228名患者（88名女性和140名男性）被分配至etrasimod组，112名患者（44名女性和68名男性）被分配至安慰剂组）。在诱导期间显示出临床反应的157名患者在维持期间被重新随机分配并接受治疗（意向治疗分析集：77名患者（35名女性和42名男性）被分配至etrasimod组，80名患者（32名女性和48名男性）被分配至安慰剂组）。

A significantly greater proportion of patients treated with etrasimod than those treated with placebo, showed clinical remission at induction week 12 (57 [25·0%] of 228 patients vs six [5·4%] of 112 patients; adjusted difference 20·4%; 95% CI 13·4%-27·4%; p<0·0001) and maintenance period week 40 (37 [48·1%] of 77 patients vs 10 [12·5%] of 80 patients; adjusted difference 35·9%; 95% CI 22·5%-49·2%; p<0·0001).

与接受安慰剂治疗的患者相比，接受etrasimod治疗的患者在诱导第12周显示出临床缓解的比例显著更高（228名患者中有57名[25·0%]，与112名患者中有6名[5·4%]；调整后的差异为20·4%；95%置信区间为13·4%-27·4%；p<0·0001），并且在维持期第40周也显示出同样的趋势（77名患者中有37名[48·1%]，与80名患者中有10名[12·5%]；调整后的差异为35·9%；95%置信区间为22·5%-49·2%；p<0·0001）。

In the induction period, the most frequently reported treatment-emergent adverse event(TEAE) was increased ALT (22 [10%] in the etrasimod group vs one [1%] in the placebo group).

在诱导期，报告最多的治疗后不良事件（TEAE）是ALT升高（etrasimod组22例[10%]对比安慰剂组1例[1%]）。

In the maintenance period, the most frequently reported TEAE was upper respiratory tract infection (14 [18%] in the etrasimod group vs 14 [17%] in the placebo group).

在维持期，报告最多的TEAE是上呼吸道感染（etrasimod组14例[18%]对比安慰剂组14例[17%]）。

Across the induction and maintenance periods, most TEAEs were mild to moderate in severity.

在诱导期和维持期，大多数治疗相关不良事件（TEAEs）的严重程度为轻度至中度。

Five (2%) of 228 patients treated with etrasimod and four (4%) of 112 patients treated with placebo discontinued study treatment due to TEAEs during the induction period, and one (1%) of 77 patients treated with etrasimod and one (1%) of 81 patients treated with placebo discontinued study treatment due to TEAEs during the maintenance period.

在诱导期，接受etrasimod治疗的228名患者中有5名（2%）和接受安慰剂治疗的112名患者中有4名（4%）因治疗相关不良事件（TEAEs）而停用研究治疗；在维持期，接受etrasimod治疗的77名患者中有1名（1%）和接受安慰剂治疗的81名患者中有1名（1%）因治疗相关不良事件（TEAEs）而停用研究治疗。

No grade 4 or higher TEAE, malignancies, or deaths were reported.

未报告4级或更高级别的治疗相关不良事件、恶性肿瘤或死亡。

interpretation

Etrasimod was effective and well tolerated as an oral induction and maintenance treatment in patients with moderately to severely active ulcerative colitis in East Asia.

Etrasimod作为口服诱导和维持治疗，在东亚患有中度至重度活动性溃疡性结肠炎的患者中是有效且耐受性良好的。

funding

Everest Medicines.

珠峰医药。

translation

For the Chinese translation of the abstract see Supplementary Materials section.

摘要的中文翻译请参见补充材料部分。