Etrasimod as a treatment for eosinophilic oesophagitis (VOYAGE): a double-blind, placebo-controlled, randomised, phase 2 trial.

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator in development for the treatment of immune-mediated inflammatory diseases.

Etrasimod是一种口服每日一次的新型选择性鞘氨醇1-磷酸（S1P）1,4,5受体调节剂，正在开发用于治疗免疫介导的炎症性疾病。

We assessed efficacy and safety of etrasimod versus placebo in adults with eosinophilic oesophagitis.

我们评估了依曲珠单抗与安慰剂在成人嗜酸性食管炎患者中的疗效和安全性。

Methods

In this double-blind, randomised, phase 2 trial, patients aged 18-65 years with a previous diagnosis of eosinophilic oesophagitis and histologically active disease from 64 clinical sites (in Australia, Belgium, Spain, Switzerland, and the USA) were randomly assigned (3:3:2) using an interactive web response system to receive oral etrasimod 2 mg or 1 mg or matching placebo for 24 weeks (centrally randomly assigned and double-blind; placebo-controlledperiod); they continued assigned etrasimod doses or were randomly assigned (1:1) from placebo to etrasimod 2 mg or 1 mg for 28 weeks (extension period).

在这项双盲、随机、二期试验中，年龄在18-65岁之间，之前被诊断为嗜酸性食管炎且组织学上疾病活跃的患者，来自澳大利亚、比利时、西班牙、瑞士和美国的64个临床中心，通过交互式网络响应系统随机分配（3:3:2），接受口服依曲珠单抗2毫克或1毫克或匹配安慰剂治疗24周（中心随机分配和双盲；安慰剂对照期）；之后，他们继续接受分配的依曲珠单抗剂量或从安慰剂随机分配（1:1）到依曲珠单抗2毫克或1毫克治疗28周（扩展期）。

Randomisation was stratified by history of oesophageal dilation and concurrent proton pump inhibitor therapy.

随机分组根据食管扩张史和同时使用质子泵抑制剂治疗的情况进行了分层。

The full analysis set and safety set consisted of all randomly assigned patients who received at least one study treatment dose.

全分析集和安全性集包括所有随机分配的患者，这些患者至少接受了一次研究治疗剂量。

The primary endpoint was percentage change from baseline in oesophageal peak eosinophil count (PEC) at week 16.

主要终点是第16周时食管最高嗜酸性粒细胞计数（PEC）从基线开始的百分比变化。

Safety was assessed up to week 52.

安全性评估持续至第52周。

Patients were analysed according to treatment received in the placebo-controlledperiod and extension period.

患者根据在安慰剂对照期和扩展期接受的治疗进行了分析。

The trial was registered with ClinicalTrials.gov, NCT04682639, and EudraCT, 2020-003226-23; completed on June 30, 2023.

该试验已在ClinicalTrials.gov（NCT04682639）和EudraCT（2020-003226-23）注册，并于2023年6月30日完成。

Results

Between Dec 15, 2020, and May 27, 2022, 41 patients were randomly assigned to etrasimod 2 mg (20 [49%] females and 21 [51%] males), 39 to etrasimod 1 mg (17 [44%] females and 22 [56%] males), and 28 to placebo (14 [50%] females and 14 [50%] males). 85 (79%) of 108 patients completed the double-blindperiod, entering the extension period.

在2020年12月15日至2022年5月27日期间，41名患者被随机分配至etrasimod 2 mg组（20名女性[49%]和21名男性[51%]），39名患者被分配至etrasimod 1 mg组（17名女性[44%]和22名男性[56%]），以及28名患者被分配至安慰剂组（14名女性[50%]和14名男性[50%]）。108名患者中有85名（79%）完成了双盲期，进入扩展期。

Median percentage changes from baseline in PEC at week 16 were -58·4% (IQR -86·2 to -26·3) for etrasimod 2 mg (p=0·010 vs placebo), -39·4% (-71·1 to 79·0) for etrasimod 1 mg (p=0·29 vs placebo) and -21·5% (-57·2 to 55·4) for placebo.

在第16周，与基线相比，PEC的中位百分比变化为etrasimod 2 mg组为-58·4%（四分位数间距IQR -86·2至-26·3）（与安慰剂组相比p=0·010），etrasimod 1 mg组为-39·4%（四分位数间距-71·1至79·0）（与安慰剂组相比p=0·29），安慰剂组为-21·5%（四分位数间距-57·2至55·4）。

In the placebo-controlledperiod, the most common treatment-emergent adverse events were gastrointestinal disorders (11 [27%] of 41 patients in the etrasimod 2 mg group, 13 [33%] of 39 patients in the etrasimod 1 mg group, and 14 [50%] of 28 patients in the placebo group).

在安慰剂对照期间，最常见的治疗后不良事件是胃肠道疾病（etrasimod 2 mg组41名患者中有11名[27%]，etrasimod 1 mg组39名患者中有13名[33%]，以及安慰剂组28名患者中有14名[50%]）。

Bradycardia events, reported by three patients (two [5%] patients in the etrasimod 2 mg group and one [4%] in the placebo group) in the placebo-controlledperiod, were mild or moderate in severity.

在安慰剂对照期间，三名患者报告了心动过缓事件（etrasimod 2 mg组两名患者[5%]，安慰剂组一名患者[4%]），这些事件的严重程度为轻度或中度。

No serious treatment-emergent adverse events or deaths occurred.

没有发生严重的治疗后不良事件或死亡事件。

interpretation

Etrasimod led to sustained histological and endoscopic improvements in eosinophilic oesophagitis over 52 weeks, symptom improvement in patients without dilation, and was well tolerated.

Etrasimod 在52周内对嗜酸性食管炎的组织学和内镜改善产生了持续效果，对于未经扩张的患者症状有所改善，并且耐受性良好。

This trial provides the first evidence that targeting the S1P pathway can improve disease activity in patients with eosinophilic oesophagitis and that S1P receptor modulation is a viable treatment target for this disease.

这项试验首次提供了针对S1P途径可以改善嗜酸性食管炎患者疾病活动性的证据，并表明S1P受体调节是该疾病的一个可行的治疗靶点。

funding

Pfizer.

辉瑞制药。