Background

AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis.

Methods

This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6–10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (<4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment.

Findings

Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73−6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug.

Interpretation

AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis.

Funding

EA Pharma and Kissei Pharmaceutical.

Translation

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

中文翻译：

---

AJM300（甲基胡萝卜素），α4-整合素的口服拮抗剂，作为中度活动性溃疡性结肠炎患者的诱导治疗：一项多中心、随机、双盲、安慰剂对照的 3 期研究

背景

AJM300 是一种口服的小分子 α4-整合素拮抗剂。我们评估了 AJM300 在中度活动性溃疡性结肠炎患者中的疗效和安全性。

方法

这项多中心、随机、双盲、安慰剂对照的 3 期研究包括两个阶段：治疗阶段和开放标签再治疗阶段。该研究在日本的 82 家医院和诊所进行。Mayo Clinic 评分为 6-10 分、内窥镜评分为 2 或更高、直肠出血评分为 1 或更高以及对美沙拉嗪反应不足或不耐受的患者被纳入研究。患者通过网站随机分配（1:1）至 AJM300（960 mg）或安慰剂，采用最小化方法，通过动态分配对 Mayo Clinic 评分（≥6 至 ≤7，≥8 至 ≤10）进行集中调整分），在疾病活动期间是否使用任何皮质类固醇、抗 TNFα 抗体或免疫抑制剂（是vs否），诱导治疗的持续时间直到随机化（<4 周vs ≥4 周）作为最小化因素。患者、研究人员、现场工作人员、评估员和申办者对治疗分配不知情。研究药物口服给药，每天 3 次，持续 8 周，如果内镜下未达到缓解或直肠出血未停止，则持续长达 24 周。主要终点是第 8 周出现临床反应的患者比例，并在全分析集中进行分析。临床反应的定义为 Mayo Clinic 评分降低 30% 或更多和 3 或更多，直肠出血评分降低 1 或更多或直肠出血子评分 1 或更少，以及内镜检查子评分每周 1 或更少8. 该研究已在 ClinicalTrials.gov 注册，NCT03531892，已停止招募。

发现

2018 年 6 月 6 日至 2020 年 7 月 22 日期间，203 名患者被随机分配至 AJM300（n=102）或安慰剂（n=101）。在第 8 周，AJM300 组 46 名 (45%) 患者和安慰剂组 21 名 (21%) 患者出现临床反应（优势比 3·30，95% CI 1·73-6·29；p=0 ·00028)。在 8 周治疗和 16 周延长治疗期间，安慰剂组 101 名患者中有 39 名（39%）和 AJM300 组 102 名患者中有 39 名（38%）发生了不良事件。我们发现组间或重复给药 AJM300 后不良事件的发生率没有差异。最常见的不良事件是鼻咽炎（安慰剂组 101 名患者中的 11 名 [11%] 和 AJM300 组 102 名患者中的 10 名 [10%]）。最常见的治疗相关不良事件也是鼻咽炎（安慰剂组 101 名患者中有 4 名 [4%] 和 AJM300 组 102 名患者中有 3 名 [3%]）。大多数不良事件的严重程度为轻度至中度。没有死亡报告。AJM300 组（一名患有肛门脓肿的患者）报告了严重的不良事件，但这被判断为与研究药物无关。

解释

AJM300 在对美沙拉嗪反应不足或不耐受的中度活动性溃疡性结肠炎患者中具有良好的耐受性并诱导了临床反应。AJM300可能是一种用于治疗中度活动性溃疡性结肠炎患者的新型诱导疗法。

资金

EA 制药和 Kissei 制药。

翻译

对于摘要的日文翻译，请参阅补充材料部分。