Ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor, was evaluated in patients with ulcerative colitis (UC) in a phase 2b trial. Model‐informed drug development strategies were applied to bridge observations from phase 2b to predictions for a proposed phase 3 study design to assess the probability of achieving the target efficacy outcome. A longitudinal exposure‐response model of the time course of the 4 Mayo subscores (rectal bleeding, stool frequency, physician's global assessment, and endoscopic subscore) in patients with UC receiving placebo or ritlecitinib was developed using population modeling approaches and an item response theory framework. The quantitative relationships between the 4 Mayo subscores accommodated the prediction of composite endpoints such as total Mayo score and partial Mayo score (key endpoints from phase 2b), and modified clinical remission and endoscopic remission (proposed phase 3 endpoints). Clinical trial simulations using the final model assessed the probability of candidate ritlecitinib dosing regimens (including those tested in phase 2b and alternative) and phase 3 study designs for achieving target efficacy outcomes benchmarked against an approved treatment for moderate‐to‐severe UC. The probabilities of achieving target modified clinical remission and endoscopic improvement outcomes at both weeks 8 and 52 for ritlecitinib 100 mg once daily was 74.8%. Model‐based assessment mitigated some of the risk associated with proceeding to pivotal phase 3 trials with dosing regimens of which there was limited clinical experience.

中文翻译：

---

Ritlecitinib 在中重度溃疡性结肠炎患者中的 3 期成功概率的模型知情评估

Ritlecitinib 是一种在肝细胞癌家族抑制剂中表达的口服 Janus 激酶 3/酪氨酸激酶，在 2b 期试验中对溃疡性结肠炎 (UC) 患者进行了评估。应用基于模型的药物开发策略将 2b 期的观察结果与拟议的 3 期研究设计的预测联系起来，以评估实现目标疗效结果的可能性。使用群体建模方法和项目反应理论框架，开发了接受安慰剂或 Ritlecitinib 的 UC 患者 4 个 Mayo 子评分（直肠出血、排便频率、医生总体评估和内镜子评分）时间过程的纵向暴露反应模型。 4 个 Mayo 子评分之间的定量关系适应了复合终点的预测，例如总 Mayo 评分和部分 Mayo 评分（2b 期的关键终点）以及改良的临床缓解和内镜缓解（提议的 3 期终点）。使用最终模型的临床试验模拟评估了候选 Ritlecitinib 给药方案（包括在 2b 期和替代方案中测试的方案）和 3 期研究设计的可能性，以实现以已批准的中重度 UC 治疗为基准的目标疗效结果。每天一次 100 mg Ritlecitinib 在第 8 周和第 52 周实现目标改良临床缓解和内镜改善结果的概率为 74.8%。基于模型的评估减轻了与临床经验有限的给药方案进行关键 3 期试验相关的一些风险。