Model-Informed Assessment of Probability of Phase 3 Success for Ritlecitinib in Patients with Moderate-to-Severe Ulcerative Colitis.

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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.