Exposure-Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended-Release Formulation

Abstract

Upadacitinib plasma concentrations, efficacy, and safety data from 216 subjects with moderate-to-severe active Crohn's disease (CD) from the 16-week induction period of the CELEST study were analyzed to characterize upadacitinib exposure-response relationships in CD. Subjects in CELEST received either placebo or upadacitinib (3, 6, 12, 24 mg b.i.d. or 24 mg q.d.). Exposure-response models were developed and utilized to simulate efficacy of induction doses of the immediate-release (IR) and extended-release (ER) formulations. Upadacitinib exposures associated with 18-24 mg b.i.d. (IR formulation) or 45-60 mg q.d. (ER formulation) are estimated to have greater efficacy during 12-week induction in patients with CD compared with lower doses. No exposure-response relations were observed with decreases in hemoglobin or lymphocytes at week 16 or with herpes zoster infections, pneumonia, or serious infections during 16 weeks of treatment in this study. These analyses informed the selection of upadacitinib induction dose for phase III studies in CD.