Exposure–Response Analyses of Upadacitinib Efficacy in Phase II Trials in Rheumatoid Arthritis and Basis for Phase III Dose Selection

The relationships between upadacitinib, an oral selective Janus kinase 1 inhibitor, plasma exposures, and its efficacy (assessed by the American College of Rheumatology 20%/50%/70% responses over time) in moderate‐to‐severe active rheumatoid arthritis (RA) were characterized using data from 574 patients, on background methotrexate and inadequate response to methotrexate or anti‐TNF therapy, from two phase II trials conducted with twice‐daily dosing of an immediate‐release formulation. The developed time‐continuous Markov models were used to simulate efficacy of once‐daily (q.d.). regimens of upadacitinib extended‐release incorporating sources of uncertainty. Upadacitinib plasma concentrations associated with 15 and 30 mg extended‐release q.d. doses were predicted to achieve that plateau of response across RA subpopulations. Results from these analyses provided the rationale that supported selection and de‐risked evaluation of upadacitinib extended‐release doses for the first time in >4,000 patients in five large phase III trials.