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.

Figure 1

Observed relationships between upadacitinib (a) average plasma concentration during a dosing interval (C_ave) or (b) minimum plasma concentration (C_min) in the phase II CELEST study and the percentages of subjects achieving clinical end points at week 16. CDAI, Clinical Disease Activity Index; NRI, nonresponder imputation. [Colour figure can be viewed at https://www.wileyonlinelibrary.com]

Figure 2

Observed (symbols) and model‐predicted percentage (solid line and shaded areas) of subjects who achieved endoscopic end points at week 12 or 16 vs. upadacitinib average plasma concentration during a dosing interval (C_ave). Symbols and error bars represent the observed NRI response by quartile of upadacitinib C_ave; solid line and shaded areas represent the model‐predictions; horizontal lines represent the spread of exposure for different doses. NRI, nonresponder imputation. [Colour figure can be viewed at https://www.wileyonlinelibrary.com]

Figure 3

Observed and model‐predicted clinical response vs. time stratified by upadacitinib immediate‐release dose evaluated in the CELEST study. Symbols represent the observed time course of the percentage of patients achieving each of the clinical end points. Solid lines and shaded areas represent the exposure–response model‐predicted median and 90% prediction intervals, respectively. [Colour figure can be viewed at https://www.wileyonlinelibrary.com]

Figure 4

Predicted percentage of subjects achieving the different clinical and endoscopic response/remission end points during the induction period for different upadacitinib immediate‐release b.i.d. and extended‐release q.d. regimens based on exposure–response analyses of the phase II CELEST study. Data are presented as medians and 5th and 95th percentiles of predictions from 100 replicates. Simulations represent 220 subjects for each dose group. [Colour figure can be viewed at https://www.wileyonlinelibrary.com]

Figure 5

Observed relationships between upadacitinib average plasma concentration during a dosing interval (C_ave) and the percentages of subjects experiencing clinically relevant safety events or changes in laboratory parameters at week 16 in the phase II CELEST study.