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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01960855 NCT02066389.

Figure 1

Schematic for Markov model analysis of the relationship between upadacitinib plasma exposures and American College of Rheumatology (ACR) responses. K01, K12, and K23 represent transition rates of the status of patients to higher levels of response. K10, K21, and K32 represent transition rates of the status of patients to lower levels of response. Model parameters K0D, K1D, K2D, and K3D represent transition of patients from different response states to dropout. C_p represents the upadacitinib plasma concentration. ACR20/50/70, American College of Rheumatology 20%/50%/70% improvement criteria. [Colour figure can be viewed at http://www.wileyonlinelibrary.com]

Figure 2

Observed and model‐predicted American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses (observed cases) vs. time stratified by dose and patient population. Symbols represent the observed time course of the percentage of patients achieving ACR20, (blue) ACR50, (black) and ACR70 (green) responses. Solid lines and shaded areas represent the exposure–response model‐predicted median and 90% prediction intervals, respectively. IR, inadequate responder; MTX, methotrexate.

Figure 3

Simulated American College of Rheumatology (ACR) responses (nonresponder imputation (NRI)) at week 12 for the immediate‐release twice daily (b.i.d.) and extended‐release once daily (q.d.) dosing regimens. Lines and shaded areas represent the median and 90% prediction intervals for the immediate‐release 3, 6, 12, and 18 mg b.i.d. dosing regimens in the BALANCE I (anti‐TNF‐inadequate responders (IRs)) and II methotrexate (MTX‐IRs) studies. Symbols and dashed lines represent the simulated median and 90% prediction intervals for the extended‐release 15 and 30 mg q.d. dosing regimens.

Figure 4

Simulated and observed American College of Rheumatology (ACR) responses (nonresponder imputation (NRI)) at week 12 in (a) methotrexate (MTX)‐inadequate responders (IRs)/conventional synthetic disease‐modifying antirheumatic drugs (csDMARD)‐IR and (b) anti‐TNF‐IR/biologics‐IR patients in phase III trials. Gray symbols and error bars represent the simulated median and 90% prediction intervals for 15 mg and 30 mg q.d. extended‐release regimens based on exposure–response analyses of the phase II studies BALANCE I and II. Black symbols represent the observed responses in phase III trials. q.d., once daily.