Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis

Abstract

Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C-reactive protein) (DAS28-CRP) ≤ 3.2, and DAS28-CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure-response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ≥ 4), or neutropenia (Grade ≥ 3) up to Week 26. Shallow exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ≥ 3 at Week 12/14, and serious infections at Week 24/26. Exposure-efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs.

Trial registration: ClinicalTrials.gov NCT02066389 NCT01960855 NCT02706847 NCT02675426 NCT02706873 NCT02629159 NCT02706951.

Conflict of interest statement

All authors are employees of AbbVie and may hold AbbVie stock or stock options.

© 2019 AbbVie. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Visual predictive checks (VPCs) for ACR responses based on the final ACR model. Symbols and error bars, observed response, and 90% confidence interval at respective time bin; lines/shaded regions: median ± 90% confidence interval (CI) for predicted responses. ACR, American College of Rheumatology.

Figure 2

Visual predictive checks (VPCs) for low disease activity / clinical remission (LDA/CR) responses based on the final LDA/CR model. Symbols and error bars = observed response and 90% confidence interval at respective time bin; lines/shaded regions: median ± 90% confidence interval (CI) for predicted responses.

Figure 3

Exposure–response quartile plots for select safety variables at Week 12/14 and Week 24/26. Cavg, average plasma concentration over a dosing interval at steady state; HGB, hemoglobin; LOCF, last observation carried forward; OBS, observed. [Colour figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Visual predictive checks for final exposure–safety logistic regression models at Week 12/14 and Week 24/26. The blue dots denote observed responses within upadacitinib average plasma concentrations deciles, orange solid lines denote median predicted responses within upadacitinib average plasma concentrations deciles, and the orange shaded areas denote the 95% prediction interval. [Colour figure can be viewed at http://wileyonlinelibrary.com]