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Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase 2 and 3 Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis

Author

Nader A1, Mohamed MF1, Winzenborg I2, Doelger E2, Noertersheuser P2, Pangan AL3, Othman AA1. Clin Pharmacol Ther. 2019 Oct 14. doi: 10.1002/cpt.1671. [Epub ahead of print]

Author Information

1 Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, United States.

2 Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.

3 Immunology Clinical Development, AbbVie, North Chicago, United States.

Abstract

Exposure-response analyses of upadacitinib (UPA) key efficacy and safety endpoints (3685 and 4577 subjects for efficacy and safety, respectively) using data from Phase 2 and Phase 3 rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving ACR20/50/70, 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 QD dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg QD; and with consistency across RA subpopulations and with UPA monotherapy or combination with csDMARDs.