FRI0138 EXPOSURE-RESPONSE ANALYSES OF UPADACITINIB EFFICACY AND SAFETY IN RHEUMATOID ARTHRITIS – ANALYSES OF PHASE 2 AND 3 STUDIES. (June 2019)

• Record Type: Journal Article
• Authors: Mohamed, Mohamed-Eslam; Nader, Ahmed; Winzenborg, Insa; Doelger, Eva; Noertersheuser, Peter; Pangan, Aileen; Othman, Ahmed
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 739
• Page End: 740
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.752
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Upadacitinib (UPA), an oral selective JAK1 inhibitor, demonstrated favorable efficacy and acceptable safety in two Phase 2 and five Phase 3 global studies in subjects with moderately to severely active rheumatoid arthritis (RA). Objectives: To characterize relationships between UPA plasma exposures and different efficacy and safety endpoints using data from Phase 2 and Phase 3 RA studies. Methods: Analyses were conducted using data from 3685 (for efficacy) and 4577 (for safety) subjects with RA enrolled in the Phase 2 and 3 studies. Relationships between UPA plasma concentrations and efficacy and selected clinically relevant safety endpoints were analyzed using Markov Chain models and logistic regression analyses, respectively. Results: Percentage of subjects achieving ACR20, ACR50, AC70, DAS28(CRP) ≤ 3.2, and DAS28(CRP) < 2.6 increased with increasing UPA exposures, with maximum efficacy reached at exposures of 15 mg to 30 mg QD. Model-estimated efficacy responses are presented in Table 1 . No relationships were observed between UPA exposure and pneumonia, herpes zoster infection, changes in platelet count (platelets ≥600×10 9 /L, platelets >400×10 9 /L), lymphopenia (Grade 4 or higher), and neutropenia (Grade 3 or higher) at Week 12/14 or Week 24/26. Shallow trends for exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin from baseline at Week 12/14 and Week 24/26, lymphopenia Grade 3 or higher at Week 12/14, and serious infections at Week 24/26. No relationship with UPA exposure was observed for Grade 3 or higher lymphopenia at Week 24/26 (Figure 1 ). Conclusion: Exposure-efficacy analyses demonstrate that UPA 15 mg QD dose maximizes efficacy in RA while 30 mg QD dose provides only a small (≤ 5%) additional incremental efficacy benefit. This was consistent across RA populations and whether UPA is used as monotherapy or on background treatment of csDMARDs. UPA plasma exposures associated with 15 mg and 30 mg QD dosing are predicted to have limited effects on the evaluated safety endpoints after 24 to 26 weeks of treatment. References: [1] Genovese, et al. Lancet. 2018; 391(10139): 2513-2524. [2] Burmester, et al. Lancet. 2018; 391(10139): 2503-2512. [3] Mohamed et al. Clin Pharmacol Drug Dev. 2018 Apr 24. Disclosure of Interests: Mohamed-Eslam Mohamed Shareholder of: AbbVie, Employee of: AbbVie, Ahmed Nader Shareholder of: AbbVie, Employee of: AbbVie, Insa Winzenborg Shareholder of: AbbVie, Employee of: AbbVie, Eva Doelger Shareholder of: AbbVie, Employee of: AbbVie, Peter Noertersheuser Shareholder of: AbbVie, Employee of: AbbVie, Aileen Pangan Shareholder of: AbbVie, Employee of: AbbVie, Ahmed Othman Shareholder of: AbbVie, Employee of: AbbVie