P341 Pharmacokinetics and exposure-response analyses of upadacitinib in patients with moderate to severe ulcerative colitis – Analyses of induction and maintenance clinical trials

Abstract

Background Upadacitinib (UPA), an oral selective and reversible JAK1 inhibitor, showed favorable efficacy and safety profile in Phase, 2b and, 3 studies in subjects with moderate to severe ulcerative colitis (UC). Population pharmacokinetics and exposure-response analyses were performed to characterize the relationships between UPA plasma exposures and key efficacy and safety endpoints using data from these studies. Methods The pharmacokinetics (PK), efficacy, and safety of UPA for induction and maintenance treatment in UC were evaluated in a Phase, 2b induction, two replicate Phase, 3 induction, and a Phase, 3 maintenance clinical trials. UPA PK was characterized using data from, 978 UC patients. UPA exposure-response relationships for key efficacy and safety endpoints at the end of induction and maintenance periods were characterized using data from, 1,234 and, 449 UC patients, respectively. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across UPA doses of, 7.5 mg to, 45 mg once daily (QD) for induction and, 15 mg to, 30 mg QD for maintenance. Results UPA PK in UC patients was consistent with other patient populations and between the induction and maintenance periods. The percentage of subjects achieving clinical and endoscopic efficacy endpoints at the end of the induction increased with increasing UPA average plasma concentration (Cavg), and became mostly flat at Cavg values approximately equivalent to the, 45 mg QD (Figure, 1). For maintenance treatment, there was a trend for increasing the percentage of subjects achieving clinical remission, steroid-free remission, endoscopic improvement, and histo-endoscopic mucosal improvement within the range of UPA plasma exposures evaluated. Exposures associated with UPA, 30 mg QD were estimated to provide a, 8% to, 10% increase in the percentage of subjects achieving these endpoints compared to, 15 mg QD (Figure, 2). There was no trend for exposure-response relationships within the range of evaluated UPA exposures for any of the evaluated safety endpoints (>2 g/dL decrease in hemoglobin and >2 g/dL decrease in hemoglobin and < lower limit for normal, hemoglobin <, 8 g/dL, lymphopenia ≥ Grade, 3, neutropenia ≥ Grade, 3, Herpes Zoster infection, serious infections, and pneumonia) at the end of induction or maintenance periods. Conclusion UPA plasma exposures associated with the, 45 mg QD induction dose maximized efficacy for clinical and endoscopic endpoints at Week, 8. Plasma exposures associated with UPA, 30 mg maintenance dose provide additional incremental benefit compared to, 15 mg QD. No trends were observed for increase in the evaluated safety events with increasing UPA plasma exposures at the end of induction or maintenance periods.

Evaluating Upadacitinib in the Treatment of Moderate-to-Severe Active Ulcerative Colitis: Design, Development, and Potential Position in Therapy

“…No new safety events were identified (eg, >2 g/dL decrease in hemoglobin, hemoglobin <8 g/dL, lymphopenia ≥ grade, 3, neutropenia ≥ grade, 3, Herpes Zoster infection, serious infections, and pneumonia). 36 …”