POS1054 UPADACITINIB PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY IN PSORIATIC ARTHRITIS – ANALYSES OF THE PHASE 3 SELECT-PsA STUDIES

Abstract

Background:Upadacitinib (UPA) is an oral, reversible, JAK inhibitor approved for the treatment of rheumatoid arthritis (RA). The efficacy and safety profile of UPA in psoriatic arthritis (PsA) has been established in the SELECT-PsA program which includes two global Phase 3 studies.Objectives:These analyses characterize UPA pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies.Methods:The SELECT-PsA program enrolled patients with prior inadequate response (IR) or intolerance to ≥1 non-bDMARD1 (N=1705) and prior IR or intolerance to ≥1 bDMARD2 (N=642). Data from both trials was integrated for patients receiving placebo (PBO), UPA 15mg once daily (QD) and UPA 30mg QD; adalimumab data was excluded from this analysis. UPA pharmacokinetics were characterized in PsA patients using Bayesian population pharmacokinetics analyses and utilizing prior information from analyses in healthy subjects and RA patients. Exposure-response analyses were conducted using logistic regression to characterize the relationships between upadacitinib average plasma concentration during a dosing interval (Cavg) and the percentage of patients achieving ACR20/50/70 at Weeks 12 and 24, static Investigator Global Assessment of psoriasis (sIGA) of 0 or 1 (clear or almost clear) and at least a 2-point improvement from baseline, and PASI75 at Weeks 16 and 24 or experiencing selected clinically relevant safety events through week 24.Results:Analyses were conducted using data from 1694 subjects (for pharmacokinetics) and 1916 subjects (for exposure-response analyses). UPA model-estimated plasma exposures in subjects with PsA who received 15mg and 30mg QD doses were comparable to previously estimated exposures in subjects with RA. Body weight and methotrexate use had no clinically relevant effects on UPA exposures. There was a statistically significant relationship between UPA Cavg and the percentage of subjects who achieved Week 12 ACR50/70, Week 16 sIGA 0/1, and Week 24 sIGA 0/1 (Figure 1). No statistically significant exposure-response relationship was observed for Week 12 ACR20, Week 16 PASI75, or Week 24 ACR20/50/70 or PASI75, indicating that the 15mg QD exposures are approximately at the plateau of response for these endpoints. No statistically significant relationships were observed between upadacitinib Cavg and the percentage of subjects experiencing pneumonia, herpes zoster, hemoglobin < 8 g/dL, Grade ≥3 lymphopenia, Grade ≥3 neutropenia. There was a shallow but statistically significant exposure-response relationships with the occurrence of serious infections and decrease in hemoglobin from baseline (>2 g/dL and >2 g/dL in combination with hemoglobin < lower limit for normal).Figure 1.Observed and Model Predicted Efficacy Responses at Week 12 (for ACR50/70) or at Weeks 16 and Week 24 (for sIGA 0/1) Versus Upadacitinib Plasma ExposuresConclusion:Exposure-response analyses demonstrated that plasma exposures associated with UPA 15 mg QD achieves robust efficacy in subjects with PsA with limited effects on the evaluated safety endpoints. UPA plasma exposures associated with UPA 15 and 30mg QD are predicted to provide similar ACR responses by week 24 while a small additional efficacy benefit with UPA 30mg is predicted for the achievement sIGA 0/1.