P630 Upadacitinib Improves Clinical Outcomes in Patients with Moderate to Severely Active Crohn’s Disease Irrespective of Previous Failure to Respond to Biologics or Conventional Therapies

Abstract Background Upadacitinib (UPA), an oral, selective Janus kinase inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) in patients (pts) with moderately to severely active Crohn’s disease (CD) in phase 3 multicentre, double-blind, PBO-controlled induction U-EXCEL and U-EXCEED, and maintenance U-ENDURE trials.1-3 This analysis compared clinical outcomes in pts treated with UPA vs PBO once daily (QD) among pts without or with a history of biologic failure. Methods Eligible pts with an average daily very soft/liquid stool frequency (SF) ≥4 and/or abdominal pain score (APS) ≥2, plus a Simple Endoscopic Score for CD (excluding the narrowing component) ≥6 (≥4 for pts with isolated ileal disease) were randomized (2:1) to UPA 45 mg (UPA45) or PBO in U-EXCEL and U-EXCEED. Induction responders (≥30% decrease in average daily very soft/liquid SF and/or APS, neither worse than baseline) to 12-week (wk) UPA45 were re-randomized 1:1:1 for maintenance to UPA 15 mg (UPA15), UPA 30 mg (UPA30) or PBO QD in U-ENDURE. Clinical remission, response (CR-100), and maintenance of clinical remission, along with adverse events (AEs) were assessed through maintenance wk 52. Results Baseline demographics/characteristics were similar for all treatment groups; pts with prior biologic failure were 71.5% PBO and 72.0% UPA45 in induction and 76.4% PBO, 73.4% UPA15 and 75.6% UPA30 in maintenance. Among pts without/with biologic failure history, those treated with UPA45 exhibited higher rates for clinical remission at wk 12 (CDAI: UPA45 54.1%/40.5% vs PBO 39.4%/19.4%; SF/APS: UPA45 54.0%/42.2% vs PBO 28.3%/14.1%, Fig. 1A). Similar results were observed at wk 52 with UPA15 and UPA30 vs PBO (Fig. 1B). Irrespective of biologic failure status, a higher proportion of patients on either UPA dose maintained clinical remission from maintenance wk 0 to wk 52 (Fig. 1C). Higher proportions of pts with prior biologic failure achieved CR-100 with UPA45 vs PBO at wk 12 (53.2% vs 26. 9%); at wk 52 differences from PBO were found for either UPA dose in pts without or with prior biologic failure (Fig. 1D). Serious AEs and serious infections were similar across treatment groups (Tables 1-2). No tuberculosis or adjudicated cardiovascular events were reported. Malignancy, opportunistic infections, thrombotic events, and gastrointestinal perforations were infrequent (<1.0% or 10 E/100PY). Conclusion All upadacitinib doses achieved greater clinical efficacy than placebo during induction and maintenance periods, irrespective of patient prior exposure to biologic therapy, with an acceptable safety profile.