S37 Efficacy and Safety of Upadacitinib Maintenance Therapy in Patients with Moderately to Severely Active Crohn’s Disease: U-ENDURE Phase 3 Results

Background: Efficacy and safety of upadacitinib (UPA) 15 mg (UPA15) once daily (QD) and UPA 30 mg QD (UPA30) maintenance therapy in patients with Crohn’s disease (CD) were evaluated in U-ENDURE. Methods: Patients with moderate to severe CD who responded (≥30% decrease average daily very soft/liquid stool frequency [SF] and/or average daily abdominal pain score [APS], neither greater than baseline) to 12-weeks (wks) of UPA 45 mg QD induction therapy were eligible for U-ENDURE. At wk0, patients were randomized (1:1:1) to receive UPA15, UPA30 or placebo (PBO) as maintenance therapy for 52 wks1. Co-primary endpoints, clinical remission per CD activity index (CDAI) or SF/APS and endoscopic response, were evaluated at wk52. Other efficacy and safety outcomes were evaluated at or through wk52. Results: At wk52, greater proportion of patients receiving UPA15 (n = 169) and UPA30 (n = 168) vs PBO (n = 165) achieved clinical remission per CDAI (37.3% [95%CI: 30.0%, 44.6%] and 47.6% [40.1%, 55.2%] vs 15.1% [9.6%, 20.6%]) and SF/APS (35.5% [28.3%, 42.7%] and 46.4% [38.9%,54.0%] vs 14.4% [9.0%,19.8%]) (all P < 0.0001 vs PBO for both doses). UPA15 and UPA30 patients attained greater rates of endoscopic response vs PBO (27.6% [95%CI: 20.8%, 34.4%] and 40.1% [32.7%, 47.6%] vs 7.3% [3.3%, 11.2%]; P < 0.0001 vs PBO for both doses). UPA15 and UPA30 were superior vs PBO for key secondary endpoints at wk52 including clinical response (41.4% and 51.2% vs 15.2%), endoscopic remission (19.1% and 28.6% vs 5.5%), maintenance of clinical remission (per CDAI: 49.5% and 65.2% vs 21.2%; per SF/APS: 50.5% and 60.0% vs 19.6%), corticosteroid-free clinical remission in all patients (per CDAI, 36.7% and 46.4% vs 14.5%; per SF/APS, 34.9% and 44.6% vs 14.4%) and in patients with baseline steroid use (per CDAI, 39.7% and 39.7% vs 4.9%; per SF/APS, 38.1% and 38.1% vs 4.9%), clinical+endoscopic remission (per CDAI, 14.8% and 23.2% vs 3.7%; per SF/APS, 13.7% and 22.6% vs 4.3%), and change from baseline in IBDQ total score (LS mean[SE]: 59.3[3.22] and 64.5[3.15] vs 46.4[4.02]) (all P < 0.01 vs PBO for both doses). UPA30-treated patients also demonstrated significant improvement from baseline in FACIT-F vs PBO (LS mean[SE]: 16.1[1.02] vs 12.0[1.34]; P < 0.001). Rates of adverse events (AE) and serious AEs were similar across UPA groups; AE leading to treatment discontinuation rates were similar across groups. Most common AE was CD worsening (UPA15: 29.7 events/100 patient-years [E/100PY], UPA30: 12.0E/100PY, PBO: 58.0E/100PY). Serious infection rates were similar across groups (6.1-8.4 E/100PY); herpes zoster rate was higher in UPA30 (7.2E/100PY) vs PBO (4.7E/100PY) and UPA15 (4.0E/100PY). Malignancies excluding non-melanoma skin cancer (NMSC) were reported in 1 UPA15 patient and 2 UPA30 patients; all events were diagnosed within 9 months of first UPA exposure. One gastrointestinal perforation was reported in each group. One event of hepatic vein thrombosis was reported in UPA30. No deaths, tuberculosis, NMSC, or adjudicated cardiovascular events occurred in any group. Conclusion(s): Among patients with moderate to severe active CD who respond to UPA induction therapy, UPA15 and UPA30 maintenance treatments were well tolerated and superior to PBO for all clinical and endoscopic outcomes, and most quality-of-life outcomes at wk52.