S1050 Efficacy and Safety of Upadacitinib Maintenance Treatment in Patients With Moderately to Severely Active Crohn’s Disease: Two Year Results From the U-ENDURE Long-Term Extension Study

Introduction: Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for treating moderately to severely active Crohn’s disease (CD). We evaluated UPA maintenance therapy efficacy for up to 2 years (yrs) and safety outcomes for at least 2 yrs (up to 5 yrs) in the ongoing U-ENDURE long-term extension (LTE) substudy. Methods: Patients who completed the U-ENDURE 52-week (wk) maintenance study were eligible for the subsequent LTE substudy and continued their previously assigned treatment (UPA 15 mg [UPA15] once daily or UPA 30 mg [UPA30] once daily). Efficacy was assessed from LTE wk0 to wk48. Clinical remission (per stool frequency/abdominal pain score [SF/APS] and CD Activity Index [CDAI]), endoscopic response, endoscopic remission, were evaluated using both as observed (AO) and nonresponder imputation (NRI) methods; mean change from induction baseline (BL) in high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) were evaluated using AO and modified as observed (mAO) methods. Safety was assessed from maintenance wk0, with up to 260 cumulative wks of maintenance and LTE treatment exposure (cutoff date: 19 Dec 2023). Results: From LTE wk0 to wk48, AO efficacy rates remained stable in each treatment group for SF/APS clinical remission (UPA15: 78.3% to 82.9%; UPA30: 84.7% to 76.6%; Figure 1A), CDAI clinical remission (UPA15: 81.3% to 83.1%; UPA30: 86.1% to 86.8%; Figure 1B), endoscopic response (UPA15: 59.6% to 67.1%; UPA30: 71.2% to 69.6%; Figure 1C), and endoscopic remission (UPA15: 42.4% to 45.1%; UPA30: 53.0% to 56.3%; Figure 1D). Clinical or endoscopic remission was sustained at LTE wk0 through wk48 as follows: clinical remission per SF/APS: UPA15 93.8%; UPA30 84.4%; per CDAI: UPA15 94.0%; UPA30 91.1%; endoscopic remission: UPA15 73.0%; UPA30 86.9% [AO]. Respectively, hs-CRP and FCP mean change from induction BL (UPA15 -12.4, -2752; UPA30 -12.7, -1850 [AO]) were stable through wk48 (UPA15 -12.7, -3191; UPA30 -11.1, -2038 [AO]) (Figure 1E-F). Similar results were found per NRI (for binary variables) or mAO analysis (for continuous variables). Event rates for serious, severe, and most adverse events of special interest were similar among UPA-treated groups, except for numerically higher rates of COVID-19 infection, herpes zoster, and lymphopenia among UPA30 vs UPA15-treated patients. Conclusion: Sustained efficacy for clinical, endoscopic, and inflammatory markers was observed in patients who completed up to 2 yrs of UPA maintenance therapy, with no new safety signals identified (see Table 1).Figure 1.: Clinical, Endoscopic, and Inflammatory Markers in Patients Treated With Upadacitinib Through Week 48 of the U-ENDURE Long-Term Extension Study. Patients were blinded until the last patient completed maintenance wk 52. AO analysis used all available data up to the initiation of open-label UPA rescue and did not impute values for missing data. For NRI analysis on binary variables, patients were categorized as “nonresponder” after initiation of any protocol rescue medications or missing data. For mAO analysis on continuous variables, all available data up to the initiation of any protocol rescue medications were used and did not impute values for missing data. 95% CIs for the response rate were based on the normal approximation to the binomial distribution. A) SF/APS Clinical remission was defined as average daily very soft or liquid SF ≤ 2.8 and average daily AP score ≤ 1.0 and both not greater than induction BL. B) Clinical remission per CDAI was defined as CDAI < 150. C) Endoscopic response was defined as a decrease in SES-CD > 50% from BL of the induction study (or for patients with an SES-CD of 4 at baseline of the induction study, at least a 2-point reduction from baseline), as scored by a central reviewer. Endoscopies were performed annually. D) Endoscopic remission was defined as SES-CD ≤ 4 and at least a 2-point reduction from BL and no subscore > 1 in any individual variable, as scored by a central reviewer and measured up to wk 48. For assessment of (E) hs-CRP and (F) FCP, BL was defined as wk 0 of induction for both induction and maintenance. AO, as observed; BL, baseline; CDAI, Crohn’s disease activity index; CI, confidence intervals; FCP, fecal calprotectin; hs-CRP, high-sensitivity C-reactive protein; LTE, long-term extension; NRI, nonresponder imputation; mAO, modified as observed; SES-CD, Simplified Endoscopic Score for Patients with Crohn’s Disease; SF/APS, stool frequency/abdominal pain score; wk, week. Table 1. - Overview of Treatment-Emergent Adverse Events in Patients Treated With Upadacitinib From Week 0 of the U-ENDURE Maintenance Study, With Up to 260 Cumulative Weeks of Maintenance and Long-Term Extension Exposure Adverse Event UPA 15 mg QD n = 221PYs = 350.7 (n, E/100 PYs) UPA 30 mg QD n = 229PYs = 432.8 (n, E/100PYs) Overview of TEAEs Any AE 993 (283.1) 1183 (273.4) Any AE leading to the discontinuation of study drug 25 (7.1) 23 (5.3) Any AE with a reasonable possibility of being related to study druga 253 (72.1) 313 (72.3) COVID-19 infection 36 (10.3) 70 (16.2) Severe AE 57 (16.3) 55 (12.7) Serious AE 56 (16.0) 63 (14.6) Deaths 1(0.3)b 0 (0) Adverse Events of Special Interest Hepatic disorder 27 (7.7) 39 (9.0) Creatine phosphokinase elevation 21 (6.0) 20 (4.6) Anemia 19 (5.4) 23 (5.3) Lymphopenia 18 (5.1) 37 (8.5) Neutropenia 12 (3.4) 11 (2.5) Serious infection 12 (3.4) 19 (4.4) Active tuberculosis 0 0 Herpes zoster 9 (2.6) 24 (5.5) Opportunistic infection, excluding tuberculosis and herpes zosterc 2 (0.6) 1 (0.2) Adjudicated gastrointestinal perforation 4 (1.1) 1 (0.2) Adjudicated MACE 0 0 Malignancies excluding NMSC 3 (0.9) 3 (0.7) Any NMSC 0 2 (0.5) Any lymphoma 0 0 Adjudicated VTE 0 1 (0.2) Renal dysfunction 0 1 (0.2) Any serious hypersensitivity reactions 0 0 Any retinal detachments 0 0 Any fractures 6 (1.7) 7 (1.6) Exposure-adjusted event rate is expressed as number of events per 100 patient-years (E/100 PYs). TEAEs are defined as any AEs with an onset date on or after the first dose of the study drug in the maintenance period and up to 30 days past the last dose of the study drug in the maintenance or LTE period or until 1 day prior to the rescue in the maintenance or LTE period. aAs assessed by the study investigator bAn event of suicide with no reasonable possibility of being related to the study drug as assessed by the investigator. cThree events of opportunistic infections (excluding tuberculosis and herpes zoster) were reported: esophageal candidiasis and Pneumocystis jirovecii pneumonia in the UPA 15 mg group, and esophageal candidiasis in the UPA 30 mg group. The event of Pneumocystis jirovecii pneumonia was serious and led to the discontinuation of study drug. dOne patient on UPA 15 mg had an event of gastrointestinal perforation that appeared twice in the table (diverticular perforation and abdominal abscess). AE, adverse event; COVID-19, coronavirus 2019; E, event; LTE, long-term extension; MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; PBO, placebo; PY, patient-year; TEAE, treatment-emergent adverse event; UPA, upadacitinib; VTE, Venous thromboembolic events.

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