S736 Efficacy and Safety of Upadacitinib Induction Therapy in Patients With Moderately to Severely Active Crohn’s Disease: Results From a Randomized Phase 3 U-EXCEL Study

Introduction: Eligible patients(N=526) with moderate to severe active Crohn’s Disease(CD), defined as average daily stool frequency(SF)≥4 and/or abdominal pain score(APS)≥2, and a Simple Endoscopic Score for CD(SES-CD) (excluding the narrowing component subscore) ≥6(≥4 for subjects with isolated ileal disease). Methods: Patients(pts) were randomized 2:1 to UPA45 or PBO for 12 weeks(wks). Pts on baseline corticosteroids(CS) initiated a protocolized tapering at wk4. The co-primary endpoints, clinical remission(per CDAI for US [CDAI< 150] or per SF/APS for EU [average daily SF ≤2.8 and APS≤1.0 and neither greater than baseline [BL]) and endoscopic response(decrease in SES-CD >50% from BL or ≥2-point reduction from BL for pts with a BL SES-CD=4), were evaluated at wk 12. Safety, primary and key secondary clinical, and endoscopic outcomes were evaluated through wk 12. Results: BL demographics and characteristics were similar between groups; 45.4% of pts had a history of prior biologic use or failure. At wk 12, significantly more pts receiving UPA45 vs PBO achieved the co-primary endpoints: clinical remission(per CDAI, UPA45 49.5% vs PBO 29.1%; per SF/APS, UPA45 50.7% vs PBO 22.2%) and endoscopic response (UPA45 45.5% vs PBO 13.1%) (P< .0001 for all endpoints; Table). UPA45 was superior to PBO for most of the ranked secondary endpoints including clinical remission per CDAI and SF/APS at wk 4, CS-free clinical remission per CDAI and SF/APS at wk 12, clinical response(CR-100; 100-point decrease in CDAI from BL at wk 2 and wk 12, and endoscopic remission at wk 12(P< .0001 or P< .01, Table). Severe AEs occurred at 8.9% and 8.5% within UPA45 and PBO groups, respectively. The most common AEs(≥5% of pts) were acne and anemia among pts treated with UPA, and CD exacerbation among pts receiving PBO. Serious infections were 1.1% and 1.7% for UPA45 and PBO groups, respectively. Herpes zoster(2.9%) was reported in the UPA45 group only, and an adjudicated cardiovascular event(0.6%) was reported only in the PBO group. No treatment-emergent deaths, malignancies, other opportunistic infections, adjudicated gastrointestinal perforations or adjudicated thrombotic events were reported in either group. Conclusion: UPA45 induction therapy was superior to PBO in achieving early response, including clinical remission, endoscopic response, and CS-free clinical remission during the U-EXCEL study. UPA45 was well tolerated, with no new safety risks and a safety profile comparable to previous UPA studies. Table 1. - Co-primary and Key Secondary Endpoints Endpoint PBO (N=176)% [95% CI] g UPA 45 mg QD (N=350)% [95% CI] g Difference vs. PBO% [95% CI] h Co-Primary Endpoints Clinical remission, wk 12 Per CDAI a Per SF/APS b 29.1 [22.4, 35.8]22.2 [16.0, 28.3] 49.5 [44.2, 54.8]50.7 [45.5, 56.0] 20.8 [12.7, 28.8]**28.7 [20.9, 36.4]** Endoscopic response c , wk 12 13.1 [8.1, 18.0] 45.5 [40.3, 50.8] 33.0 [26.2, 39.9]** Key Secondary Endpoints Clinical Remission, wk 4 Per CDAI a Per SF/APS b 26.7 [20.2, 33.3]14.8 [9.5, 20.0] 37.1 [32.1, 42.2]35.7 [30.7, 40.7] 10.8 [2.9, 18.6]*21.2 [14.3, 28.2]** Corticosteroid-free clinical remission, wk 12 per CDAI d per SF/APS d (N=64)15.7 [6.8, 24.7]12.5 [4.4, 20.6] (N=126)42.9 [34.2, 51.5]44.4 [35.8, 53.1] 27.7 [15.7, 39.8]**32.6 [21.5, 43.7]** Clinical Response CR-100 e Week 2 Week 12 20.4 [14.4, 26.5]37.3 [30.1, 44.5] 32.2 [27.3, 37.1]56.6 [51.4, 61.8] 11.7 [4.2, 19.2]*19.8 [11.3, 28.4]** Endoscopic remission f , wk 12 7.4 [3.5, 11.3] 28.9 [24.2, 33.7] 21.8 [15.8, 27.8]** Patient randomization was stratified by baseline corticosteroid use, endoscopic disease severity, and the number of previously failed biologics. All patients within this dataset were included here within the ITT population.aClinical remission per CDAI = per US, CDAI < 150.bClinical remission per SF/APS = per EU, average daily SF ≤ 2.8 and average daily APS ≤ 1.0 and both not greater than baselinecEndoscopic response = decrease in SES-CD > 50% from baseline (or for subjects with a baseline SES-CD of 4, at least a 2-point reduction from baseline), as scored by a central reviewer.dCorticosteroid-free clinical remission = discontinuation of corticosteroid use and achievement of clinical remission per CDAI or SF/APS at wk 12 among patients on corticosteroids at baseline.eClinical response-100 = decrease of ≥ 100 points in CDAI from baseline.fEndoscopic remission = SES-CD ≤ 4, at least a 2-point reduction versus baseline and no subscore >1 in any individual variable, as scored by a central reviewer.gResults are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C).h95% CI for adjusted difference and p-value are calculated according to the Cochran-Mantel-Haenszel (CMH) test adjusted for randomization strata.**P ≤ .0001 or *P ≤ .01 vs PBO; Average daily abdominal pain score, APS; Coronavirus disease 2019, COVID-19; Confidence Interval, CI; Crohn’s Disease Activity Index, CDAI; Simple Endoscopic Score for CD, SES-CD, Placebo, PBO; Once daily, QD; average daily very soft/liquid stool frequency, SF; Upadacitinib, UPA.

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