S733 Impact of Inflammatory Burden on Efficacy of Upadacitinib Maintenance Therapy in Ulcerative Colitis: Results From the Phase 3 U-ACHIEVE Study

Abstract

Introduction: Upadacitinib (UPA) has demonstrated superior efficacy to placebo (PBO) and a favorable safety profile in patients with moderately to severely active ulcerative colitis (UC) in trial U-ACHIEVE Maintenance, in which two maintenance doses of UPA (30mg and 15mg once daily [QD]) were evaluated.1–3 However, data are limited on the impact of inflammatory burden on the efficacy of the two maintenance doses. Methods: The primary efficacy analysis of U-ACHIEVE Maintenance included the first 451 patients who achieved a clinical response (per Adapted Mayo score) after 8 weeks of UPA 45mg QD treatment in the induction trials. The primary endpoint was clinical remission per Adapted Mayo score at Week 52 and a key secondary endpoint was endoscopic improvement at Week 52. This post hoc analysis evaluated the efficacy, based on these endpoints, of UPA 30mg vs UPA 15mg maintenance therapy in patients in U-ACHIEVE Maintenance stratified by three measures of inflammatory burden: baseline Full Mayo score >9 vs ≤9, presence of pancolitis (yes vs no), and presence of ≥1 extraintestinal manifestation (yes vs no). Results: Overall, 451 patients (PBO: n=149, UPA 15mg: n=148, and UPA 30mg: n=154) were included in the intent-to-treat maintenance population. Both UPA 30mg and UPA 15mg demonstrated favorable efficacy compared with PBO, regardless of the inflammatory burden (Table). However, the differences in proportions of responders who achieved clinical remission at Week 52 and who received UPA 30mg vs UPA 15mg were greater in patients with a high inflammatory burden (difference range: 12.0–22.0%) than those patients without a high inflammatory burden (difference range: 1.4–6.2%; Table). Similar results were seen for proportions of patients who achieved endoscopic improvement at Week 52 (high inflammatory burden [difference range: 12.0–26.1%] relative to those without high inflammatory burden [difference range: 0.2–14.1%]). Conclusion: Both UPA maintenance doses were efficacious compared with PBO, regardless of inflammatory burden, in the achievement of clinical remission and endoscopic improvement. Although results should be interpreted with respect to the small sample size in some subgroups and the post hoc nature of the analysis, these data suggest that patients with a high inflammatory burden of UC may have a relatively greater benefit from UPA 30mg than UPA 15mg, compared with those without high inflammatory burden. Table 1. - PBO, n/N (%)(N=149) UPA 15 mg QD, n/N (%)(N=148) UPA 30 mg QD, n/N (%)(N=154) Difference between UPA 30 mg vs UPA 15 mg a , % Primary endpoint: Clinical remission b at Week 52 per Adapted Mayo Score BL Full Mayo score ≤9 BL Full Mayo score >9 7/74 (9.5)11/75 (14.8) 40/75 (53.1)23/73 (31.2) 40/73 (54.5)40/79 (50.4) 1.419.2 Pancolitis at BL, noPancolitis at BL, yes 13/79 (16.5)5/70 (7.1) 31/66 (46.6)32/82 (38.8) 36/68 (52.8)44/86 (50.8) 6.212.0 EIM at BL, noEIM at BL, yes 13/112 (11.6)5/37 (13.7) 50/112 (44.3)13/36 (36.1) 56/113 (49.4)24/41 (58.1) 5.122.0 Key secondary endpoint: Endoscopic improvement c at Week 52 BL Full Mayo score ≤9BL Full Mayo score >9 8/74 (10.8)14/75 (18.1) 45/75 (60.4)27/73 (36.7) 44/73 (60.6)50/79 (62.8) 0.226.1 Pancolitis at BL, noPancolitis at BL, yes 16/79 (20.3)6/70 (8.0) 33/66 (49.6)39/82 (47.9) 43/68 (63.7)52/86 (59.9) 14.112.0 EIM at BL, noEIM at BL, yes 15/112 (13.7)6/37 (16.9) 57/112 (50.9)15/36 (41.7) 68/113 (60.2)27/41 (65.4) 9.323.7 Data are from the ITT population, defined as the first 450 randomized and treated patients with 8-week UPA 45 mg QD induction treatment who were enrolled in Cohort 1 under the protocol for the 52-week maintenance treatment period. The actual number of patients in the analysis was 451 due to the same enrollment date of the 450th and 451st patients. Non-responder imputation incorporating multiple imputations was performed to handle missing data due to COVID-19 incidence.aNot part of the predefined statistical analyses.bAdapted Mayo score ≤2, with stool frequency subscore ≤1 (and not greater than induction baseline), rectal bleeding subscore of 0, and endoscopic subscore ≤1.cEndoscopic subscore ≤1.BL, baseline; EIM, extraintestinal manifestation; ITT, intent-to-treat; PBO, placebo; QD, once daily; UPA, upadacitinib.