S1474 Efficacy and Safety of Upadacitinib After 3 Years of Treatment in Patients With Moderately to Severely Active Ulcerative Colitis: Interim Long-Term Data From the Phase 3 Open-Label Extension Study (U-ACTIVATE)

Introduction: Long-term efficacy and safety has been established for upadacitinib (UPA), an oral, reversible JAK inhibitor, through studies of multiple autoimmune conditions. Methods: Efficacy and safety of UPA are reported after almost 3 years (yrs) of therapy in patients (pts) with moderately to severely active ulcerative colitis (UC) from the U-ACTIVATE study, including 1 yr maintenance and 96 weeks (wks) of long-term extension (LTE). Pts aged 16–75 yrs with UC for ≥90 days prior to study entry, Adapted Mayo score (AMS) of 5–9, and endoscopic subscore of 2 or 3 were eligible for induction studies (U-ACCOMPLISH; U-ACHIEVE) and randomized to placebo (PBO) or UPA 45 mg once daily (QD) for 8 wks. Clinical responders were re-randomized to PBO, UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for 52 wks maintenance (U-ACHIEVE). Pts completing maintenance were eligible to enter LTE on their maintenance dose. Efficacy was evaluated by clinical remission (per AMS and Partial Mayo score), maintenance of clinical remission per AMS, clinical response, endoscopic remission, endoscopic improvement and maintenance of endoscopic remission at LTE Wk96 (Table 1). Safety was assessed by treatment-emergent adverse events (TEAEs) and exposure-adjusted event rates (EAERs). Data (cutoff: June 30, 2023) were analyzed as observed without imputation for missing values. Results: At LTE Wk96, about 75% of UPA-treated pts achieved clinical remission (Table 1). Of pts in clinical remission at LTE Wk0, a similar proportion maintained response with UPA15 and slightly higher response rate was observed with UPA30 at LTE Wk96. Clinical outcomes and endoscopic improvement were observed in the majority of pts in both UPA groups. Endoscopic remission was achieved by almost half of pts treated with UPA. Of endoscopic remitters at LTE Wk0, more than half maintained remission status at LTE Wk96, with slightly higher response rate observed with UPA30. For safety, 369 pts with 789.4 patient-years (PY) of exposure were analyzed (Table 1). Rates of serious TEAEs and TEAEs leading to treatment discontinuation were similar across treatment groups. No deaths were reported with UPA15; 1 TEAE leading to death with UPA30 (EAER: 0.2 E/100 PY) occurred in a pt requiring prolonged hospitalization for worsening COVID-19 infection. Conclusion: Continued benefit of UPA therapy after almost 3 years in pts with UC was observed by achievement of clinical and endoscopic endpoints at LTE Wk96. The long-term safety profile for UPA was consistent with previous findings. Table 1. - Summary of efficacy and safety (as observed) Efficacy endpoints at Week 96a n/N (%) [95% CI] UPA 15 mg QD UPA 30 mg QD Clinical remission per Adapted Mayo scoreb ----------Clinical remission per Partial Mayo scorec 69/91 (75.8) [67.0, 84.6]----------83/92 (90.2) [84.1, 96.3] 104/141 (73.8) [66.5, 81.0]----------123/143 (86.0) [80.3, 91.7] Maintenance of clinical remissiond 50/64 (78.1) [68.0, 88.3] 69/82 (84.1) [76.2, 92.1] Clinical response per Adapted Mayo scoree 89/91 (97.8) [94.8, 100.0] 136/141 (96.5) [93.4, 99.5] Endoscopic improvementf ----------Endoscopic remissiong 78/95 (82.1) [74.4, 89.8]----------45/95 (47.4) [37.3, 57.4] 126/153 (82.4) [76.3, 88.4]----------69/153 (45.1) [37.2, 53.0] Maintenance of endoscopic remissionh 20/31 (64.5) [47.7, 81.4] 37/51 (72.5) [60.3, 84.8] TEAEs a E (E/100 PY) UPA 15 mg QD (n=142; PY=302.5) UPA 30 mg QD (n=227; PY=486.9) Any TEAEsi Serious TEAEsTEAEs leading to discontinuation of study drugTEAEs leading to death 699 (231.1)32 (10.6)15 (5.0)0 1097 (225.3)60 (12.3)17 (3.5)1j (0.2) aEfficacy and safety populations included induction responders (UPA 45 mg for 8 weeks) who completed 52 weeks of maintenance treatment and enrolled in this LTE analysis. Patients who were not in clinical remission could escalate their dose upon entry to this LTE.bAdapted Mayo score ≤2 with stool frequency subscore ≤1 and not greater than baseline of induction studies, RBS=0 and ES ≤1 without friability.cPartial Mayo score ≤2 with no subscore >1.dClinical remission per Adapted Mayo score at Week 96 in those who achieved clinical remission at Week 0 of the LTE study.eDecrease in Adapted Mayo score ≥2 points and ≥30% from baseline of induction studies, plus a decrease in RBS ≥1 or an absolute RBS ≤1.fES ≤1 without friability.gES=0.hPatients who achieved endoscopic remission at Week 96 among those who achieved endoscopic remission at Week 0 of the LTE study.iTEAEs are defined as events that begin either on or after the first dose of study drug in the LTE study, and within the earlier of the first dose change in the LTE study and the last dose of study drug in the LTE study plus 30 days.jFifty-seven-year-old male who experienced a suspected pulmonary thromboembolism event while hospitalised for worsening of COVID-19 infection and acute renal failure. Primary cause of death was pulmonary embolism. Risk factors included medical history of arterial hypertension, former cigarette smoker, concurrent COVID-19 infection and prolonged hospitalisation.CI, confidence interval; E, events; ES, endoscopic subscore; LTE, long-term extension; PY, patient years; QD, once daily; RBS, rectal bleeding subscore; TEAE, treatment-emergent adverse event; UPA, upadacitinib.

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