S722 Efficacy and Safety of Upadacitinib in Patients With Moderate to Severe Active Ulcerative Colitis Receiving 16 Weeks Extended Induction Treatment Followed by 52 Weeks Maintenance Treatment in U-ACHIEVE/U-ACCOMPLISH Trials

Introduction: This analysis evaluated efficacy and safety of UPA after extended induction treatment(UPA 45mg QD for 16 wks) and subsequent maintenance treatment(UPA 15mg QD or UPA 30mg QD for 52 wks). Methods: Patients who did not achieve clinical response(Adapted Mayo score decrease ≥2 points and ≥30% from baseline, plus ≥1 point decrease in rectal bleeding score [RBS] or absolute RBS ≤1) following initial 8 weeks (wks) UPA 45mg once daily (QD) treatment in induction trials were eligible to receive additional 8-wk, open-label extended treatment with UPA 45mg QD. Patients with clinical response following completion of the extended induction(Wk 16) were re-randomized 1:1 to UPA 15mg QD or UPA 30mg QD in U-ACHIEVE Maintenance trial(NCT02819635). Results: Of patients who received UPA 45mg QD in the induction trials, 125 did not achieve clinical response at 8 wks and received further 8 wks induction treatment. At Wk 16, 73/125(58.4%) subsequently responded and were re-randomized to maintenance UPA 15mg QD or UPA 30mg QD. Among 16-wk responders who entered the maintenance trial, a greater proportion of patients who received UPA 30mg QD vs UPA 15mg QD achieved the primary endpoint of clinical remission at 52 wks(43.6% vs 26.5%, respectively), and secondary endpoints of clinical response(78.1% vs 49.1%, respectively) and endoscopic improvement(51.3% vs 34.3%, respectively) at 52 wks (Table). A similar pattern was seen across clinical, endoscopic, and histologic endpoints (Table). At Wk 52, the proportions of patients with serious adverse events(AEs) were 2.9% with UPA 15mg QD and 10.0% with UPA 30mg QD. Selected AEs of special interest with UPA 15mg QD and UPA 30mg QD included serious infection(2.9% vs 5.0% of patients, respectively), herpes zoster(0% vs 5.0%, respectively), adjudicated major adverse cardiovascular events(0% vs 2.5%, respectively), and non-melanoma skin cancer(NMSC; 0% vs 2.5%, respectively). No adjudicated venous thromboembolic events or cases of malignancy excluding NMSC were reported with UPA doses. Conclusion: Extended induction treatment for further 8 wks with UPA 45mg QD induced response in over half of patients with UC who did not achieve a response after 8 wks. The benefit of maintenance therapy in delayed responders was shown with both UPA doses, though UPA 30mg QD provided greater benefit than UPA 15mg QD. UPA was well tolerated with no new safety signals and selected AEs of special interest were reported infrequently with both maintenance doses. Table 1. - Primary and key secondary endpoints, % UPA 45 mg QD at Week 16 (induction) a (N=125) UPA 15 mg QD at Week 52 (maintenance) b (N=34) UPA 30 mg QD at Week 52 (maintenance) b (N=39) Primary endpoint: Clinical remission c 5.6 26.5 43.6 Clinical response d 58.4 (N=25)49.1 (N=32)78.1 No abdominal pain 40.0 38.2 48.7 No bowel urgency 30.4 32.4 59.0 Endoscopic improvement e Endoscopic remission f 14.34.9 34.312.2 51.317.9 Histologic-endoscopic mucosal improvement g Mucosal healing h 11.03.4 21.912.0 41.012.8 Among patients who achieved clinical remission at the end of induction: Clinical remission c Clinical remission c and corticosteroid free for ≥90 days immediately prior to Week 52 N/AN/A (N=3) 00 (N=4) 100100 Among patients who achieved endoscopic improvement at the end of induction: Endoscopic improvement e N/A (N=7)42.9 (N=9)66.7 Data are presented for the ITT population comprising patients who achieved a clinical response with 16-week UPA 45 mg QD induction therapy and were re-randomized to receive UPA 15 mg or 30 mg QD maintenance therapy.aTwo patients were excluded from analysis owing to site non-compliance as prespecified in the statistical analysis plan.bIncluded patients who had completed, or had the potential to complete, 52 weeks’ maintenance treatment.cPer Adapted Mayo score ≤2: stool frequency subscore ≤1 and not greater than induction baseline, RBS=0, and ES ≤1.dInduction therapy (UPA 45 mg QD): Clincal response, defined as a decrease in Adapted Mayo score ≥2 and ≥30% from induction baseline, plus a decrease in RBS ≥1 or an absolute RBS ≤1, at Week 16. Maintenance therapy (UPA 15 mg or 30 mg, QD): Maintenance of clinical response at Week 52 among patients who achieved clinical response at the end of the 16-week induction therapy.eES ≤1.fES=0.gES ≤1 and Geboes score ≤3.1.hES=0 and Geboes score < 2.ES, endoscopic subscore; ITT, intent-to-treat; N/A, not applicable; QD, once daily; RBS, rectal bleeding subscore; UPA, upadacitinib.

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