S777 Benefit–Risk Assessment of Upadacitinib Treatment in Patients With Moderately to Severely Active Ulcerative Colitis

Introduction: Efficacy and safety of upadacitinib(UPA) as induction and maintenance therapy in patients with moderate to severe active ulcerative colitis have been demonstrated in a Phase 3 clinical trial program.1–3 Methods: Patients with clinical response(per Adapted Mayo score) after 8 weeks (wks) of UPA 45mg once daily(QD) induction treatment in U-ACHIEVE Induction(NCT02819635) or U-ACCOMPLISH(NCT03653026) were re-randomized to U-ACHIEVE Maintenance(NTC02819635) receiving UPA 15mg QD, UPA 30mg QD, or placebo(PBO) maintenance therapy. We present 52wk efficacy and safety benefit–risk assessment of UPA 15mg and UPA 30mg vs PBO. For efficacy outcomes, point estimates and 95% confidence intervals(CI) of PBO-adjusted treatment effect were calculated. For risk analysis, exposure-adjusted event rates(events per 100 patient-years [E/100 PY]) of selected adverse events of special interest were evaluated. Results: Overall, 681 patients were analyzed for efficacy(UPA 15mg, 225; UPA 30mg, 233; PBO, 223). For primary endpoint of clinical remission at wk 52, point estimates of PBO-adjusted treatment effect were 30.1%(95% CI: 22.7, 37.4) with UPA 15mg and 42.9%(35.4, 50.4) with UPA 30mg(p< 0.001 for both; Table). Significant differences were observed across secondary endpoints for UPA doses vs PBO(all p< 0.001; Table). Rates of serious infections were 5.9 E/100 PY with PBO vs 5.0 and 3.2 for UPA 15mg and UPA 30mg, respectively. No events of herpes zoster were reported with PBO, while rates with UPA 15mg and UPA 30mg were 6.0 and 7.3 E/100 PY, respectively. Rates of malignancy excluding non-melanoma skin cancer were 0.7 E/100 PY with PBO vs 0.5 and 0.9 with UPA 15mg and UPA 30mg, respectively; rates of non-melanoma skin cancer were 1.4 E/100 PY with UPA 30mg, with no cases reported with UPA 15mg or PBO. Adjudicated venous thromboembolic events were low in UPA groups and no cases were reported with PBO; adjudicated major adverse cardiovascular events were low with PBO and UPA 30mg, and none with UPA 15mg (Table). Conclusion: Response rates were significantly greater with UPA 15mg and UPA 30mg versus PBO across endpoints assessed. UPA doses were well tolerated. Rates of herpes zoster and creatine phosphokinase elevation, known safety signals of JAK inhibitors,4 were dose-dependent. The data suggest that UPA 15mg and UPA 30mg QD have a favorable benefit–risk profile after 52wks maintenance therapy. The safety of UPA continues to be monitored in long-term extension study. Table 1. - Primary and key secondary endpoints at Week 52 UPA 15 mg QD – PBO response rate difference, % (95% CI) a UPA 30 mg QD – PBO response rate difference, % (95% CI) a Clinical remission b 30.1 (22.7, 37.4)*** 42.9 (35.4, 50.4)*** Endoscopic improvement c 34.4 (26.7, 42.1)*** 49.0 (41.4, 56.7)*** Maintenance of clinical remission d 34.9 (21.2, 48.5)*** 46.9 (34.0, 59.8)*** Corticosteroid-free clinical remission e 33.7 (20.0, 47.3)*** 45.5 (32.6, 58.5)*** Maintenance of endoscopic improvement f 42.2 (30.4, 53.9)*** 51.5 (40.9, 62.1)*** Endoscopic remission g 18.6 (12.2, 25.0)*** 21.9 (15.4, 28.5)*** Histologic-endoscopic mucosal improvement h 28.5 (21.1, 35.9)*** 43.8 (36.1, 51.5)*** Mucosal healing i 13.5 (7.8, 19.3)*** 17.2 (11.2, 23.3)*** Selected adverse events of special interest j PBO, E (E/100 PY) (N=245) UPA 15 mg QD, E (E/100 PY) (N=250) UPA 30 mg QD, E (E/100 PY) (N=251) Serious infection 8 (5.9) 10 (5.0) 7 (3.2) Herpes zoster 0 12 (6.0) 16 (7.3) CPK elevation 5 (3.7) 16 (8.0) 22 (10.1) Malignancy (excluding NMSC) 1 (0.7) 1 (0.5) 2 (0.9) NMSC 0 0 3 (1.4) Adjudicated MACE 1 (0.7) 0 1 (0.5) Adjudicated VTE 0 2 (1.0) 2 (0.9) ***p< 0.001.aThe efficacy analysis was based on the ITT population. Results are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19. The point estimate and 95% CI for treatment difference are based on Cochran–Mantel–Haenszel tests adjusted for strata (corticosteroid use at Week 0 [yes or no], clinical remission status at Week 0 [yes or no], biologic-IR status at baseline [biologic-IR or non-biologic-IR]).bStool frequency subscore ≤1 and not greater than baseline (of induction), RBS=0, and ES ≤1.cES ≤1.dAmong patients with clinical remission at the end of the induction therapy.eClinical remission at Week 52 and corticosteroid free for ≥90 days prior to Week 52 among patients with clinical remission at the end of the induction therapy.fEndoscopic improvement at Week 52 among patients with endoscopic improvement at the end of the induction therapy.gES=0.hES ≤1 and Geboes score ≤3.1.iES=0 and Geboes score < 2.jThe safety analysis included all patients who received ≥1 dose of study therapy (ITT population plus patients who received up to 44 weeks’ maintenance therapy under earlier versions of protocol amendments).CI, confidence interval; CPK, creatine phosphokinase; E, event; ES, endoscopic subscore; IR, inadequate responder; ITT, intention-to-treat; MACE, major adverse cardiovascular event; NMSC, non-melanoma skin cancer; QD, once daily; PBO, placebo; PY, patient-years; RBS, rectal bleeding subscore; UPA, upadacitinib; VTE, venous thromboembolic event.

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