Safety of Upadacitinib in IBD: Pooled Analysis of Phase 3 Maintenance Studies, U-ACHIEVE and U-ENDURE, In Patients With Moderately to Severely Active Ulcerative Colitis or Crohn's Disease

Introduction: Upadacitinib (UPA), an oral and reversible Janus kinase inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for maintenance treatment in patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD) in two phase 3, double-blind, PBO-controlled trials, U-ACHIEVE1 (NCT02819635) and U-ENDURE2 (NCT03345823). UPA is approved for the treatment of patients with moderate to severe UC and CD.3-5 Safety analysis of UPA supports the benefit/risk assessment in the management of UC and CD patients. Reported here are adverse events (AEs) through week (wk) 52 of maintenance for the integrated intent-to-treat population from both studies, for patients treated with UPA 15 mg (UPA15), UPA 30 mg QD (UPA30) or PBO. Methods: AEs were pooled among patients who responded to an induction dose of UPA 45 mg QD at wk 8 (UC) or wk 12 (CD) and then received at least one dose of PBO, UPA15 or UPA30 during maintenance. As the randomization ratios were identical for each study 1:1:1 there was no need to stratify the pooling by study. Results: Overall, 1419 patients (U-ACHIEVE N=746; U-ENDURE N=673) were included in the analysis with 246.4 patient years (PY) of exposure in PBO, 353.1PY in UPA15, and 395.7PY in UPA30. At baseline of induction, demographics and disease characteristics were balanced across treatment arms (Table 1). Rates of serious AEs, AE leading to treatment discontinuation and serious infections were similar across both UPA doses, and lower than PBO; rates of herpes zoster were higher with UPA than PBO, with slightly more cases in UPA30. One gastrointestinal perforation was reported in each UPA treatment group (0.3/100PY), while 2 were reported in PBO (0.8/100PY). Adjudicated major adverse cardiovascular events were reported in 1 patient treated with UPA30 (0.3/100PY) and 1 with PBO (0.4/100PY), while 2 patients had adjudicated venous thromboembolic events among each of the UPA treatment groups (0.5-0.6/100PY) compared to none among PBO. Malignancies excluding non-melanoma skin cancer (NMSC) were reported in 2 patients on UPA15 (0.6/100PY), 4 patients on UPA30 (1.0/100PY), and 1 on PBO (0.4/100PY); NMSC was observed in 3 patients on UPA30 (0.8/100PY). No tuberculosis, lymphoma, or death occurred in any treatment group. Conclusion: UPA is generally well-tolerated and both maintenance doses have an acceptable safety profile in patients with moderate to severe UC and CD. No new safety signals were observed. Table 1. - The analyzed pooled population includes all patients who received at least 1 dose of UPA 15 mg, UPA 30 mg QD or PBO during U-ACHIEVE or U-ENDURE Baseline Characteristics and Demographics, n (%) PBO (Pooled) n=468 UPA15 (Pooled) n=471 UPA30 (Pooled) n=480 Sex Females 222 (47.4) 178 (37.8) 195 (40.6) Males 246 (52.6) 293 (62.2) 285 (59.4) Age, mean (SD) 40.7 (14.0) 39.8 (14.0) 40.0 (14.1) Race American Indian or Alaska Native 1 (0.2) 0 0 Asian 111 (23.7) 124 (26.3) 133 (27.7) Black or African American 18 (3.8) 17 (3.6) 16 (3.3) Multiple 10 (2.1) 2 (0.4) 4 (0.8) Native Hawaiian or other Pacific Islander 1 (0.2) 0 1 (0.2) White 327 (69.9) 328 (69.6) 326 (67.9) Body mass index, kg/m2, mean (SD) 24.9 (5.9) 24.6 (5.8) 24.9 (6.1) Medications at baseline Steroids 178 (38.0) 178 (37.8) 178 (37.1) Immunomodulators 14 (3.0) 7 (1.5) 12 (2.5) Any cardiovascular risk factor† 358 (76.5) 353 (74.9) 384 (80.0) Prior biologic history With failure 303 (64.7) 290 (61.6) 293 (61.0) Without failure 165 (35.3) 181 (38.4) 187 (39.0) > 1 biologic 191 (40.8) 178 (37.8) 194 (40.4) Treatment-Emergent Adverse EventsNumber of events (Events/100 patient-years) Patient-years 246.4 353.1 395.7 Any AE 1190 (482.9) 1166 (330.2) 1266 (319.9) Serious AE 69 (28.0) 61 (17.3) 57 (14.4) Severe AE 68 (27.6) 56 (15.9) 54 (13.6) Any AE leading to discontinuation of study drug 34 (13.8) 30 (8.5) 33 (8.3) Any AE with reasonable possibility of being related to study drug 326 (132.3) 317 (89.8) 380 (96.0) Death 0 0 0 Treatment-Emergent Adverse Events of Special InterestNumber of events (Events/100 patient-years) Serious infections 18 (7.3) 19 (5.4) 20 (5.1) Opportunistic infections excluding tuberculosis and herpes zoster 2 (0.8) 3 (0.8) 3 (0.8) Active tuberculosis 0 0 0 Herpes zoster 5 (2.0) 18 (5.1) 29 (7.3) Anemia 32 (13.0) 27 (7.6) 21 (5.3) Neutropenia 8 (3.2) 14 (4.0) 25 (6.3) Lymphopenia 15 (6.1) 16 (4.5) 18 (4.5) Creatine phosphokinase (CPK) elevation 8 (3.2) 21 (5.9) 32 (8.1) Renal dysfunction 3 (1.2) 1 (0.3) 1 (0.3) Hepatic disorder§§ 11 (4.5) 46 (13.0) 37 (9.4) Exposure-Adjusted Incidence RatesNumber of patients/patient years (n/100 patient years)§ Adjudicated gastrointestinal perforations 2/246.7 (0.8) 1/353.4 (0.3) 1/395.9 (0.3) Adjudicated MACE†† 1/246.4 (0.4) 0/353.1 1/394.9 (0.3) Adjudicated VTE‡ 0/246.4 2/352.8 (0.6) 2/395.7 (0.5) Malignances excluding NMSC‡‡ 1/246.4 (0.4) 2/353.4 (0.6) 4/396.3 (1.0) NMSC 0/246.4 0/353.1 3/394.6 (0.8) Lymphoma 0/246.4 0/353.1 0/395.7 Adverse events are reported as exposure-adjusted events per 100 patient-years (E/100PY). To adjust for potentially different follow-up times between treatment groups, exposure-adjusted event rates (EAER) were calculated for the overview of number of adverse events reported (all AEs, serious AEs, severe AEs, AEs leading to premature discontinuation, and AEs possibly related to study drug). For event rate calculation, the numerator was the total number of AEs reported for the event within a particular treatment group (i.e., a patient can contribute more than one event to the numerator), and the denominator was the total exposure time (based upon last dose date and first dose date) among subjects within the particular treatment group or population. ¶Number of patients for Body mass index, N=468 PBO; N=471 UPA15; N=478 UPA30 †Cardiovascular risk factors included: Prior history of cardiovascular event(s), hypertension, diabetes mellitus, current tobacco/nicotine use, elevated LDL-C (≥ 3.36 mmol/L), depressed HDL-C (≤ 1.55 mmol/L). §Adverse events that typically occur in a single instance are presented as exposure-adjusted incidence rates (n/100PY) §§Hepatic disorders were generally mild or moderate transaminase elevations that rarely led to treatment discontinuation. †† MACE: Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction and non-fatal stroke ‡ VTE: Venous Thromboembolic Events, defined as deep vein thrombosis and pulmonary embolism (fatal and non-fatal). ‡‡Malignancy excluding NMSC: Invasive breast carcinoma in the placebo group, invasive breast carcinoma and ovarian cancer metastatic in the UPA 15 mg group, and small cell carcinoma, invasive lobular breast carcinoma and adenocarcinoma of colon (n=2) in the UPA 30 mg group.