Long-Term Safety of Upadacitinib in Patients With Inflammatory Bowel Disease: Integrated Analysis of Phase 2/3 Studies

BACKGROUND & AIMS: Upadacitinib (UPA) is an oral, reversible Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We assessed the long-term safety of UPA in both inflammatory bowel disease (IBD) entities. METHODS: Safety from 6 UC/CD trials assessed UPA 45 mg (UPA45) once daily (QD) induction, UPA 15 mg and 30 mg (UPA 15/30 QD) maintenance/long-term extension (LTE) doses, and rescue therapy (UPA30 QD). Adverse events (AEs) were reported as events per 100 patient-years (E/100 PY). RESULTS: Overall, 2118 patients received placebo (PBO; n = 725) or UPA45 (n = 1393) induction; 1419 received PBO (n = 468), UPA15 (n = 471), or UPA30 (n = 480) maintenance/LTE. During maintenance/LTE, UPA cumulative exposure was 5149.3 patient-years (n = 1910). Median treatment duration was 8.7 weeks (interquartile range [IQR], 8.0-12.0 weeks) for UPA45 induction; median maintenance/LTE treatment duration was 58.1 weeks (IQR, 30.4-164.0 weeks) for UPA15, and 130.9 weeks (IQR, 39.4-175.1 weeks) for UPA30. AE incidence was comparable between UPA and PBO during induction and maintenance/LTE; AEs leading to study drug discontinuation and serious or severe AEs were lower with UPA. During maintenance/LTE, rates (UPA15/30 vs PBO) of venous thromboembolic events (0.3/0.4 vs 0 E/100 PY), gastrointestinal perforations (0.4/<0.1 vs 0.8 E/100 PY), and AEs leading to death (0.2/<0.1 vs 0 E/100 PY) were low. Herpes zoster, neutropenia, lymphopenia, creatine phosphokinase elevation, hepatic disorder, and COVID-19 were higher across UPA groups vs PBO; COVID-19 and herpes zoster were among the most common AEs during maintenance. CONCLUSIONS: Long-term, UPA was generally well-tolerated. This integrated analysis supports the favorable safety profile of UPA and treatment decisions for patients with IBD. CLINICALTRIALS: gov, Numbers: NCT02819635, NCT03653026, NCT03006068, NCT03345836, NCT03345849, and NCT03345823.