Remo Panaccione, Julián Panés, Laurent Peyrin-Biroulet, Jean-Frédéric Colombel, J O Lindsay, Filip J. Baert, Raja Atreya, Séverine Vermeire, Toshimitsu Fujii, Elena Dubcenco, Justin Klaff, Benjamin Duncan, Smitha Suravaram, Irina Fish, Ana P. Lacerda, Ramona Vladea, Sharanya Ford, Saajan Shah, S. Anyanwu, David T. Rubin
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.