Benefit-Risk Profile of Upadacitinib: Exploratory Post Hoc Analysis of Phase 2b/3 Studies in Patients With Moderately to Severely Active Ulcerative Colitis or Crohn’s Disease

Abstract Background and Aims Upadacitinib (UPA)—an oral, reversible selective Janus kinase inhibitor—has a favorable benefit-risk profile for patients with Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated the benefit-risk of UPA in select subgroups with CD or UC. Methods Patients were randomized to UPA 45 mg (UPA45) once daily (QD) or placebo (PBO) induction for 12 (CD: U-EXCEED, U-EXCEL) or 8 weeks (UC: U-ACHIEVE, U-ACCOMPLISH). Clinical responders were re-randomized to QD UPA 15 mg (UPA15), UPA 30 mg (UPA30), or PBO for 52-week maintenance (CD: U-ENDURE; UC: U-ACHIEVE). This exploratory post-hoc analysis assessed efficacy and safety outcomes (adverse events of special interest [AESIs]: serious infections, major adverse cardiovascular [CV] events, malignancies, and venous thromboembolic events) by CV risk, prior treatment failure, and age. Results This analysis included 1021 patients with CD and 1097 with UC during induction, and 673 with CD and 746 with UC during maintenance. Improved efficacy outcomes comparable to the overall study populations were observed with UPA versus PBO across subgroups. Patients receiving UPA30 generally showed numerically higher rates of improvements versus UPA15. AESI rates were generally comparable between UPA and PBO across subgroups except for numerically higher rates of herpes zoster and serious infections in CD with UPA. Conclusions UPA resulted in consistent benefit versus placebo across CV risk, prior treatment failure, and age subgroups. No treatment differences were seen in AESIs across subgroups except herpes zoster and serious infections, reinforcing the favorable benefit-risk profile for UPA in CD and UC seen in the overall study populations. Clinical Trial Numbers NCT02819635, NCT03653026, NCT03345836, NCT03345849, NCT03345823