The preclinical discovery and development of upadacitinib for the treatment of Crohn's disease

Abstract

Introduction: The JAK-STAT pathway plays a pivotal role in immune regulation and is implicated in the pathogenesis of Crohn's disease (CD). Upadacitinib is a JAK inhibitor with greater selectivity for JAK1 over JAK2 and JAK3, and is emerging as a promising alternative to biologic therapies in CD.

Areas covered: A literature search of MEDLINE and EMBASE up to February 2025 was conducted using defined keywords to identify preclinical, clinical, and real-world studies on upadacitinib in CD. In early trials, upadacitinib demonstrated efficacy in reducing proinflammatory cytokines, improving intestinal barrier integrity, and achieving high intracellular drug concentrations in target tissues. The phase II CELEST trial demonstrated that upadacitinib induced both endoscopic and clinical responses in patients with moderate-to-severe CD. Subsequent phase III studies (U-EXCEED, U-EXCEL, U-ENDURE) confirmed rapid clinical remission, sustained efficacy, and a manageable safety profile, leading to regulatory approval. The efficacy and safety of this molecule in CD have been confirmed by real-world studies.

Expert opinion: The currently available data suggests that upadacitinib is an effective oral therapy for CD, offering an alternative to biologics with predictable pharmacokinetics, rapid symptom relief, and sustained long-term benefits. Future research will refine its role in treatment algorithms, biomarker-driven personalization, and combination therapies.

Keywords: CELEST study; U-ENDURE; U-EXCEED; U-EXCEL; Upadacitinib; crohn’s disease.