Biologic and small-molecule therapies for inflammatory bowel disease: mechanisms, comparative evidence and the emerging pipeline

Abstract

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic immune-mediated disorder of rising global prevalence, with newly industrialised nations now entering the phase of most rapid growth. Its therapeutic landscape has transformed since 2020. Three selective interleukin (IL)-23p19 antagonists have been approved for both UC and CD; two sphingosine-1-phosphate receptor modulators and a second-generation Janus kinase (JAK) inhibitor have entered routine practice; subcutaneous formulations have altered delivery; and the first formal head-to-head trials, together with placebo-controlled trials incorporating an active reference arm, have begun to replace indirect comparison with direct evidence. In parallel, the ORAL Surveillance trial prompted a class-wide boxed warning that recalibrated, but did not eliminate, the role of JAK inhibitors. Three further strategies have generated late-phase data: anti-TL1A antibodies, which target a pathway not previously addressed pharmacologically in IBD; the miR-124 enhancer obefazimod; and the oral IL-23 receptor antagonist peptide icotrokinra. Several of these results are available only from conference presentations or company announcements and await peer review. Despite this expansion, induction remission rates remain clustered between roughly 15% and 50%, and endoscopic remission rates lower still. This review synthesises the mechanistic basis, pivotal evidence, comparative effectiveness, safety and regulatory status of approved and investigational therapies for IBD, and how treat-to-target principles, early advanced therapy and emerging biomarkers are reshaping positioning. It also covers two areas comparable reviews omit: acute severe ulcerative colitis, where advanced therapy is least well evidenced, and positioning in newly industrialised nations, where tuberculosis and hepatitis B endemicity and reimbursement, not efficacy alone, often determine the choice of mechanism.