Targeting the IL-23 pathway in inflammatory bowel disease: from cytokine inhibition to oral IL-23 receptor blockade

Interleukin (IL)-23 inhibition is now an established therapeutic strategy in inflammatory bowel disease (IBD), supported by the efficacy of selective IL-23p19 monoclonal antibodies in both Crohn's disease (CD) and ulcerative colitis (UC). Advances in peptide engineering have also enabled direct oral targeting of the IL-23 receptor (IL-23R), introducing an alternative approach to inhibition of the same inflammatory pathway. This narrative review examines the biological rationale for targeting the IL-23-IL-23R axis and the clinical evidence establishing selective IL-23p19 inhibition in IBD. Particular attention is given to the clinical development of icotrokinra, an oral macrocyclic peptide IL-23R antagonist. Phase 3 studies in psoriasis have established the efficacy of oral IL-23R antagonism, while the phase 2b ANTHEM-UC study has provided clinical evidence of efficacy in IBD, with improvements in clinical and endoscopic outcomes accompanied by translational evidence of pathway suppression. Ongoing phase 3 programmes in UC and CD will determine whether oral IL-23R antagonism can achieve durable clinical and endoscopic efficacy and establish its place alongside existing IL-23p19 monoclonal antibodies. If successful, this approach could represent a broader shift towards highly selective oral targeting of extracellular inflammatory pathways that have traditionally required biological therapy.