Targeting the IL-23 pathway in inflammatory bowel disease: from cytokine inhibition to oral IL-23 receptor blockade
Year: 2026
Type: review
Abstract: 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.
Source: eGastroenterology
Institutions: St George’s University Hospitals NHS Foundation Trust, City St George's, University of London, Goethe University Frankfurt, Agaplesion Markus Hospital, Western University, Universidade do Porto, Centre for Health Technology and Services Research, IRCCS Ospedale San Raffaele, Northwestern Medicine
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7224993379