Targeting IL-23p19 in Inflammatory Bowel Disease: The Road Ahead

Selective interleukin-23p19 (IL-23p19) inhibition represents a major advance in the management of inflammatory bowel disease (IBD). Risankizumab, mirikizumab, and guselkumab - three monoclonal antibodies targeting the p19 subunit of IL-23 - have each completed Phase 3 clinical development programs in both Crohn's disease (CD) and ulcerative colitis (UC), demonstrating consistent efficacy across a broad spectrum of disease severity. Unlike ustekinumab, which blocks the shared p40 subunit of IL-12 and IL-23, selective p19 inhibition preserves IL-12-mediated host defense while more precisely targeting the IL-23/Th17 axis implicated in chronic intestinal inflammation. In phase 3 trials, all three agents significantly outperformed placebo for co-primary endpoints combining clinical remission and endoscopic response or remission, with benefits sustained across both induction and maintenance phases. Head-to-head data from the SEQUENCE trial demonstrate superiority of risankizumab over ustekinumab for endoscopic remission in CD, a finding corroborated by active comparator arms in GALAXI-2/3. Network meta-analyses consistently rank IL-23p19 inhibitors among the most effective therapies for moderate-to-severe CD. Real-world data, predominantly available for risankizumab in CD and mirikizumab in UC, confirm meaningful clinical and endoscopic responses in refractory populations, including patients with prior ustekinumab exposure. Safety profiles are favorable across indications, with no class-specific signals for serious infection, malignancy, or cardiovascular events. Approved indications for psoriasis and psoriatic arthritis (risankizumab and guselkumab) and pediatric psoriasis (guselkumab) offer additional therapeutic value for IBD patients with extraintestinal manifestations. Key evidence gaps persist, including the absence of head-to-head data in UC, limited long-term outcomes beyond 52 weeks, and the lack of validated predictive biomarkers for patient stratification. This narrative review synthesizes the biological rationale, clinical trial evidence, real-world data, and safety profiles, focusing on clinical positioning of IL-23p19 inhibitors in IBD in the context of precision medicine.