Efficacy of Interleukin‐12/23 and Interleukin‐23 Inhibitors for Moderately to Severely Active Crohn's Disease in Advanced Treatment Failure Populations: Systematic Review and Network Meta‐Analysis

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ABSTRACT Background and Aims Earlier trials of advanced treatments indicated for moderately to severely active Crohn's disease used predominantly re‐randomized induction responder designs, whereas newer treatments were evaluated using treat‐through designs. Combining heterogeneous trial designs in network meta‐analysis violates core statistical assumptions and may bias estimates of efficacy in maintenance. This study compared the efficacy of interleukin‐12/23 and −23 inhibitors using only treat‐through trials among advanced treatment‐failure populations. Methods A systematic literature review was conducted to identify treat‐through trials among advanced treatment‐failure populations of regulatory‐approved interleukin‐12/23 and −23 inhibitors (ustekinumab, risankizumab, mirikizumab, guselkumab) (PROSPERO ID: CRD420251153930). Bayesian network meta‐analysis assessed comparative efficacy in clinical remission, endoscopic response, and endoscopic remission at approximately 1 year of treatment. Results 4 trials across 5 records, constituting 3065 patients were included. All treatments were found to be statistically superior to placebo across all outcomes, with risankizumab being the highest‐ranking treatment, followed by guselkumab, mirikizumab, and ustekinumab. In clinical remission and endoscopic response, both risankizumab and guselkumab maintenance doses were statistically superior to ustekinumab, with risankizumab also being statistically superior to mirikizumab and low maintenance dose guselkumab for the outcome of endoscopic response. For the outcome of endoscopic remission, risankizumab and guselkumab high maintenance dose were statistically superior to ustekinumab, with risankizumab also being statistically superior to mirikizumab. Conclusions This study suggests risankizumab has greater efficacy relative to other interleukin‐12/23 and −23 inhibitors for the assessed outcomes in an advanced treatment failure population of Crohn's disease patients. These findings may help guide clinical decision makers in treatment selections.