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Introduction Perianal fistulizing Crohn’s disease (CD) is a challenging and debilitating phenotype associated with persistent drainage, abscesses, repeated surgery, and impaired quality of life. Despite combined medical-surgical management, durable fistula healing is difficult, and few dedicated randomized studies have evaluated therapies in this population. Guselkumab (GUS), a dual-acting IL-23 inhibitor approved for moderately-to-severely active CD, was evaluated in FUZION ( NCT05347095), an ongoing Phase 3, randomized, placebo-controlled, double-blind, multicenter study in adults with active perianal fistulizing CD. Week (W)24 findings are reported here.Methods Adults with ≥1 active draining perianal fistula confirmed by blinded central MRI review, CD Activity Index [CDAI] <350, and inadequate response to oral corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, or up to 2 advanced-therapy classes were eligible. Participants were randomly assigned (2:2:1) to GUS 200mg intravenous (IV) induction at W0/4/8 followed by 100mg subcutaneous (SC) every 8W (Q8W) maintenance, GUS 200mg IV induction at W0/4/8 followed by 200mg SC Q4W maintenance, or placebo (PBO). Randomization was stratified by baseline proctitis and bio-naïve status. The primary endpoint was combined fistula remission at W24, which was defined as meeting all of the following criteria: (1) 100% closure of all treated external openings without development of new fistulas or abscesses and without any drainage by the external openings (occurring spontaneously or after gentle finger compression) and (2) absence of collections >2cm of the perianal fistulas in at least two of three dimensions, confirmed by a blinded central review of the MRI results.Results Among 286 participants (pts) in the full analysis set, 113 received GUS 100mg SC Q8W, 115 received GUS 200mg SC Q4W, and 58 received PBO. 91.3% completed the 24 weeks of treatment. Baseline demographic and disease characteristics were generally balanced across arms; mean age was 36.5 years, 71.7% were male, mean CDAI was 148.7, 58% had 1 open or draining fistula, and 42% had multiple open or draining fistulas.The primary endpoint was met; GUS demonstrated significantly higher rates of combined fistula remission at W24 vs PBO (100mg SC Q8W 28.3%, 200mg SC Q4W 27.0%, and PBO 10.3%; Δ [95% confidence interval] 100mg SC Q8W vs PBO 18.0 [7.0, 29.0], p=0.007; 200mg SC Q4W vs PBO 16.6 [5.6, 27.6], p=0.013). Adverse events were consistent with the known safety profile of GUS in CD.Conclusion GUS induction and maintenance therapy is an efficacious treatment of perianal fistulizing CD at W24 with no new safety signals. FUZION is the first and only randomized, controlled trial to show efficacy of an IL-23p19 antagonist in perianal fistulizing Crohn’s disease.