S1998 Molecular Differentiation of Guselkumab and Ustekinumab in Moderately to Severely Active Crohn’s Disease: Post Hoc Analysis of the GALAXI 2 and 3 Phase 3 Studies

Introduction: Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23. In patients with moderately to severely active Crohn’s disease (CD), the GALAXI-2 and GALAXI-3 Phase 3 studies established short- and long-term efficacy of GUS compared to placebo, and statistical superiority to ustekinumab (UST) in prespecified analyses of pooled data at Week (WK48). Here we report molecular differentiation of GUS compared with UST in isolated ileal disease using pooled samples from the GALAXI studies. Methods: Patients (pts) in GALAXI-2 (n = 508) and GALAXI-3 (n = 513) were randomized 2:2:2:1 to receive GUS 200 mg IV every 4 weeks x3 → GUS 200 mg SC every 4 weeks or GUS 100 mg SC every 8 weeks, UST ⁓6 mg/kg → UST 90 mg SC every 8 weeks or placebo (PBO). Serum biomarkers were measured in a subset of (n = 50) pts per group at WK0, WK4 and WK12. Matched ileal and rectal biopsies were evaluated at WK0, WK12 and WK48 in a subset of 344 pts representative of the study population. Transcriptional profiling was performed with RNA sequencing using transcriptional modules. Analysis was performed using molecularly inflamed samples at baseline. Serum proteins and transcriptional modules were evaluated for differential expression stratified by ileal, colonic and ileocolonic disease. Results: In pts with isolated ileal disease, GUS decreased serum levels of IL-22, IL-17A and IFNγ at WK12 while UST only reduced IFNγ. In ileal tissue, GUS significantly altered inflammatory transcriptomic modules at WK12 and WK48 including reductions in neutrophil, inflamed epithelium, IL-23/Th17 and inflammatory fibroblast biology compared with UST. In pts with colonic or ileocolonic disease, both GUS and UST decreased IL-23-dependent serum proteins towards normal levels compared with independent healthy control sera. In rectal tissue, both GUS and UST significantly altered key inflammatory transcriptional modules in rectal biopsies at WK12 and WK48. Conclusion: GUS decreased IL-23-dependent serum proteins and improved tissue transcriptional profiles in pts with isolated ileal disease while UST had a minimal impact on IL-23-dependent transcriptional modules. These data suggest potential differences in IL-23 and IL-12 pathway enrichment in isolated ileal disease where inhibition of IL-23p19 subunit with GUS achieved greater molecular treatment effects early which were maintained through WK48 and associated with differential clinical outcomes in patients with isolated ileal disease.