S1559 Comparison of Serum IL-22 and Tissue Molecular Changes Between Guselkumab Subcutaneous and Intravenous Induction in Moderately to Severely Active Crohn’s Disease: Post Hoc Analysis of the GRAVITI and GALAXI Studies

Introduction: Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that blocks IL-23 and binds to CD64, a receptor on cells that produce IL-23. GUS demonstrated short- and long-term efficacy with intravenous (IV) and subcutaneous (SC) induction dosing followed by SC maintenance treatment in patients (pts) with moderately to severely active Crohn’s disease (CD) in the GALAXI and GRAVITI Ph3 trials. Here, we present a comparison of the tissue molecular effects of GUS SC and GUS IV induction treatment in CD. Methods: Serum IL-22 was measured in a subset of participants and changes in protein abundance were assessed at WK0 and WK12 following GUS 400 mg SC every 4 weeks induction (n = 202) compared with placebo (PBO) (n = 86) (GRAVITI) or, GUS 200 mg IV every 4 weeks induction (n = 50) compared with PBO (n = 50) (GALAXI), and healthy control sera (n = 30). Transcriptional profiling of ileum and rectum segments was performed using samples from 277 GRAVITI patients randomized to PBO or GUS 400 mg SC, and from a subset of GALAXI patients (n = 259) randomized to PBO or GUS 200 mg IV at baseline (BL) and WK12. Gene co-expression modules were evaluated in ileum and rectum segments, and in patients stratified by prior history of inadequate response to biologics. Results: GUS SC and IV induction showed similar WK12 decreases in serum IL-22 levels and is consistent with reductions in IFNγ, IL-17A, CRP and fecal calprotectin levels (P < 0.05) previously reported. In tissue, changes in gene modules at WK12 observed with GUS 400 mg SC every 4 weeks induction were significantly correlated with those observed with GUS 200 mg IV every 4 weeks induction (R = 0.97, P < 0.05 in ileum and R = 0.93, P < 0.05 in rectum). Similar effects were observed in patients stratified by previous biologic exposure. GUS SC induction reduced key cellular and inflammatory transcriptional modules at WK12 including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology (FDR< 0.05), consistent with molecular analyses of GUS IV induction. Similar changes were observed for tissue IFNγ, IL-17A, and IL-22 gene expression with levels approaching those of the non-IBD controls at WK12. Conclusion: GUS SC and IV induction regimens demonstrate similar molecular effects. Transcriptional changes observed with GUS SC induction in GRAVITI were highly correlated with those observed with GUS IV induction from GALAXI Ph3 in ileum and rectum segments. These data are consistent with previously reported results demonstrating comparable efficacy between GUS SC and IV induction regimen.