S1521 Impact of Subcutaneous Guselkumab Induction Therapy on Molecular Inflammation in Patients With Ulcerative Colitis: Results From the Phase 3 ASTRO Study

Introduction: Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that neutralizes interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23. GUS was effective and safe as intravenous (IV) induction and subcutaneous (SC) maintenance therapy in patients with moderately to severely active ulcerative colitis (UC) (QUASAR). Week 12 (WK12) results from the ASTRO phase 3 study demonstrated the efficacy of SC induction therapy with guselkumab in UC. Molecular changes occurring from induction baseline WK0 to WK12 evaluated in patients from the ASTRO study are presented here. Methods: Transcriptional profiling of biopsies from 339 patients from ASTRO was performed with RNA sequencing. Molecular analysis was performed comparing induction WK12 to baseline. A comparative analysis was performed with biopsy samples previously analyzed from 593 patients from the QUASAR Phase 3 induction study. Molecular changes were assessed in the context of clinical remission and combined histologic and endoscopic mucosal improvement (HEMI) at WK12. Serum IL-22 proteomic profiling of 355 patients was conducted using a high-sensitivity IL-22 assay and change in protein abundance was assessed. Results: GUS SC induction demonstrated significant downregulation of inflammatory modules including Th17, IFNγ, inflamed epithelium, plasma cell, neutrophil and inflammatory fibroblast, and upregulation of goblet cell and healthy epithelium gene modules at WK12 (FDR <0.05). Significant correlation was observed with GUS 200 mg IV induction in QUASAR (r = 0.98, P < 0.0001). Patients who achieved clinical remission and HEMI at WK12 demonstrated the most changes in gene module expression from baseline (P < 0.0001), nearing non-IBD controls. Subgroup analyses defined by prior treatment history demonstrated similar magnitude of changes in both treatment-naïve and -resistant groups (R = 0.93, P < 0.0001). Serum IL-22 was significantly decreased at WK12 (P < 0.05) with GUS SC induction, similar to IV induction. Patients who achieved clinical remission at WK12 demonstrated a robust decrease in Geboes total scores (P < 0.05) compared to non-remitters. Conclusion: Mechanistic observations confirm that GUS SC and IV induction show significant correlation, supporting the efficacy of both routes of administration in UC. These data demonstrate that GUS SC induction reduced inflammatory biology towards a normal state while upregulating genes associated with healthy epithelium in patients who achieved clinical remission or HEMI at WK12.