POS1606 DIFFERENTIAL AND COMBINATORIAL MECHANISM OF ACTION OF GOLIMUMAB AND GUSELKUMAB IN ULCERATIVE COLITIS INDUCTION THERAPY: IL-23 BLOCKADE DRIVES RESTORATION OF NORMAL EPITHELIUM AND MUCOSAL HEALING

Background The combination treatment of golimumab (GOL), a tumor necrosis factor-alpha (TNFα) antagonist, and guselkumab (GUS), an interleukin (IL)-23 inhibitor was shown to induce higher rates clinical remission, endoscopic improvement, histologic remission than each monotherapy in randomized phase 2 induction study TNFα-naïve patients with moderate-to-severely active ulcerative colitis (UC) (VEGA; NCT03662542 ). Objectives To investigate the underlying mechanism action GOL, GUS, (GUS+GOL). Methods Colon biopsies were obtained at screening Week 12 who received GOL (n=48), GUS (n=52), or GUS+GOL (n=50). Tissue transcriptional profiles determined RNA-seq. Differentially expressed genes analyzed context cell-type specific modules by first defining gene correlation network unsupervised clustering. We then developed method create single-cell-derived co-expression using published UC single-cell data provide high-resolution associated cell types pathways. Gene set variation analysis (GSVA) used quantitatively assess changes biologic responder non-responder analyses. Results By 12, therapy induced greater magnitude colon compared (Table 1). These IL-23/Th17/myeloid-related processes, inflammation, epithelial homeostasis. Significant observed Th17 cells inflammatory that achieved improvement (subscore 0 1) non-responders change relative baseline arms alone. consistent decrease crypt destruction responders as Geboes score. Genes modulated indicative suppression particularly myeloid activation fibroblast development. In contrast, either increased normalization decreased activity Conclusion Combination GOL+GUS for weeks drove reduction inflammation homeostasis monotherapy, demonstrating differential complementary mechanisms TNFα IL-23 blockade. drives significant increase overall response marked restoration normal epithelium. Table 1. pre-treatment Golimumab Guselkumab Number up 633 495 4,776 down 709 613 4,867 module: Responder vs Non-Responder (p-value) <0.001 Baseline <0.05 NS 0.01 Epithelial <0.01 P-values GSVA enrichment 12. REFERENCES: NIL. Acknowledgements: Disclosure Interests Prerak Desai Employee of: Janssen Research & Development, LLC may own stock options Johnson Johnson., Patrick Branigan Dylan Richards Dennis McGonagle Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, UCB, Marion Vetter Daniel Cua Thomas Freeman Johnson.