P0126GS-8670: An Intestinally Targeted Farnesoid X Receptor Agonist Restoring Barrier Integrity and Demonstrating Robust Efficacy in Colitis Models

Background Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease, arises from a complex interplay of immune dysregulation, genetic predisposition, epithelial barrier disruption, and altered microbiota composition. Barrier defects are a hallmark of UC, allowing translocation of bacterial products and amplifying immune responses. (1) Current advanced therapies primarily target immune pathways but do not directly restore barrier integrity — a critical unmet need. Farnesoid X receptor (FXR), a nuclear receptor highly expressed in intestinal epithelium and liver, regulates bile acid homeostasis and barrier function. FXR activation induces genes involved in bile acid transport, antimicrobial defense and epithelial integrity (2,3). We investigated GS-8670, a selective, intestinally focused FXR agonist, as a barrier-promoting therapy in preclinical colitis models. Methods GS-8670 was evaluated in IL10 knockout mice with endoscopy-confirmed, established colitis and in the DSS-induced acute colitis model. GS-8670 was administered orally, and efficacy was assessed via endoscopy and histology. Barrier integrity was examined in vitro using transepithelial electrical resistance (TEER) in human colonic epithelial cells. Results GS-8670 halted disease progression in IL10 knockout mice in a dose-dependent manner, significantly improving endoscopic and histological scores comparable to anti-p40 control. Follow up mechanistic studies in this model revealed that GS-8670 reduced intestinal permeability prior to modulating immune infiltration, indicating efficacy independent of direct immunosuppression. In DSS colitis, GS-8670 significantly decreased disease severity and intestinal permeability. To validate the direct impact of FXR agonism on barrier function, GS-8670 was tested in an in vitro model of barrier integrity; here, GS-8670 enhanced TEER over time, confirming improved epithelial barrier function in human colonic epithelial cells. Conclusion GS-8670 demonstrated robust efficacy in two distinct colitis models and promoted epithelial barrier restoration both in vivo and in vitro. These findings support GS-8670 as a promising oral therapy for IBD, complementing current anti-inflammatory approaches by directly targeting barrier integrity. References: 1.Antoni L, Nuding S, Wehkamp J, Stange EF. Intestinal barrier in inflammatory bowel disease. World J Gastroenterol 2014;20 (5):1165-79. 2.Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011;60 (4):463-72. 3.Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 2006;103 (10):3920-5. Conflict of interest: Dr. Chavarria-Smith, Joseph: Is a current employee of Gilead Sciences, Inc. Spalinger, Marianne: Grant: ECCO Multi-Year Grant Scharl, Michael: Grant: M.S. received research grants from Abbvie, Takeda, Gilead, Gnubiotics, Roche, Axalbion, Pharmabiome, Topadur, Basilea, MBiomics, Storm Therapeutics, LimmatTech, Zealand Pharma, NodThera, Calypso Biotech, Pileje, Herbodee, Vifor. Personal Fees: Advisor for Abbvie, Gilead, Fresenius, Topadur, Takeda, Roche and Celltrion. Speaker’s honoraria from Falk Pharma, Vifor Pharma, Pileje and Bromatech Other: M.S. has shares and is co-founder of Recolony AG, Zurich, CH and has shares in PharmaBiome AG, Zurich, CH. Kelly, Staiger: Is a current employee of Gilead Sciences, Inc. Thompson, Stephen: Is a current employee of Gilead Sciences, Inc. Jabbour, Jacob: Is a current employee of Gilead Sciences, Inc. Minto, Wesley: Is a current employee of Gilead Sciences, Inc. Pike, Kaitlyn: Is a current employee of Gilead Sciences, Inc. Mohanan, Sunish: Is a current employee of Gilead Sciences, Inc. Balasubramanian, Ganesh: Is a current employee of Gilead Sciences, Inc. Min-Oo, Gundula: Is a current employee of Gilead Sciences, Inc.