EVALUATION OF THE CLINICAL STAGE FXR AGONIST FXR314 IN HUMAN PRIMARY CELL 3D MODELS OF CROHN’S DISEASE AND ULCERATIVE COLITIS

Abstract

Abstract There is a critical need for novel approaches to treat inflammatory bowel disease (IBD) that extend beyond modulating the immune response. These innovative strategies should also focus on enhancing the integrity of the intestinal barrier and addressing fibrotic tissue development throughout the course of the disease, both critical components of IBD, to improve long term outcomes. Targeting the ligand-activated nuclear Farnesoid X Receptor (FXR) represents such an emerging opportunity. Intestinal epithelial cells exhibit high expression of FXR which is pivotal for intestinal function by regulating the innate immune response, reducing bacterial translocation into the intestinal wall, preserving the integrity of the epithelial barrier, and potentially reducing fibrotic deposition. We have developed a human 3D co-culture model of multiple cell types derived from Crohn’s disease (CD) or ulcerative colitis patients (UC). These 3D-culture CD and UC models faithfully replicate various aspects of the IBD disease state, including differences in gene expression patterns relative to intestinal tissues from healthy donors, compromised epithelial barrier integrity (as measured by Fluorescein isothiocyanate-dextran and TEER assays) and disrupted fibrotic deposition (as determined via fibrosis biomarkers and quantitative collagen deposition). FXR314 is an orally administered non-bile acid FXR agonist that has completed a Phase 2a clinical trial in NASH and is being considered as a novel therapeutic approach for IBD. We assessed the capacity of FXR314 to improve disease biomarkers in 3D models of human IBD. Specifically, its effects were characterized in five CD donors and three UC donors. Target engagement was demonstrated in all CD and UC donors tested through activation of FGF19, a well-accepted target of FXR activation. In CD donors, FXR314 broadly improved measures of epithelial barrier function in a subset of donors, and fibrotic markers in all five donors. In UC donors, FXR314 improved epithelial barrier function and fibrotic activity in all three donors. As anticipated, the effects seen across the different metrics were concentration dependent. These primary multicellular 3D human IBD models (CD, UC) constitute a powerful tool to more accurately predict the relevance of specific targets and assess the efficacy of therapeutic candidates. Consequently, this could enhance the probability of success when conducting clinical trials. In this study, we demonstrated that the non-bile acid FXR agonist FXR314 improves multiple aspects of Crohn’s disease and ulcerative colitis in human donors, thereby strengthening its potential as a novel therapeutic approach for IBD.