A novel, highly potent, non-bile acid FXR agonist for the treatment of NASH and cholestasis

Abstract

The Farnesoid X Receptor (FXR) is a bile acid (BA)-activated nuclear receptor and a key regulator of bile acid metabolism. FXR agonists decrease hepatic triglyceride synthesis leading to reduced steatosis; inhibit hepatic stellate cell activation reducing liver fibrosis; improve gut barrier function which reduces hepatic inflammation and increase FGF19 leading to improved hepatic insulin sensitivity. In clinical studies, obeticholic acid (OCA), a bile acid-derived FXR agonist, showed efficacy in both Primary Biliary Cirrhosis (PBC) and nonalcoholic steatohepatitis (NASH) patients; however OCA treatment was associated with increased pruritus. Here we describe a novel, non-bile acid FXR agonist LJN452. In both biochemical and cellular assays, LJN452 showed high potency (EC50 = 0.3 nM) on FXR with no activity on other nuclear receptors or TGR5. LJN452 stimulated expression of FXR target genes in primary human hepatocytes, and in rat liver and intestine in vivo, and increased circulating FGF15 protein levels in a dose- and time-dependent manner. In a rodent model of cholestasis, LJN452 effectively reduced liver damage and fibrosis. Due to the non-bile acid structure of LJN452, lack of TGR5 activity and very low peripheral exposure a reduced side effect profile relative to OCA may be observed. These preclinical data describe a novel, non-bile acid derived FXR agonist LJN452 which has the potential for a best-in-class profile in PBC and NASH.