Development of Cilofexor, an intestinally-biased Farnesoid X Receptor agonist, for the treatment of fatty liver disease
The farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid, lipid, and cholesterol metabolism. FXR-targeted therapies have shown potential in advanced clinical trials for treating non-alcoholic steatohepatitis (NASH). In this study, we used clinical data from our first non-steroidal FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to develop cilofexor—a potent non-steroidal FXR agonist with an improved safety profile. While Px-102 demonstrated the expected pharmacodynamic (PD) effects in healthy volunteers, it led to a twofold increase in alanine aminotransferase (ALT) levels and altered cholesterol levels. These findings informed the development of a high-fat diet mouse model to screen FXR agonists based on ALT and cholesterol changes. Cilofexor was identified as causing minimal changes in these parameters. The difference in ALT and cholesterol effects between cilofexor and Px-102 could not be attributed to differences in potency or specificity, leading us to hypothesize that the relative activation of FXR in the intestine versus the liver might play a role. Gene expression analysis in rodents revealed that cilofexor, unlike Px-102, preferentially GS-9674 activated FXR in the intestine over the liver. Fluorescent imaging in hepatoma cells showed similar subcellular localization for both cilofexor and Px-102, but cilofexor had a quicker washout, suggesting a shorter membrane residence time that may contribute to its reduced hepatic transcriptional effects. Cilofexor demonstrated antisteatotic and antifibrotic efficacy in rodent models and antisteatotic effects in a monkey model, while showing the expected PD effects and a manageable safety profile in human phase I trials.
Significance Statement: FXR agonists have shown promise in treating NASH and other liver diseases, but managing efficacy alongside unwanted side effects has been challenging. This study explored the preclinical and clinical outcomes of the first-generation FXR agonist Px-102 to guide the development of cilofexor, an analog with distinct properties that reduce side effects while retaining efficacy. Cilofexor remains one of the few FXR agonists in active clinical development.