FXR agonists with systemic rather than intestinal selective exposure are more efficacious in a diet-induced obese NASH mouse model

Brandee Wagner¹, Dan Brigham¹, Kyoung-Jin Lee¹, Alvaro Ortiz¹, Nhin Lu¹, Jing Qian¹, Karensa Douglas¹, Johnny Nagasawa¹, Steve Govek¹, Michael Feigh², Sanne Veidal², Niels Vrang², Ken Song¹, and Nick Smith¹

1. Metacrine, San Diego, USA
2. Gubra, Hørsholm, Denmark

Background and aims:  The farnesoid X receptor (FXR) is a ligand activated transcription factor highly expressed in the liver and gastrointestinal tract.  Relative liver and gastrointestinal FXR activity can be monitored via specific gene expression changes.  FXR can also indirectly regulate gene expression in the liver via FXR upregulation of intestinal FGF15/19.  The aim of this study was to compare efficacy of systemic versus intestinal selective FXR agonists in a diet-induced obese mouse model of non-alcoholic steatohepatitis (NASH)

Methods:  Pharmacokinetic and pharmacodynamic effects of three non-bile acid FXR agonists – M450, M780, and M790 – were studied.  In lean male C57Bl/6 mice, evidence of direct FXR engagement in ileum and liver was measured 8 hours post FXR agonist dosing by qPCR analysis of FGF15 in ileum and SHP in liver. FXR agonists were also evaluated in a diet-induced NASH model in which male C57BL/6 mice were fed a diet containing 40% fat, 20% fructose and 2% cholesterol. At 32 weeks, mice underwent biopsy to histologically confirm NASH and obtain a baseline NAFLD activity score (NAS). Animals were then stratified into groups (n=10-12) and treated with the three FXR agonists at 100 mg/kg or vehicle for 8 weeks by daily oral gavage.  At study completion, repeat examination of the livers were done for NAS and fibrosis assessment (stage 0-4 scale).

Results:  Based on FGF15 and SHP gene expression, M790 was the most GI selective FXR agonist, M450 had the highest systemic FXR activity and M780 had intermediate activity (see table).  In the NASH model, M450, the compound with highest systemic activity, showed the best effect on liver NAS and fibrosis. NAS scores were improved from 4.8 (baseline) to 3.8 (p<0.05), 2.9 (p<0.001) and 0.2 (p<0.001) for M790, M780, and M450 respectively. All three components of the NAS score (steatosis, inflammation, and ballooning degeneration) were significantly improved with M450 treatment.  The fibrosis score was also significantly reduced by M450 treatment (p>0.001) whereas the effect of M790 and M780 did not reach statistical significance.

Conclusions:  In a murine diet-induced mouse model of biopsy-confirmed NASH, FXR agonists with systemic activity appear more efficacious than FXR agonists that preferentially target FXR receptors in the GI tract.  These findings may have implications on choice of FXR compound profiles for clinical development.