Open-label phase II study evaluating safety and efficacy of the non-steroidal farnesoid X receptor agonist PX-104 in non-alcoholic fatty liver disease

BACKGROUND: The PX-104 is an oral non-steroidal agonist for the farnesoid X receptor (FXR), a key regulator of bile acid (BA), glucose and lipid homeostasis. AIMS AND METHODS: This single center, proof of concept study evaluated the efficacy, safety and tolerability of PX-104 in non-diabetic NAFLD patients. 12 individuals were treated daily with 5 mg of PX-104 orally for 4 weeks. Serum liver enzymes, insulin sensitivity by clamp like index (CLIX) and hepatic fat by proton (1)H‑MRS, MRI-PDFF and CAP were assessed. Hepatic energy metabolism and Kupffer cell function were evaluated by phosphorus (31)P‑MRS and superparamagnetic iron oxide MRI (SPIO-MRI). Other readouts included serum lipids and markers of BA metabolism/signaling besides fecal microbiome and BA analysis. RESULTS: A significant decrease in ALT (p = 0.027; 1‑tailed) and GGT (p = 0.019) was observed, without changes in serum alkaline phosphatase or serum lipids. Insulin sensitivity improved in 92% of patients (p = 0.02). However, hepatic steatosis measured by PDFF-MRI, (1)H‑MRS and CAP besides extended serum lipoprotein and BA profiles did not change. NADPH/γATP ratios at (31)P‑MRS significantly decreased (p = 0.022) possibly reflecting reduced hepatic inflammatory stress, but SPIO-MRI remained unchanged. Reduced preponderance of Coriobacteriaceae (p = 0.036) correlated with a relative reduction of total fecal BAs. There were no serious adverse events but short intervals of cardiac arrhythmia recorded in 2 patients led to termination of the study. CONCLUSION: The non-steroidal FXR agonist PX-104 improved insulin sensitivity and liver enzymes after 4 weeks of treatment in non-diabetic NAFLD patients. Changes in fecal BAs and gut microbiota deserve more extensive investigations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00508-020-01735-5) contains supplementary material, which is available to authorized users.