• Stefan Traussnigg, Emina Halilbasic, Harald Hofer, Petra Munda, Tatjana Stojakovic, Günter Fauler, Karl Kashofer, Martin Krssak, Michael Wolzt, and Michael Trauner.
• Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
• Wien. Klin. Wochenschr. 2021 May 1; 133 (9-10): 441-451.

BackgroundThe 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 MethodsThis 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 1H‑MRS, MRI-PDFF and CAP were assessed. Hepatic energy metabolism and Kupffer cell function were evaluated by phosphorus 31P‑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.ResultsA 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, 1H‑MRS and CAP besides extended serum lipoprotein and BA profiles did not change. NADPH/γATP ratios at 31P‑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.ConclusionThe 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.

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