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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.

Abstract：

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 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. 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, 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. 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.

journal_name

Wien Klin Wochenschr

journal_title

Wiener klinische Wochenschrift

authors

Traussnigg S,Halilbasic E,Hofer H,Munda P,Stojakovic T,Fauler G,Kashofer K,Krssak M,Wolzt M,Trauner M

doi

10.1007/s00508-020-01735-5

subject

Has Abstract

pub_date

2020-09-15 00:00:00

eissn

0043-5325

issn

1613-7671

pii

10.1007/s00508-020-01735-5

pub_type

杂志文章

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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.