Farnesoid X Receptor (FXR) Program

FXR agonist Px-104 for the treatment of Non-alcoholic Steatohepatitis (NASH) and acute complications of Liver Cirrhosis

The primary indications for Phenex FXR agonist Px-104 are Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH). The incidences for NAFLD and NASH are dramatically rising worldwide and these liver diseases have their origin in the fast growing number of people with Metabolic Syndrome, a combined state of obesity, hyperlipidemia, hypertension and insulin resistance. As an outcome of unhealthy sedentary lifestyle together with overnutrition fat accumulates in the liver ("steatosis"). This steatosis − if untreated − can further progress to liver inflammation, liver tissue damage and fibrosis, the next severe stage after NAFLD which is called Non-alcoholic Steatohepatitis (NASH). The prevalence of NASH is estimated to approach 5% of the total population in industrialized countries. NASH markedly increases the likelihood to develop liver cancer or end stage liver cirrhosis. Currently, there is no approved therapy for NAFLD or NASH.

NASH

A new hope comes from the discovery of synthetic FXR agonists. Pharmacological activation of the FXR receptor by Phenex´ FXR agonist Px-104 attacks the underlying causes of NAFLD and NASH. It lowers liver lipids and improves hepatic insulin sensitivity (see: Publications and Posters), combined with a liver specific anti-fibrotic and anti-inflammatory effect. This was demonstrated for Px-104 and other FXR agonists in animal models of metabolic syndrome and NASH. Phenex drug candidate Px-104 has demonstrated excellent safety and tolerability together with potent activation of pharmacodynamic markers in two Phase I clinical studies.



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Phenex has just started a Phase II pilot study in patients with NAFLD to establish a dose regimen for a subsequent Phase IIb study in NASH patients.

NASH

In addition to its clinical development program in NAFLD / NASH, Phenex pursues pilot studies in acute complications of liver cirrhosis. Liver Cirrhosis is the end stage for liver diseases of different etiologies including HBV or HCV infection, alcohol abuse or NASH. It is characterized by a loss of liver function, an increased portal vein pressure (“Portal Hypertension” potentially leading to life threatening variceal bleeding and an increased susceptibility to develop Hepatocellular Carcinoma (HCC). Further complications of patients with advanced liver cirrhosis are mental deterioration called Hepatic Encephalopathy and an increased susceptibility for bacterial infections. Such patients are endangered to run into an acute worsening of liver function, the so-called Acute-on-chronic Liver Failure (AcoLF) which is characterized by a high short term mortality if it cannot be resolved by liver transplantation.

Phenex is currently planning a phase II pilot study in patients with such acute complications of liver cirrhosis.


FXR agonist Px-102 shows striking clearance of severe steatosis in a mouse model of STZ induced NASH after 10 weeks of treatment. Pictures below show representative OilRed O stained liver sections.


NASH

Treatment with FXR agonist Px-102 shows efficacy in a rat model of liver fibrosis. After 6 weeks of treatment liver sections show a reduction in Lipid droplet size as well as a decrease of fibrotic structures. Pictures below show representative Haematoxylin/Eosin or Sirius Red stained liver sections.

NASH