In chronic hepatitis B
Hepatitis B remains a major worldwide public health problem with over 260 millions of chronically-infected people despite extensive vaccination programs. Chronic hepatitis B evolves towards life threatening complications including liver cirrhosis and cancer. Current therapeutic regimen, pegylated interferons and polymerase inhibitors, often fail to cure HBV and are lifelong treatments. HBV cure is thus a major unmet medical need.
Hepatitis B virions enter hepatocytes through the binding of its surface protein to two cellular receptors, the heparan sulfate proteoglycans and to the bile salt transporter NTCP expressed at the basolateral membrane of hepatocytes. Viral capsids migrate to nuclear pores and the genome is released in the nucleus where the circular, partially double stranded DNA viral genome is completed and closed to form the cccDNA. The cccDNA associates with histones and other cellular and viral proteins (predominantly HBc and HBx). cccDNA complexes are organized in minichromosomes that persist in the nucleus and are transmitted to daughter cells.
HBV covalently closed circular DNA (cccDNA) is the molecular complex responsible for persistence, latency and reactivation of the virus. It contains four promoters and two enhancers that regulate its transcription and the synthesis of viral mRNAs including the pre-genomic RNA. The founder’s INSERM team identified two response elements for the farnesoid X receptor alpha (the nuclear bile acid receptor: FXR) in the enhancer II/core promoter region and showed that modulation of FXR activity controls the cccDNA pool size and HBV protein synthesis. Based on this discovery, ENYO Pharma is developing EYP001, a lead compound with specific FXR modulation capacity that reduces the cccDNA reservoir, blocks its transcription and the deleterious expression of viral proteins. EYP001 was safe and well-tolerated in healthy volunteers and patients phase I clinical trials. In combination with currently approved drugs, EYP001 is expected to cure HBV after a six-month treatment.
In NASH (Non-Alcoholic steatohepatitis)
NASH is the most common liver disorder in Western countries and results in liver fat accumulation leading to inflammation and hepatocyte injury. It is estimated that more than 5% of the population has an advanced NASH. Its main consequence is liver fibrosis, cirrhosis and hepatocarcinoma. Currently no treatment exists for this disease which represents an important challenge.
The class of FXR agonists is gaining attention as potential therapeutic agents in hepatobiliary and metabolic diseases. FXR activation has a favorable effect on liver growth and regeneration and has been shown to prevent and resolve liver fibrosis in rodents and humans. FXR regulates several metabolic pathways and in particular it controls the fate of bile acids in the liver and intestine, it influences the insulin sensitivity of tissues where it is highly expressed and impacts lipid metabolism.