NASH & PBC

Commitment to Research and Development for Diseases of the Liver

Enanta’s commitment to pursue therapies for liver disease’s continues as we pursue a program in non-alcoholic steatohepatitis (NASH).

The World Health Organization (WHO) has declared that NASH and its precursor, Non-alcoholic fatty liver disease, (NAFLD) are now the number one causes of liver disease in Western countries and represent a major global health concern. Primary Biliary Cholangitis (PBC), is another disease of the liver that can result in liver damage, liver failure, or hepatocellular carcinoma.

NAFLD, NASH and FXR
Non-alcoholic fatty liver disease (NAFLD) is the accumulation in patients of excessive fat in the form of triglycerides in liver cells (steatosis) that is not caused by alcohol.  NAFLD is widely considered to be the liver expression of metabolic disease associated with type 2 diabetes, insulin resistance, obesity, and hyperlipidemia.  A subgroup of NAFLD patients has liver cell injury and inflammation in addition to excessive fat (steatohepatitis).  Progression of this condition leads to non-alcoholic steatohepatitis (NASH). Patients with NASH can develop fibrosis and ultimately cirrhosis of the liver, potentially leading to hepatocellular carcinoma or requiring a liver transplant. Farnesoid X receptor (FXR) is a nuclear receptor and a main regulator of bile acid levels in the liver and small intestine. It responds to bile acids by regulating gene transcription of key enzymes and transporters, many of which play important roles in lipid metabolism, insulin resistance, inflammation, and fibrosis.

Primary Biliary Cholangitis (PBC)
Primary biliary Cholangitis, or PBC, is a chronic, or long-term, disease of the liver that slowly destroys the medium-sized bile ducts within the liver. Bile is a digestive liquid that is made in the liver. It travels through the bile ducts to the small intestine, where it helps digest fats and fatty vitamins.

In patients with PBC, the bile ducts are destroyed by inflammation. This causes bile to remain in the liver, where gradual injury damages liver cells and causes cirrhosis, or scarring of the liver. As cirrhosis progresses and the amount of scar tissue in the liver increases, the liver loses its ability to function, leading to potential liver failure, liver transplantation or hepatocellular carcinoma.

EDP-305, a Farnesoid X Receptor
EDP-305 is a potent FXR agonist and Enanta’s lead product candidate being developed for the treatment of NASH.  EDP-305 represents a new class of FXR agonists that has been designed to take advantage of increased binding interactions with the receptor.  Further, this non-bile acid class contains steroid and non-steroid components, and does not contain the carboxylic acid group normally present in other classes of FXR agonists and natural bile acids that can lead to the formation of taurine and glycine conjugates.  EDP-305 is currently in Phase 1 clinical development.

About NASH and PBC

According to the World Gastroenterology Organization Global Guidelines 2014, NASH is an increasingly common chronic liver disease with worldwide distribution that is closely associated with diabetes and obesity, which have both reached epidemic proportions. It is estimated that there are at least 1.46 billion obese adults worldwide. Approximately 6 million individuals in the USA are estimated to have progressed to NASH and some 600,000 to NASH-related cirrhosis. NASH and NAFLD are now considered the number one cause of liver disease in Western countries.

In the U.S., the incidence of Primary Biliary Cholangitis has been estimated as 4.5 cases for women and 0.7 cases per 100,000 for men.