NASH (or nonalcoholic steatohepatitis) is an increasingly common, progressive form of fatty-liver disease that is associated with diabetes and obesity, both of which have reached epidemic proportions. Accumulation of fat in the liver (steatosis) induces chronic inflammation, which causes progressive fibrosis (scarring), cirrhosis and eventually end-stage liver disease. Currently, there are no approved therapies for the treatment of NASH. It is estimated that as many as 5% of the U.S. population has NASH and that eight million patients worldwide have the advanced form of the disease. NASH is projected to become the leading indication for liver transplant by 2020.
FXR is a nuclear hormone receptor expressed in the liver, intestine, kidney and fat (adipose) tissue. FXR has been a target of great interest to biotech and pharmaceutical companies over the past decade because of its role as a master regulator of carbohydrate and lipid metabolism, bile-acid homeostasis, inflammation and fibrosis, all of which are associated with the pathology and progression of NASH. FXR is a clinically validated target for NASH and other liver diseases, such as primary biliary cirrhosis (PBC).
Accumulation of lipids (steatosis) within the liver cells (hepatocytes) leads to fatty liver disease, which is followed by chronic liver inflammation and liver fibrosis resulting in progression of fatty liver disease to NASH. FXR plays a key role in regulating each of these stages of NASH.
Over the past decade, multiple FXR agonists have entered the clinic, including both bile-acid and non-bile-acid drugs. These trials have validated FXR as a target for NASH based on clinical and histological biomarkers of the disease. However, these trials have also shown a need for FXR agonists with better efficacy and improved safety.
Utilizing extensive expertise and experience in the discovery and development of drugs targeting nuclear hormone receptors, including FXR, we are developing small molecule, non-bile acid FXR agonists that have high affinity, potency and selectivity for FXR and a pharmacokinetic and pharmacodynamic profile that should provide significantly improved tolerability in NASH patients. Our lead candidate is currently in preclinical, IND-enabling toxicology and safety pharmacology studies with first-in-human studies planned for early 2017.
We have demonstrated robust in vivo proof of concept with our lead development candidate in animal models of steatosis and fibrosis. We believe that our lead compound should provide a broad therapeutic window in which to significantly increase the activity of FXR in the target tissue, thereby having a profound impact on fibrosis, the key underlying pathology of NASH.