Our Approach

Developing a better treatment
for NASH and chronic liver diseases

About NASH

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.

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About FXR

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).

Farnesoid X Receptor

NASH and FXR

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.

NASH FXR Agonist Diagram
NASH and FXR Lipid Accumulation
FXR agonists reduce lipid accumulation

Lipid accumulation

FXR agonists reduce the expression of key genes (SREBP and FAS) controlling synthesis of triglycerides in liver cells. Animal studies and human clinical studies have shown that treatment with FXR agonists reduces liver steatosis. Additionally, FXR agonists improve the responsiveness of tissues to insulin, and lower the release of free fatty acids from fat (adipose) tissue and reduce their uptake by the liver.
NASH and FXR Inflammation
FXR agonists reduce inflammation

Inflammation

Inflammation arises from compromised gut barrier function and the toxic effects associated with fatty acids. Inflammatory stimuli activate hepatic inflammatory cells (Kupffer cells) and release inflammatory factors that further recruit immune cells from outside of the liver. FXR agonists reduce the activity of NF-κB, a key element of the inflammatory signaling cascade, and reduce the infiltration of immune cells to the liver.
NASH and FXRFibrosis
FXR agonists block the progression of fibrosis

Fibrosis

Chronic inflammation and hepatocyte injury due to accumulation of fat stimulate the proliferation of pro-fibrotic cells in the liver (stellate cells) and the secretion of collagen, a primary component of scar tissue. FXR agonists inhibit the proliferation of stellate cells and lower the expression of several fibrotic markers.

Our Program

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.

Akarna FXR Agonist Program

We are developing small molecule, non-bile acid FXR agonist drugs

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.