Farnesoid X Receptor (FXR) Agonism and TERN-101
FXR is a nuclear receptor expressed in high amounts in the liver and small intestine. Bile acids (BA) are natural ligands of FXR, and their binding with and activation of FXR is critical to the regulation of cellular pathways that modulate BA synthesis, lipid metabolism, inflammation and fibrosis. It is believed by many in the scientific community that FXR agonism and activation has potential as a new treatment modality for nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). TERN-101 is a potent non-bile acid FXR agonist being developed as a therapeutic for NASH.
Semicarbazide-Sensitive Amine Oxidase (SSAO) Inhibition and TERN-201
SSAO, also known as VAP-1 (Vascular Adhesion Protein-1), is a dual-function amine oxidase which promotes recruitment of white blood cells in the liver, and can result in increased oxidative stress, inflammation and hepatic fibrosis. The level of surface SSAO is upregulated in the vasculature of inflamed tissues, and soluble SSAO levels are elevated in patients with NASH. Inhibition of SSAO is believed to have therapeutic benefit for the treatment of NAFLD, NASH and other chronic fibrotic liver diseases. TERN-201 is a potent SSAO inhibitor which may provide an additional treatment mechanism for NASH by reducing oxidative stress and recruitment of white blood cells to the liver.
Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinases (MAPK) family, is activated by multiple stimuli, including oxidative and endoplasmic reticulum (ER) stress, resulting in downstream p38 and c-Jun N-terminal kinases (JNK) pathway activation. An activated ASK1 pathway is found in the livers of NASH patients leading to the induction of stress response pathways that worsen hepatic inflammation, apoptosis, and fibrosis. Terns is exploring pharmacologic inhibition of ASK1 as a novel therapy for NAFLD and NASH patients.
Excessive hepatic lipid synthesis leads to hepatic fat accumulation and steatohepatitis. Steatosis is a contributing early driver of NAFLD, and eventually NASH. Thyroid hormones regulate plasma cholesterol, triglycerides, lipid metabolism in multiple tissues including the liver. Selective thyroid hormone receptor activation in the liver is therefore a promising target to adjust lipid metabolism dysregulation associated with NASH. The reduction of hepatic steatosis has the potential for significant impact on NASH as it removes the key driver of inflammation. Terns is pursuing a novel therapeutic approach to selectively activate the β thyroid hormone receptor in the liver.
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), which is caused by the accumulation of excess fat in the liver. NASH is associated with chronic liver inflammation and liver cell injury, and it can lead to fibrosis, cirrhosis and eventually liver cancer or liver failure. Global rates of NAFLD and NASH are increasing rapidly, in tandem with rising rates of obesity. It is estimated that 15 percent of the Chinese adult population has NAFLD. Of those patients, an estimated 20 percent will develop NASH. There is currently no approved medication for the treatment of NASH.