Cathepsins are a family of proteases that have been implicated in many diseases.
Virobay compounds are highly potent, orally active and drug-like; addressing common problems in the design of cathepsin inhibitors.
Chronic liver injury can result in liver fibrosis, which is the accumulation of an excess of connective tissue in the liver. Fibrosis occurs in response to chronic liver injuries which involve inflammation such as bacterial or viral infections in the liver or disorders of metabolism. Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders characterized by accumulation of fat in the liver (steatosis) of which a subset can progress to liver fibrosis and cirrhosis. Advanced fibrosis can lead to portal hypertension, cirrhosis and loss of liver function and may require liver transplantation.
A common source of liver injury, hepatitis C infection, is associated with persistent liver inflammation. This inflammation can lead to progressive liver fibrosis and eventually cirrhosis. A majority of the serious complications associated with chronic hepatitis C infection result from liver cirrhosis. Treatment for fibrotic liver disease associated with chronic HCV infection could improve clinical outcomes.
A body of compelling data in the literature indicate that liver disease and fibrogenesis are reduced by cathepsin B inhibition. Genetic or pharmacologic inactivation of cathepsin B results in efficacy in a variety of animal models of liver injury-induced fibrosis including models of cholestasis, cold-induced perfusion injury, TNFα-induced hepatic cell death, and carbon tetrachloride-induced injury. Both genetic and pharmacologic inhibition of cathepsin B reduces hepatic apoptosis, histologic evidence of liver injury, hepatic inflammation, hepatic stellate cell activation, and collagen deposition in animal models of liver injury. In human non-alcoholic fatty liver disease (NAFLD), cathepsin B is redistributed into the cytosol and is correlated with disease severity.
Published studies have established a key role for cathepsin B protease activity in triggering hepatic apoptosis. Cathepsin B activation results in cleavage of pro-apoptotic regulators and the activation of caspase-dependent cell death in hepatocytes. Ongoing hepatic cell death is a key feature in the development of fibrosis.
At Virobay, we have shown that selective cathepsin B inhibitor VBY-376 inhibits the development of fibrosis and can also cause regression of established fibrosis in the carbon tetrachloride model of liver fibrosis. We have evaluated VBY-376 in a Phase I study in humans and we have demonstrated that sufficient exposure is obtained with VBY-376 to effectively inhibit cathepsin B.