Background on Liver Disease
Liver disease, both chronic and acute on chronic (e.g., acute liver failure in patients with underlying liver cirrhosis), affects hundreds of millions of patients worldwide and can be caused by many different injuries to the liver, such as infection with HCV and HBV, obesity, chronic excessive alcohol use, or autoimmune diseases. While the responses seen in the liver for these different diseases are not identical, there are remarkable pathological similarities. Typically in such diseases, inflammatory activity and an increase in the number of cells dying by apoptosis occurs (see Figure 1). With time, the more severely affected individuals develop fibrosis, a process in which collagen is deposited in the liver in a manner similar to scarring.
Given the role of apoptosis during the inflammatory insult to the liver and the fact that inflammation may be present to varying degrees in patients with liver disease where the primary insult is still present, emricasan has the potential to be used in both acute (including acute on chronic) and liver disease. The liver has remarkable excess functional capacity and usually the first clinically detectable signal of liver damage and apoptosis is elevated liver enzymes (the transaminase enzymes, ALT and AST) released into the blood stream from dying liver cells. Typically, elevated transaminases, to varying degrees, will continue to be observed as long as there is ongoing insult to the liver tissue. Only in advanced cirrhosis where hepatocyte volume actually starts to diminish, will transaminase levels slowly begin to decrease.
Figure 1. Effects of various insults to the liver.
Eventually, cirrhosis develops as the organ's capacity to function deteriorates and it can no longer repair the damage caused by fibrosis. At this stage, liver function tests which evaluate the liver's capacity to synthesize proteins and degrade waste show abnormalities. This includes, but is not limited to, elevations in bilirubin and decreases in albumin, protein and vitamin K synthesis, reflected as a prolongation of INR (International Normalized Ratio). Accordingly, it is only possible to detect improvements in liver function in studies involving severely ill patients. In the early clinical trials conducted thus far, drug activity has been measured by reduction in liver enzymes (transaminases). In order to achieve an indication for the treatment of liver fibrosis, liver biopsy (histopathology) will be used as an endpoint in the Phase 3 clinical trials to directly assess fibrosis progression. In acute and/or acute on chronic indications such as alcoholic hepatitis, it is believed that morbidity/mortality type endpoints may be required in Phase 3.