Severe liver diseases, including severe acute alcoholic hepatitis, and advanced liver cirrhosis from NASH, hepatitis, alcohol, and other etiologies, represent a significant area of high unmet need for patients and providers.
The Wnt/β-catenin signal plays an important role in liver homeostasis and in regeneration of hepatocytes in response to injuries. Increased Wnt signaling enhances liver regeneration. In severe liver diseases, there is a deficiency of functional hepatocytes and, in chronic patients, often underlying fibrosis caused by activation of hepatic stellate cells. Both hepatocytes and stellate cells are capable of responding to Wnt that is elevated in injured liver. If a therapeutic molecule enhances Wnt signaling specifically in hepatocytes, but not in stellate cells, it can promote proliferation of healthy hepatocytes without stellate cell activation that could lead to transdifferentiation into fibrogenic myofibroblast-like cells.
The hepatocyte targeted R-spondin-mimetic (SWEETS), SZN-043, has the potential to stimulate hepatocyte regeneration in acute and chronic liver disease. In vivo research has demonstrated proof-of-concept in chronic liver injury models showing that SZN-043 can stimulate hepatocyte regeneration, improve liver synthetic function, and reduce fibrosis.
We plan to focus initially on settings of acute severe hepatocyte loss, such as severe acute alcoholic hepatitis (AAH), where SZN-043 may have a rapid impact on hepatocyte regeneration. There are nearly 100,000 hospitalizations due to severe acute alcoholic hepatitis in the U.S. alone, with a 90-day mortality of about 30 percent, and few therapeutic options.¹
A successful clinical proof-of-concept study in an acute setting may then lead to the evaluation of SZN-043 in advanced cirrhosis of various etiologies such as in non-alcoholic steatohepatitis (NASH), alcoholic liver disease or viral hepatitis. Liver cirrhosis is characterized by a decline in liver synthetic function and an increase in liver fibrosis, culminating in various complications such as portal hypertension, ascites, varices, and hepatic encephalopathy, which impact approximately 200,000 cases of decompensated liver cirrhosis per year in the U.S., and many more patients with advanced cirrhosis who are highly susceptible to decompensation.¹ There are no effective drug treatments available for these severe or end-stage liver failure patients, who often require, and frequently do not get, a liver transplant. Furthermore, there are no effective treatments to reverse the course of the disease in patients with advanced cirrhosis who are at risk of decompensation and end-stage liver failure.