Severe liver diseases, including severe alcoholic hepatitis, 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 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 function, and reduce fibrosis.
We plan to focus initially on settings of severe hepatocyte loss, such as severe alcoholic hepatitis (AH), where SZN-043 may have a rapid impact on hepatocyte regeneration. It is estimated that there are about 100,000 hospitalizations per year due to severe alcoholic hepatitis in the U.S., with a mortality rate among these patients of about 30% within 90 days, 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 other acute and chronic severe liver diseases.