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Chemistry: Generation 2+ LICA

ION224 is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, to treat patients with NASH, or nonalcoholic steatohepatitis. NASH is a common liver disease characterized by excessive triglycerides in the liver with concurrent inflammation and cellular damage. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver. In animal studies, antisense inhibition of DGAT2 significantly improved liver steatosis, lowered blood lipid levels and reversed diet-induced insulin resistance in animal models of obesity and fatty liver disease.4,5

NASH is sometimes considered a “silent” liver disease because people with early-stage NASH feel well, even though they are starting to accumulate fat in their livers, and may not be aware that they have the disease. However, NASH can develop into more severe diseases such as liver cirrhosis and liver failure. Currently, liver transplant is the only therapeutic option for patients with liver cirrhosis. In addition, NASH has been shown to be a major risk factor for the development of liver cancer.

About NASH

Non-alcoholic fatty liver disease (NAFLD) describes the full spectrum of liver disease progression from fatty liver to non-alcoholic steatohepatitis (NASH) to cirrhosis to hepatocellular carcinoma. While fatty liver is often asymptomatic, NASH, which is characterized by liver steatosis, inflammation, and scarring, can lead to increased risk of cardiovascular disease, need for liver transplantation, and early death. NASH epidemiology studies have estimated 13-32% of the global population has NAFLD, 1.5%-6.5% have NASH, and approximately 9% of NASH patients progress to advanced liver disease. There are currently no commercially available NASH medications.