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ION224

Generation 2+ LICA antisense drug

ION224 is a Generation 2+ ligand-conjugated antisense (LICA) drug 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. [3,5]

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

NASH is a liver disease characterized by the presence of excessive liver fat (steatosis) that is accompanied by inflammation and cellular damage. NASH is considered a “silent” liver disease because in the early stages of the disease, patients generally feel well and are unaware they have the disease. However, as NASH progresses, scarring, or fibrosis, begins to accumulate in the liver. Ultimately, cirrhosis of the liver develops and the liver can no longer function normally. About 20 percent of NASH patients are reported to develop cirrhosis, and 30 to 40 percent of patients with NASH cirrhosis experience liver-related death. [4] Currently, liver transplantation is the only treatment for advanced cirrhosis and liver failure. Because of the high prevalence of NASH, it has recently become the third most common indication for liver transplantation in the US. [2] The exact cause of NASH is not well understood but the development of fatty liver diseases has been linked to obesity. As the number of people with obesity continues to rise globally, a parallel increase in the incidence of NASH has also been observed. Currently, it is estimated that 2 to 3 percent of the general population have NASH. [1] However, with the growing obesity epidemic, it is likely that the number of patients with NASH will also continue to rise.

ION839

Generation 2.5 LICA antisense drug

ION839, formerly known as IONIS-AZ6-2.5-LRx and AZD2693, is a generation 2.5 ligand-conjugated (LICA) antisense drug designed to inhibit the production of patatin-like phospholipase domain-containing 3 (PNPLA3) protein. PNPLA3 is a protein that is found on the surface of intracellular lipid droplets. Studies have shown that a common genetic mutation of PNPLA3 is strongly associated with an increased risk for non-alcoholic steatohepatitis (NASH), an accumulation of fat in the liver that causes liver damage. The mutant PNPLA3 protein is resistant to degradation, causing it to accumulate on the surface of lipid droplets, which disrupts the normal process for degrading lipid droplets, leading to increased liver fat accumulation, the underlying pathology of NASH. In a mouse model of NASH that results from the expression of mutant PNPLA3, intervention with an antisense drug targeting PNPLA3 reduced hepatic mutant protein expression. This inhibition of mutant protein expression reduced liver fat accumulation, inflammation, and fibrosis, all hallmarks of NASH pathology in the mutant mouse model.

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.