Chemistry: Generation 2.5 LICA
ION839, formerly known as IONIS-AZ6-2.5-LRx and AZD2693, is a ligand-conjugated (LICA) investigational antisense medicine 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.
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.