ION839 (formerly IONIS-AZ6-2.5-LRx), also known as AZD2693, is an investigational ligand-conjugated antisense (LICA) 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 metabolic dysfunction-associated steatohepatitis (MASH), previously known as 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 MASH. In a mouse model of MASH 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 MASH pathology in the mutant mouse model.
About Metabolic Dysfunction-Associated Steatohepatitis (MASH)
MASH is the more severe form of metabolic dysfunction-associated fatty liver disease (MASLD). It is related to the epidemic of obesity, pre-diabetes and diabetes. Unlike liver disease caused by alcohol consumption, MASH is the result of an accumulation of fat in the liver, which can lead to inflammation, cirrhosis and liver-related death.
Safety and efficacy have not been evaluated by any regulatory authorities for the indications described.