The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia.

Increased triglyceride levels (higher than ∼1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apo-CIII) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. While loss of function mutations in the gene encoding apo-CIII (APOC3) are associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD), overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apo-CIII concentrations), there are many patients who still have severe hypertriglyceridemia and are at risk for pancreatitis and potentially CVD. The antisense oligonucleotide (ASO) against APOC3 mRNA volanesorsen (previously called ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx) robustly decreases both, apo-CIII production and triglyceride concentrations and is being currently evaluated in phase 3 trials. In this narrative review we present the currently available clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia.