Antisense Oligonucleotides for the Treatment of Hypertriglyceridemia and Hyperlipoproteinemia(a)

Abstract

Elevated triglycerides are associated with an increased risk of both pancreatitis and cardiovascular disease (CVD). Increased lipoprotein(a) [Lp(a)] levels are a risk factor for CVD. The purpose of this review is to discuss the use of antisense oligonucleotides (ASOs) for the treatment of hypertriglyceridemia and hyperlipoproteinemia(a). While a number of current therapeutic options for hypertriglyceridemia such as fibrates and omega 3 fatty acids may decrease triglyceride levels by up to ~ 50%, many patients cannot achieve normal levels or even levels below the pancreatitis threshold of 500–1000 mg/dL. Recently, a new treatment option for hypertriglyceridemia has emerged, namely volanesorsen, an ASO targeting apolipoprotein C-III (ApoC-III) which has been shown to decrease triglyceride levels by > 70%. ApoC-III plays a central role in the metabolism of triglycerides and the development of CVD. Further, there is strong evidence to suggest that Lp(a) is causally associated with CVD. There are currently no pharmacologic therapeutic options to robustly decrease elevated Lp(a) levels. Extended-release niacin, a drug poorly tolerated and not available in many countries, can decrease Lp(a) by 20–30%. Recently, two ASOs against apolipoprotein(a) [apo(a)], IONIS-APO(a)Rx and its ligand-conjugated form IONIS-APO(a)LRx, have been shown in phase 2 and 1/2a trials to decrease Lp(a) concentrations by > 70 and > 90%, respectively. Two new ASOs, volanesorsen targeting ApoC-III and IONIS-APO(a)LRx targeting apo(a), are promising new agents for the treatment of hypertriglyceridemia and hyperlipoproteinemia(a), respectively. Longer studies with clinical endpoints are under way to establish the efficacy and safety profile of these agents and their role in clinical practice.