Olezarsen for the Treatment of Hypertriglyceridemia.

Hypertriglyceridemia (HTG) is a common dyslipidemic disorder characterized by fasting serum triglyceride (TG) concentrations exceeding 150 mg/dL. Elevated TG levels contribute substantially to cardiovascular risk, as remnant lipoprotein particles derived from triglyceride-rich lipoproteins (TRL) exhibit marked atherogenicity. Conventional therapies, such as statins and fibrates, often fail to adequately lower TG levels or improve clinical outcomes. Advances in antisense technology have enabled the development of precise oligonucleotide-based therapies that reduce TG levels by targeting key regulators of lipid metabolism. Apolipoprotein C-III (ApoC-III) is a key regulator of TLR clearance, positioning it as a critical therapeutic target. Olezarsen, a next-generation N-acetylgalactosamine-conjugated antisense oligonucleotide (ASO) designed to induce RNase H-mediated degradation of APOC3 mRNA, received FDA approval in December 2024 as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). In this chapter, we review the pharmacological mechanism, clinical development, and safety profile of olezarsen for FCS and broader hypertriglyceridemia-related indications.