Olezarsen (TRYNGOLZA™) is a first-in-class, GalNAc-conjugated antisense oligonucleotide being developed by Ionis Pharmaceuticals for the treatment of familial chylomicronaemia syndrome (FCS) and severe hypertriglyceridaemia. It binds to apoC-III mRNA, promoting its degradation and lowering serum apoC-III protein levels. This action lowers triglyceride levels by enhancing the clearance of plasma triglyceride-rich lipoproteins such as chylomicrons and very-low-density lipoproteins. GalNAc conjugation improves hepatocyte uptake, which helps localise oligonucleotide treatment to the liver; this enables lower dosing, reduced injection volume and frequency, potentially reducing the risk of adverse events such as thrombocytopenia. Olezarsen received its first approval in the USA on 19 December 2024 under priority review as an adjunct to diet to reduce triglycerides in adults with FCS. This article summarizes the milestones in the development of olezarsen leading to this first approval for FCS.
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Olezarsen: First Approval.
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March 2025
Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
Olezarsen (TRYNGOLZA™) is a first-in-class, GalNAc-conjugated antisense oligonucleotide being developed by Ionis Pharmaceuticals for the treatment of familial chylomicronaemia syndrome (FCS) and severe hypertriglyceridaemia. It binds to apoC-III mRNA, promoting its degradation and lowering serum apoC-III protein levels. This action lowers triglyceride levels by enhancing the clearance of plasma triglyceride-rich lipoproteins such as chylomicrons and very-low-density lipoproteins.
View Article and Find Full Text PDFApolipoprotein C-III inhibitors for the treatment of hypertriglyceridemia: A meta-analysis of randomized controlled trials.
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Department of Cardiology, Federal University of Paraná, Brazil.
Introduction: Hypertriglyceridemia is related to atherosclerotic cardiovascular risk and pancreatitis risk. The efficacy and safety of apolipoprotein C-III (APOC-III) inhibitors remains unclear.
Aim: To investigate the effects of APOC-III inhibitors on hypertriglyceridemia and its complications.
Familial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA.
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Division of Endocrinology and Metabolism, Department of Medicine, M0682, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, USA. Electronic address:
Familial chylomicronemia syndrome (FCS) is a rare, recessive monogenic disorder characterized by severely elevated plasma triglyceride (TG) levels due to absent or markedly impaired lipoprotein lipase activity, leading to a greatly increased risk of acute pancreatitis. Naturally occurring very low levels of apoC-III are associated with low TG levels; thus, apoC-III is a target for TG lowering, and therapies have been developed to reduce apoC-III. Strategies to inhibit hepatic apoC-III synthesis include antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs).
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TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Severe hypertriglyceridemia (HTG), defined as a serum triglyceride (TG) concentration ≥500 mg/dl, is present in approximately 1 in every 500 individuals and carries direct clinical consequences, including pancreatitis, which can be life-threatening. Olezarsen is an investigational antisense oligonucleotide targeted to the mRNA for apolipoprotein C-III (apoC-III), a protein known to impair TG clearance by inhibiting lipoprotein lipase and the hepatic uptake of triglycerides and triglyceride-rich remnants. Olezarsen has been evaluated in patients with predominantly moderate HTG (150-499 mg/dl) and a rare genetic condition known as Familial Chylomicronemia Syndrome (FCS), with TG lowering effects of 53% and 44%, respectively, and reductions in pancreatitis among the FCS population.
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Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Purpose Of Review: The aim of this review is to examine recent advancements in RNA-targeted therapies for the management of severe hypertriglyceridemia (sHTG) and prevention of sHTG-associated acute pancreatitis.
Recent Findings: Recent developments in RNA-targeted therapies, aimed at inhibiting apolipoprotein C-III (apoC-III), have demonstrated substantial and sustained reductions in triglyceride levels. Novel therapies, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), such as volanesorsen, olezarsen, and plozasiran, have shown promising results in recent trials.
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