By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Aministration has approved olezarsen, a first-in-class drug to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). Olezarsen is an antisense oligonucleotide (ASO)-directed inhibitor of apolipoprotein C-III (APOC3) messenger ribonucleic acid (mRNA). It is conjugated to a ligand containing three N-acetyl galactosamine residues to enable delivery to hepatocytes. Olezarsen received a priority review and Fast Track breakthrough therapy as well as orphan status designations.1
Indications
Olezarsen is indicated as an adjunct to diet to reduce triglycerides in adults with FCS.2
Dosage
The recommended dose is 80 mg administered subcutaneously once monthly into the abdomen or the front of the thigh.2 It also can be injected into the back of the upper arm if administered by a healthcare provider or caregiver. Olezarsen is available as 80 mg/0.8 mL in a single-dose autoinjector.
Potential Advantages
Olezarsen is the first-in-class drug for the treatment of FCS. It reduces APOC3, triglycerides, and atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease, FCS, and severe hypertriglyceridemia.3,4
Potential Disadvantages
Olezarsen elevates low-density lipoprotein cholesterol and total apolipoprotein B.2,3 Frequency (vs. placebo) of adverse reactions include injection site reaction (19% vs. 9%, respectively), decrease in platelet count (12% vs. 4%, respectively), and arthalgia (9% vs. 0%, respectively).2
Comments
Binding of olezarsen to APOC3 mRNA results in reduction of serum APOC3 protein and increased clearance of plasma triglycerides and very low-density lipoprotein levels.2 The efficacy of olezarsen was demonstrated in a randomized, placebo-controlled, double-blind trial in adults with genetically identified FCS and fasting triglyceride levels ≥ 880 mg/dL.2,4 After a four-week or longer run-in period on a low-fat diet (≤ 20 grams fat per day), subjects were randomized to olezarsen 80 mg (n = 22) every four weeks or matching placebo (n = 23) given subcutaneously over a 53-week treatment period.
At baseline, the mean age of subjects was 46 years, 87% white, roughly equal numbers of male/female, 49% were on fibrates, 27% were on statins, and 71% had a documented acute pancreatitis in the prior 10 years. The median triglyceride level was 2,604 mg/dL (olezarsen group) and 2,303 mg/dL (placebo group) (range 334 mg/dL to 6,898 mg/dL). The primary efficacy endpoint was percent change in fasting triglycerides from baseline to month 6 (average of weeks 23, 25, and 27) compared to placebo. Triglycerides decreased by 30% vs. increased by 12% for placebo (treatment difference of -42.5% [95% confidence interval, -74.1 to -10.9]). Non-high-density lipoprotein cholesterol decreased by 18% vs. +5.7%, respectively (difference of -23.4% [-45.3% to -1.5%]). Low-density lipoprotein cholesterol increased by 64% vs. +9% (difference of +55.0% (0.7% to 109.4%) and total ApoB was +20% vs. +9% (difference of +11% (-12.6 to 35.9), respectively.
Both low-density lipoprotein cholesterol and total APOB were within the low-to-normal range in this study population.4 Fasting triglyceride reduction was observed by month 1. Over the 12-month treatment period, one subject (5%) in the olezarsen had an acute pancreatitis incident, compared to seven (30%) in the placebo group. All these subjects had a prior history of pancreatitis within 10 years prior to screening.2
Clinical Implications
FCS is a rare genetic disorder with a prevalence of 1 to 10 per 1 million people.1 Individuals with FCS can have triglyceride levels in the thousands, which can cause severe abdominal pain, acute pancreatitis and xanthomas. Traditional pharmacological treatment includes statins, omega-3 fatty acids, and fibrates.5 Olezarsen represents the first-in-class antisense oligonucleotide that effectively targets APOC3 and lowers triglyceride levels in patients with FCS. It is priced at $49,584 per 80 mg dose or nearly $600,000 for 12 months.
References
- U.S. Food and Drug Administration. FDA approves drug to reduce triglycerides in adult patients with familial chylomicronemia syndrome. Dec. 19, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-triglycerides-adult-patients-familial-chylomicronemia-syndrome
- Ionis Pharmaceuticals, Inc. Tryngolza prescribing information. Revised December 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218614s000lbl.pdf
- Tardif J-C, Karwatowska-Prokopczuk E, St. Amour E, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022;43(14):1401-1412.
- Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med. 2024;390(19):1781-1792.
- Gouni-Berhold I, Schwarz J, Berthold HK. Updates in drug treatment of severe hypertriglyceridemia. Curr Atheroscler Rep. 2023;25(10):701-709.
The U.S. Food and Drug Aministration has approved olezarsen, a first-in-class drug to reduce triglycerides in adults with familial chylomicronemia syndrome. Olezarsen is an antisense oligonucleotide-directed inhibitor of apolipoprotein C-III messenger ribonucleic acid.
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