The US FDA has approved olezarsen (Tryngolza, Ionis Pharmaceuticals), in combination with diet, to reduce triglyceride levels and the risk of acute pancreatitis in adults with severe hypertriglyceridemia. 

Olezarsen received priority review and breakthrough therapy designations for this indication.

Olezarsen was approved in 2024 as an adjunct to diet for adults living with familial chylomicronemia syndrome, based on results of the phase 3 BALANCE trial. 

The expanded indication was supported by data from two randomized, double-blind, placebo-controlled phase 3 trials — CORE-TIMI 72a and CORE2-TIMI 72b — involving more than 1000 adults with severe hypertriglyceridemia. 

Across both trials, patients had a mean baseline triglyceride level of 1116 mg/dL. Severe hypertriglyceridemia is generally defined as fasting triglyceride levels of at least 500 mg/dL and is associated with an increased risk of acute pancreatitis.

At 6 months, patients receiving once-monthly subcutaneous olezarsen experienced significant reductions in fasting triglyceride levels. In the first trial, triglyceride levels fell by an average of 63% with the 50-mg dose and 72% with the 80-mg dose compared with placebo. In the second trial, reductions were 49% and 55%, respectively, compared with placebo. 

An integrated analysis of the two trials found that treatment with olezarsen significantly reduced the rate of acute pancreatitis compared with placebo. 

Results from the CORE-TIMI 72a and CORE2-TIMI 72b trials were presented in a late-breaking session at American Heart Association Scientific Sessions 2025 and published simultaneously in The New England Journal of Medicine. Medscape previously reported the findings. 

The most common adverse events in patients treated with olezarsen for severe hypertriglyceridemia were injection-site reactions and elevations in liver enzymes. 

The prescribing information recommends considering liver function testing before treatment initiation, after dose increases, and as clinically indicated during therapy. If liver enzyme elevations persist, dose interruption and/or reduction may be considered, the FDA advised. 

Hypersensitivity reactions — including rash, urticaria, facial swelling, chills, and dyspnea — have been reported. Patients experiencing signs or symptoms of an allergic reaction should be advised to stop treatment and seek immediate medical attention.