FDA Accepts Olezarsen’s sNDA for Severe Hypertriglyceridemia, Grants Priority Review

On February 26, 2026, the US Food and Drug Administration (FDA) accepted the supplemental New Drug Application (NDA) for olezarsen for the treatment of severe hypertriglyceridemia (sHTG), granting it priority review.1

Announced by parent company Ionis Pharmaceuticals, the FDA has set a Prescription User Drug Fee Act (PDUFA) date of June 30, 2026. The sNDA submission is a result of positive results from the phase 3 CORE and CORE2 studies of olezarsen in 2025, during which olezarsen displayed substantial reductions in fasting triglyceride levels at 6 months and sustained it through 12 months.1,2

“Current standard of care therapies for sHTG provide limited benefit, leaving people vulnerable to recurrent and debilitating acute pancreatitis attacks with serious, long-term health consequences,” Brett Monia, PhD, chief executive officer of Ionis, said in a statement. “The FDA’s Priority Review designation underscores the urgent need for additional treatment options and will enable us to bring olezarsen to patients as quickly as possible.”1

Olezarsen is an investigative antisense oligonucleotide designed to lower apolipoprotein C-III (apoC-III) production by regulating triglyceride metabolism in the blood. This slows triglyceride clearance, as well as limiting the liver’s uptake of triglyceride-rich particles. Olezarsen has already been approved for chylomicronemia syndrome in the US and EU.2

The CORE and CORE2 trials were both double-blind, randomized, placebo-controlled trials enrolling patients with sHTG and randomly assigning them in a 1:1:1 ratio to either olezarsen 50 mg, olezarsen 80 mg, or placebo monthly for 12 months. Both studies’ primary endpoint was percent change in triglyceride levels at 6 months, with secondary lipid endpoints including percent change in triglyceride levels at 12 months and in apoC-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 and 12 months.3

A total of 1061 patients were included across both trials, with 617 in CORE and 444 in CORE2. By 6 months, investigators recorded a placebo-adjusted, least-squares mean change in triglyceride levels from baseline of -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group during CORE. In CORE2, the olezarsen 50-mg arm saw a -49.2 percentage point mean change, while the olezarsen 80-mg group saw a -54.4 percentage point mean change (P <.001 for all).3

Additionally, apoC-III, remnant cholesterol, and non-HDL cholesterol reductions were all greater among the olezarsen arms than with placebo. Acute pancreatitis incidence was lower with olezarsen than placebo (mean rate ratio, 0.15; 95% CI, 0.05-0.4; P <.001). Adverse event incidence was similar across both trial groups, and elevations in liver-enzyme levels and thrombocytopenia were more common among patients receiving 80 mg of olezarsen. A dose-dependent increase in the hepatic fat fraction was also recorded.3

The FDA’s acceptance of olezarsen’s sNDA – and the assignment of priority review status – illustrate the magnitude of these trial results. Additionally, the FDA granted Breakthrough Therapy designation to olezarsen in November 2025, following the announcement of CORE and CORE2’s positive results.1

“This milestone represents a significant step towards our goal of delivering the first-ever treatment shown to reduce the risk of potentially life-threatening acute pancreatitis attacks in people with sHTG,” Monia said.1

References

1. Ionis Pharmaceuticals. Olezarsen sNDA accepted by the FDA for Priority Review for the treatment of severe hypertriglyceridemia (sHTG). BusinessWire. February 26, 2026. Accessed February 26, 2026. https://www.businesswire.com/news/home/20260226109569/en/Olezarsen-sNDA-accepted-by-the-FDA-for-Priority-Review-for-the-treatment-of-severe-hypertriglyceridemia-sHTG

2. Marston NA. Olezarsen Proves Efficacy in Severe Hypertriglyceridemia, With Nicholas Marston, MD. HCPLive. November 18, 2025. Accessed February 26, 2026. https://www.hcplive.com/view/olezarsen-proves-efficacy-in-severe-hypertriglyceridemia-with-nicholas-marston-md

3. Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. New England Journal of Medicine. 2026;394(5):429-441. doi:10.1056/nejmoa2512761