FDA Approves Olezarsen (Tryngolza) for Severe Hypertriglyceridemia

The United States (US) Food and Drug Administration (FDA) has approved olezarsen (Tryngolza; Ionis Pharmaceuticals) as an adjunct to diet to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia (sHTG; triglycerides ≥500 mg/dL), Ionis announced today.¹ The approval, which arrived ahead of the June 30, 2026, PDUFA date, makes olezarsen the first therapy approved specifically to reduce acute pancreatitis risk in sHTG. Tryngolza is self-administered once monthly via subcutaneous autoinjector and will be available in the US in July.

The approval follows FDA acceptance of the supplemental New Drug Application in February 2026, which was granted priority review and Breakthrough Therapy designation.² Olezarsen was previously approved in the US and EU for familial chylomicronemia syndrome, a rare monogenic form of sHTG; the new indication extends its use to the broader sHTG population, which Ionis estimates at more than 3 million people in the US.

Efficacy in the CORE and CORE2 trials

The approval was based on results from CORE (n = 617) and CORE2 (n = 446), 2 Phase 3, randomized, double-blind, placebo-controlled trials published in the New England Journal of Medicine.³ Participants aged 18 and older with fasting triglycerides ≥500 mg/dL were enrolled; all were required to be on standard-of-care lipid-lowering therapy at baseline. Participants were randomized 1:1:1 to olezarsen 50 mg, olezarsen 80 mg, or placebo via monthly subcutaneous injection for 12 months.

Both trials met their primary endpoint of percent change in fasting triglycerides at 6 months. In CORE, placebo-adjusted least-squares mean reductions were 62.9 percentage points with olezarsen 50 mg and 72.2 percentage points with olezarsen 80 mg (P <.001 for both).³ In CORE2, the corresponding reductions were 49.2 and 54.4 percentage points, respectively (P <.001 for both).³ Across both trials, the 50 mg dose produced triglyceride reductions of 49%–63% versus placebo at 6 months, and the 80 mg dose produced reductions of 55%–72%; both were sustained through 12 months.¹

Olezarsen also significantly reduced acute pancreatitis events. At 12 months, the 50 mg dose reduced pancreatitis events by 91% and the 80 mg dose by 76%, with a pooled reduction of 85% across both trials and both doses.¹ The pooled mean rate ratio for acute pancreatitis was 0.15 (95% CI, 0.05–0.4; P <.001).³ Among participants with paired baseline and 12-month data, 86% of olezarsen-treated patients achieved triglycerides below 500 mg/dL.¹ Secondary lipid endpoints, including reductions in apolipoprotein C-III (apoC-III), remnant cholesterol, and non-HDL cholesterol, all favored olezarsen over placebo at both 6 and 12 months.³

Safety profile and prescribing considerations

Adverse event (AE) incidence was broadly similar between olezarsen and placebo arms across both trials. The most common AEs in the sHTG indication occurring at ≥2% higher frequency than placebo were injection site reactions and liver enzyme increases.¹ Liver enzyme elevations and a dose-dependent increase in hepatic fat fraction were more common with the 80 mg dose than the 50 mg dose, and Ionis recommends considering liver enzyme testing before initiation or dose escalation and when clinically indicated during treatment.¹ Thrombocytopenia was observed more frequently with 80 mg olezarsen in the trial data.³ Persistent liver enzyme elevations should prompt dose interruption or reduction; serious hepatic injury with hyperbilirubinemia or jaundice warrants prompt discontinuation.

Olezarsen is contraindicated in patients with a history of serious hypersensitivity to the drug or any excipient. Hypersensitivity reactions including bronchospasm, urticaria, and facial swelling have been reported in the clinical program.¹

Olezarsen is an antisense oligonucleotide (ASO) targeting hepatic apoC-III messenger RNA, reducing apoC-III protein production and thereby accelerating triglyceride clearance from the bloodstream. It is available in 50 mg and 80 mg doses

References

1. Ionis Pharmaceuticals. TRYNGOLZA (olezarsen) approved by the FDA as the first and only treatment to reduce triglycerides and the risk of acute pancreatitis in patients with severe hypertriglyceridemia (sHTG). Press release. June 24, 2026. https://www.businesswire.com/news/home/20260624119051/en/TRYNGOLZA-olezarsen-approved-by-the-FDA-as-the-first-and-only-treatment-to-reduce-triglycerides-and-the-risk-of-acute-pancreatitis-in-patients-with-severe-hypertriglyceridemia-sHTG

2. Ionis Pharmaceuticals. Olezarsen sNDA accepted by the FDA for priority review for the treatment of severe hypertriglyceridemia (sHTG). Press release. 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

3. Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2026;394(5):429-441. doi:10.1056/nejmoa2512761