Olezarsen Receives FDA Approval to Reduce Triglycerides, Risk of Acute Pancreatitis in Severe Hypertriglyceridemia

The FDA approved olezarsen (Tryngolza; Ionis Pharmaceuticals) used with diet to reduce triglycerides and the risk of acute pancreatitis in adult patients with severe hypertriglyceridemia.¹

What is Severe Hypertriglyceridemia?

Severe hypertriglyceridemia is defined by fasting triglyceride levels of at least 500 mg/dL. Guidelines recommend lowering triglycerides when levels are higher than 500 mg/dL to reduce the risk of acute pancreatitis, or the sudden inflammation of the pancreas that can be serious or life-threatening. Normal triglyceride levels are less than 150 mg/dL.^1,2

Standard treatment for severe hypertriglyceridemia includes lifestyle and diet modifications (eg, treatment of obesity and diabetes, regular exercise, limited to no alcohol consumption, and low-fat diet) and medications. The news release announcing the approval noted that previous FDA-approved medications to lower triglycerides in patients with severe hypertriglyceridemia have not had enough cases of acute pancreatitis in their trials to be able to show a reduced risk of acute pancreatitis.¹

Olezarsen was approved in December 2024 as an adjunct to diet to reduce triglycerides in adults with familiar chylomicronemia syndrome (FCS), which is a rare, genetic form of severe hypertriglyceridemia. The agent is injected subcutaneously once per month.^1,2

Clinical Data Supporting the Approved Indication

Olezarsen demonstrated its efficacy and safety in 2 phase 3 clinical trials, CORE-TIMI 72a (NCT05079919)³ and CORE2-TIMI 72b (NCT05552326)⁴. Both were randomized, double-blind, placebo-controlled multicenter trials comparing the efficacy of olezarsen with placebo in patients with severe hypertriglyceridemia.^3,4

A total of 1061 patients (CORE-TIMI 72a: 617 patients; CORE2-TIMI 72b: 444 patients) were randomly assigned in a 1:1:1 ratio to receive either olezarsen at a dose of 50 mg or 80 mg or placebo monthly for 12 months. The trials’ primary outcome was the percent change in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change). Secondary lipid outcomes included the percent change in the triglyceride level at 12 months and in apolipoprotein C-III, remnant cholesterol, and non–high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months. Acute pancreatitis events were assessed across both trials. Clinical findings were published in The New England Journal of Medicine.^3-5

Olezarsen Significantly Reduces Triglyceride Level at 6 Months

At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was –62.9 percentage points in the olezarsen 50-mg group and –72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial. In CORE2-TIMI 72b, these were –49.2 and –54.5, respectively (P < .001 for all comparisons of olezarsen with placebo). Additionally, decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P < .001 for all comparisons). Acute pancreatitis incidence was also lower with olezarsen than with placebo (mean rate ratio, 0.15 [95% CI, 0.05-0.40]; P < .001).⁵

In these trials, the incidence of any adverse events (AEs) appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000/mcL) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted, the authors wrote.⁵

The most common AEs in patients treated with olezarsen for severe hypertriglyceridemia are injection site reactions and liver enzyme increases. Potential allergic reactions (eg, redness of the skin, hives, swelling of the face, chills, trouble breathing) have been reported in patients treated with olezarsen.¹

"With limited options to lower triglycerides, people living with [severe hypertriglyceridemia] often face a constant and real fear that a debilitating acute pancreatitis attack could strike at any time without warning,” Emily Draud, interim executive director, National Pancreas Foundation, said in the news release. “The availability of [olezarsen] for [severe hypertriglyceridemia] represents an important new option for this community, offering hope for people who have been waiting for a new treatment to reduce the risk of acute pancreatitis by significantly lowering their triglyceride levels. It also underscores the urgent need for continued innovation and improved care for patients living with this serious condition."

REFERENCES

1. 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). Businesswire. News release. June 24, 2026. Accessed 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. TRYNGOLZA™ (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet. Ionis Pharmaceuitcals. News release. December 19, 2024. Accessed June 24, 2026. https://ir.ionis.com/news-releases/news-release-details/tryngolzatm-olezarsen-approved-us-first-ever-treatment-adults

3. A Study of Olezarsen (ISIS 678354) Administered to Participants With Severe Hypertriglyceridemia. ClinicalTrials.gov identifier: NCT05079919. Updated February 10, 2026. Accessed June 24, 2026. https://clinicaltrials.gov/study/NCT05079919

4. A Study of Olezarsen Administered Subcutaneously to Participants With Severe Hypertriglyceridemia. ClinicalTrials.gov identifier: NCT05552326. Updated October 22, 2025. Accessed June 24, 2026. https://clinicaltrials.gov/study/NCT05552326

5. 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