The US Food and Drug Administration has approved olezarsen (Tryngolza) as an adjunct to diet to reduce triglycerides and the risk of acute pancreatitis in adults with severe hypertriglyceridemia (sHTG) — making it the first agent shown to lower acute pancreatitis risk in this population.
The decision, which came ahead of the drug's June 30 target action date, expands the label for olezarsen, an antisense oligonucleotide the agency first cleared in December 2024 for adults with familial chylomicronemia syndrome (FCS), a rare genetic form of sHTG. The new indication covers the much larger sHTG population, defined by fasting triglyceride levels of at least 500 mg/dL — well above the normal threshold of less than 150 mg/dL.
For gastroenterologists, the clinical relevance is the pancreatitis signal. Hypertriglyceridemia is a recognized cause of acute pancreatitis, and CORE/CORE2 showed that olezarsen significantly reduced acute pancreatitis events in adults with severe hypertriglyceridemia — a clinical endpoint not previously demonstrated in sHTG phase 3 trials of triglyceride-lowering therapy.
Mechanism
Olezarsen is a ligand-conjugated antisense oligonucleotide that reduces hepatic production of apolipoprotein C-III (apoC-III), a protein that regulates triglyceride metabolism. Lowering apoC-III increases clearance of triglyceride-rich lipoproteins. It is administered as a once-monthly subcutaneous injection.
Trial data
The approval rests on two phase 3, randomized, double-blind, placebo-controlled trials — CORE (CORE-TIMI 72a) and CORE2 (CORE2-TIMI 72b) — that together enrolled 1,061 adults with sHTG and a mean baseline triglyceride level of 1,116 mg/dL. The primary endpoint in both trials was the percent change in fasting triglycerides from baseline to month 6 versus placebo.
In CORE, placebo-adjusted reductions in triglycerides were 63% for the 50-mg dose and 72% for the 80-mg dose. In CORE2, the corresponding reductions were 49% and 55%. In a pooled analysis of the two trials, the incidence of acute pancreatitis was significantly lower with olezarsen than with placebo (rate ratio, 0.15; 95% CI, 0.05–0.40; P < .001), according to the results published in the New England Journal of Medicine.
Safety
The most common adverse reactions were injection-site reactions and liver enzyme elevations. The FDA advises liver enzyme testing before starting therapy or increasing the dose, and as clinically indicated thereafter; persistent elevations may warrant dose interruption or reduction.
Allergic reactions — including skin redness, hives, facial swelling, chills, or trouble breathing — have been reported. Clinicians should counsel patients on the signs and symptoms of these reactions and instruct them to seek medical attention promptly and discontinue olezarsen if they occur.
Full prescribing information can be found here.