Olezarsen Proves Efficacy in Severe Hypertriglyceridemia, With Nicholas Marston, MD

The phase 3 CORE and CORE2 trials have highlighted the efficacy of olezarsen in patients with severe hypertriglyceridemia (sHTG) by triggering a highly significant mean reduction in fasting triglyceride levels at 6 months and sustaining it through 12.1

Data from both trials were presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana, by Nicholas Marston, MD, cardiologist and assistant professor of medicine at Brigham and Women’s Hospital. The editorial team at HCPLive sat down with Marston to discuss the implications of these data for cardiovascular care, as well as next steps for olezarsen as indicated in the MRI substudy.1

“At this point, we’re not seeing a clinical context here, just an imaging finding,” Marston told HCPLive. “We’re following this over time in the open-label extension, to see if this is something that plateaus. Ultimately, I think it will be something we’ll learn more about, and we’ll keep an eye on it.”

Olezarsen, an investigative antisense oligonucleotide in testing for sHTG treatment, is designed to lower apoC-III production. This protein regulates triglyceride metabolism in the blood, slowing triglyceride clearance and the liver’s uptake of triglyceride-rich particles. Although it has already received approval for chylomicronemia syndrome in the US and EU, its safety and efficacy have not been established for sHTG.1

CORE and CORE2 were each double-blind, randomized, placebo-controlled trials by the full names CORE-TIMI 72a and CORE2-TIMI 72b. The primary endpoint in both trials was percent change from baseline in triglycerides at 6 months. Secondary lipid outcomes included the percent change from baseline in triglyceride at 12 months and in apo-C III, remnant cholesterol, and non-HDL-C levels at 6 and 12 months. Additionally, investigators assessed acute pancreatitis events across both trials.2

A total of 1063 patients with sHTG were included overall, with 617 in the CORE trial and 446 in the CORE2 trial. They were then randomly assigned in a 1:1:1 ratio to either olezarsen 50 mg, olezarsen 80 mg, or placebo, all of which were administered monthly for 12 months. Both trials included an MRI substudy, assessing changes in hepatic fat at 1 year. The median age across both trials was 54 years, and median baseline triglyceride level was 796 mg/dL.1

At 6 months, Marston and colleagues found a placebo-adjusted least-squares mean change in triglyceride level of -62.9 percentage points in the olezarsen 50 mg arm and of -72.2 percentage points in the olezarsen 80 mg arm in the CORE trial. By comparison, mean triglyceride level change in CORE2 was -49.2 percentage points in olezarsen 50 mg and -54.5 percentage points in olezarsen 80 mg.2

The team also documented greater decreases in triglyceride, apoC-III, remnant cholesterol, and non-HDL-C in the olezarsen arms compared to placebo across both studies. Acute pancreatitis incidence was also lower with olezarsen than placebo (mean rate ratio, 0.15; 95% CI, 0.05 to 0.4; P <.001). Elevations in liver-enzyme levels and thrombocytopenia were more common in the olezarsen 80 mg arms, and a dose-dependent increase in hepatic fat fractions was noted.2

Ultimately, Marston discussed potential applications for olezarsen should it receive approval in sHTG. He addressed its potential as an add-on therapy, but ultimately suggested that its relatively rapid effectiveness may position it as a starting therapy for patients at the highest risk levels.

“I think it could be viewed as an add-on, but I think for the highest risk patients, who have already had pancreatitis, we wouldn’t want to delay in getting them on olezarsen,” Marston said. “I could envision it being the first line for those highest-risk patients.”

References

1. Marston N, Bergmark B, Alexander V, et al. Olezarsen in Patients with Severe Hypertriglyceridemia: The CORE-TIMI 72a and CORE2-TIMI 72b Trials. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

2. Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. New England Journal of Medicine. Published online November 8, 2025. doi:10.1056/nejmoa2512761