CORE/CORE2: Olezarsen Achieves Primary Endpoint in Severe Hypertriglyceridemia

Olezarsen has achieved its primary endpoint in the phase 3 CORE and CORE2 trials, causing a highly significant mean reduction in fasting triglyceride (TG) levels in patients with severe hypertriglyceridemia (sHTG) at 6 months, which was sustained through 12 months.1

These data were presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana, by Nicholas Marston, MD, MPH, a cardiologist at Brigham and Women’s Hospital, Harvard Medical School.1

“CORE and CORE2 are the first studies to show a significant reduction in acute pancreatitis events in sHTG, with most patients on olezarsen achieving TG levels below the risk threshold for those potentially life-threatening episodes,” Marston said in a statement. “As a lipid specialist who takes care of sHTG patients, I have seen the major consequences of acute pancreatitis, including cases with recurrent events requiring frequent hospitalizations. Given the modest effects of conventional therapies, these impactful data are a welcome advance and underscore the potential of olezarsen to transform the way we treat sHTG.”1

Olezarsen is an investigative antisense oligonucleotide targeting the mRNA of apolipoprotein C-III (apoC-III). This protein slows TG clearance by inhibiting lipoprotein lipase activity, as well as the liver’s uptake of triglyceride-rich particles. Olezarsen has received approval in the US and EU as TRYNGOLZA, for adults with familial chylomicronemia syndrome.1,2

CORE and CORE2 included 617 and 446 patients, respectively. These patients were randomly assigned in a 1:1 ratio to either olezarsen 50 mg or 80 mg. This was followed by another 2:1 random assignment within each cohort to olezarsen or matching placebo, which were given subcutaneously every 4 weeks. Each trial lasted for 12 months and included an MRI substudy, which assessed changes in hepatic fat at 1 year.2

Across both trials, the median age was 54 years, and the median triglyceride level was 794 mg/dl. In total, 43% (n = 455) of patients had TG of ≥880 mg/dl, and 18% (n = 195) had a history of pancreatitis. 333 patients also participated in the hepatic MRI substudy.2

Ultimately, olezarsen demonstrated a placebo-adjusted mean reduction in fasting TG of ≤72% at 6 months, which was sustained over the 12-month trial period. Additionally, olezarsen demonstrated a significant 85% reduction in adjudicated acute pancreatitis events at 12 months (P <.001); these data were based on 22 total events in 17 patients in the placebo group, compared to 7 events in 5 patients in the olezarsen group. Olezarsen also displayed a favorable lipid profile, with substantial reductions in the secondary endpoints of apoC-III, remnant cholesterol, and non-HDL-C.1

“Building on olezarsen’s success in treating familial chylomicronemia syndrome, a rare form of sHTG, these groundbreaking results position us to reach a significantly larger patient population who remain at risk of dangerous acute pancreatitis attacks,” Brett Monia, PhD, chief executive officer of Ionis, said in a statement. “Olezarsen will be one of two independent launches for Ionis in 2026, our first in a broad population if approved, and is a powerful example of how we are turning groundbreaking science into meaningful medicines that have the potential to change lives.”1

According to a press release, Ionis plans to submit a supplemental New Drug Application for both doses of olezarsen by the end of the year. Additionally, an open-label extension study of olezarsen for sHTG is ongoing, with >90% of patients who completed CORE and CORE2 choosing to continue into the extension.1

References

1. Ionis Pharmaceuticals. Groundbreaking pivotal study results of olezarsen for severe hypertriglyceridemia (sHTG) presented as a late breaker at AHA Scientific Sessions. BusinessWire. November 8, 2025. Accessed November 8, 2025. https://www.businesswire.com/news/home/20251108258773/en/Groundbreaking-pivotal-study-results-of-olezarsen-for-severe-hypertriglyceridemia-sHTG-presented-as-a-late-breaker-at-AHA-Scientific-Sessions

2. 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.