Olezarsen, an experimental treatment for severe hypertriglyceridemia (sHTG), has met its primary endpoint in the phase 3 CORE and CORE2 trials, demonstrating significant reductions in fasting triglyceride (TG) levels at the six-month mark. This reduction was maintained through 12 months, presenting promising data for patients suffering from this serious condition. The findings were unveiled on November 12, 2025, at the American Heart Association’s Scientific Sessions in New Orleans.
Dr. Nicholas Marston, a cardiologist at Brigham and Women’s Hospital, highlighted the significance of these trials. He stated, “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, who specializes in lipid disorders, emphasized the severe consequences of acute pancreatitis, including recurrent hospitalizations. He noted that the modest effects of conventional therapies make these results especially impactful.
At the heart of olezarsen’s mechanism is its role as an antisense oligonucleotide targeting the mRNA of apolipoprotein C-III (apoC-III). This protein is known to impede TG clearance by inhibiting lipoprotein lipase activity and reducing the liver’s uptake of triglyceride-rich particles. Olezarsen has already received regulatory approval in the United States and the European Union under the brand name TRYNGOLZA, specifically for adults diagnosed with familial chylomicronemia syndrome.
Trial Details and Results
The CORE and CORE2 trials included a total of 1,063 patients, with 617 participants in CORE and 446 in CORE2. Patients were randomly assigned in a 1:1 ratio to receive either olezarsen at doses of 50 mg or 80 mg. This was followed by an additional random assignment in a 2:1 ratio to receive olezarsen or a matching placebo, administered subcutaneously every four weeks over a span of 12 months. An MRI substudy was also conducted to assess changes in hepatic fat at the one-year mark.
The median age of participants across both trials was 54 years, with a median baseline triglyceride level of 794 mg/dl. Notably, 43% of these patients had triglyceride levels of ≥880 mg/dl, and 18% had a history of pancreatitis. In total, 333 patients participated in the hepatic MRI substudy.
Olezarsen yielded a remarkable placebo-adjusted mean reduction in fasting TG levels of up to 72% at the six-month evaluation, a figure that remained consistent throughout the 12-month trial duration. Furthermore, it demonstrated an impressive 85% reduction in adjudicated acute pancreatitis events at the 12-month endpoint.
Future Implications
The results from these trials indicate a substantial potential for olezarsen to transform the management of severe hypertriglyceridemia. With over 90% of patients who completed the CORE and CORE2 trials opting to continue into the extension phase, there is strong interest in further exploring the long-term benefits of this treatment.
As the medical community continues to grapple with the implications of triglyceride management in sHTG, olezarsen stands out as a promising option, offering hope for improved patient outcomes and reduced risks associated with acute pancreatitis. The ongoing commitment to research and development in this area could pave the way for enhanced standards of care for patients facing severe lipid disorders.
