Olezarsen has achieved its primary endpoint in the phase 3 CORE and CORE2 trials, demonstrating a significant mean reduction in fasting triglyceride (TG) levels among patients with severe hypertriglyceridemia (sHTG). The results, presented by Dr. Nicholas Marston at the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana, indicate that this reduction is not only substantial but also sustained over a 12-month period.
The CORE and CORE2 trials represent a significant advancement in the treatment of sHTG. According to Dr. Marston, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, these studies are the first to demonstrate a marked decrease in acute pancreatitis events among patients with sHTG. He noted that most patients receiving olezarsen achieved TG levels below the threshold associated with potentially life-threatening pancreatitis.
As Dr. Marston explained, “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.”
Olezarsen is an investigational antisense oligonucleotide designed to target the mRNA of apolipoprotein C-III (apoC-III), a protein that inhibits the clearance of triglycerides by affecting lipoprotein lipase activity and the liver’s ability to uptake triglyceride-rich particles. The drug has already received approval in both the United States and Europe under the name TRYNGOLZA for adults diagnosed with familial chylomicronemia syndrome.
Study Details and Findings
The CORE and CORE2 trials collectively involved 1,063 participants, with 617 patients in CORE and 446 in CORE2. Participants were randomly assigned in a 1:1 ratio to receive either olezarsen at dosages of 50 mg or 80 mg. Following this, patients were further randomized in a 2:1 ratio within each group to receive olezarsen or a matching placebo, administered subcutaneously every four weeks. Each trial lasted for a total of 12 months and featured an MRI substudy to evaluate changes in hepatic fat over the year.
The median age among participants was 54 years, with a median initial TG level of 794 mg/dl. Notably, 43% of the patients had TG levels of ≥880 mg/dl, and 18% reported a history of pancreatitis. Additionally, 333 patients participated in the hepatic MRI substudy.
Overall, olezarsen demonstrated a placebo-adjusted mean reduction in fasting TG levels of up to 72% at the six-month mark, with this reduction maintained throughout the 12-month trial period. Furthermore, the treatment was associated with a significant 85% reduction in adjudicated acute pancreatitis events after 12 months.
Future Implications
The promising results have led to a considerable interest in the continued development and potential use of olezarsen in clinical practice. More than 90% of patients who completed the CORE and CORE2 trials have opted to continue into an extension phase, indicating a strong belief in the treatment’s efficacy and safety.
As the medical community evaluates these findings, the implications of olezarsen could be transformative for the management of severe hypertriglyceridemia and its associated complications. The research highlights the need for innovative treatment options in a field often characterized by limited therapeutic success.
