Olezarsen has successfully achieved its primary endpoint in the phase 3 CORE and CORE2 trials, significantly reducing fasting triglyceride (TG) levels in patients with severe hypertriglyceridemia (sHTG) after six months, a reduction that remained consistent through twelve months. These results were presented by Dr. Nicholas Marston, a cardiologist at Brigham and Women’s Hospital and Harvard Medical School, during the American Heart Association’s Scientific Sessions 2025 held in New Orleans, Louisiana.
Dr. Marston emphasized the importance of these findings, stating, “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.” He highlighted the severe consequences of acute pancreatitis, showcasing the need for effective treatments in this patient population. Given the limited efficacy of conventional therapies, he noted, “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 messenger RNA of apolipoprotein C-III (apoC-III). This protein plays a role in delaying the clearance of triglycerides by inhibiting lipoprotein lipase activity and the liver’s ability to uptake triglyceride-rich particles. Currently, olezarsen has been approved in the United States and European Union under the brand name TRYNGOLZA for adults diagnosed with familial chylomicronemia syndrome.
Trial Details and Patient Profile
The CORE and CORE2 trials involved 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. Following this, a further random assignment within each cohort allocated patients to either olezarsen or a matching placebo, administered subcutaneously every four weeks over a 12-month period. A substudy involving MRI assessments of hepatic fat was also conducted, further informing the efficacy of olezarsen.
The median age of participants across both trials was 54 years, with a median triglyceride level of 794 mg/dl. Notably, 43% (n = 455) of the patients had triglyceride levels of ≥880 mg/dl, and 18% (n = 195) had a documented history of pancreatitis. Additionally, 333 patients participated in the hepatic MRI substudy.
Olezarsen demonstrated a placebo-adjusted mean reduction in fasting triglycerides of up to 72% at six months, a benefit that was sustained throughout the twelve-month period. Furthermore, it showed an impressive 85% reduction in adjudicated acute pancreatitis events at the 12-month mark, with over 90% of patients who completed the CORE and CORE2 trials opting to continue into the extension phase of the studies.
The implications of these findings are significant, as they provide a promising new avenue for treating patients suffering from severe hypertriglyceridemia, potentially reducing the risk of serious complications such as acute pancreatitis. As ongoing research continues, olezarsen may play a crucial role in reshaping treatment approaches for this challenging condition.
