Olezarsen has demonstrated significant effectiveness in treating severe hypertriglyceridemia (sHTG) during the phase 3 CORE and CORE2 clinical trials. The trials revealed a substantial mean reduction in fasting triglyceride (TG) levels after six months, with these results maintained through twelve months. This pivotal data was presented by Dr. Nicholas Marston, a cardiologist at Brigham and Women’s Hospital, during the American Heart Association’s Scientific Sessions 2025 in New Orleans, Louisiana.
Dr. Marston highlighted the significance of these trials, stating, “CORE and CORE2 are the first studies to show a significant reduction in acute pancreatitis events in sHTG.” He noted that most patients receiving olezarsen achieved TG levels below the critical threshold associated with potentially life-threatening pancreatitis episodes. With conventional therapies often yielding modest results, he expressed optimism about olezarsen’s potential to transform treatment approaches for these patients.
Olezarsen is an investigational antisense oligonucleotide that targets the mRNA of apolipoprotein C-III (apoC-III). This protein is known to impede triglyceride clearance by inhibiting lipoprotein lipase activity and the liver’s uptake of triglyceride-rich particles. Currently, olezarsen has been approved in the United States and Europe under the name TRYNGOLZA for adults diagnosed with familial chylomicronemia syndrome.
Trial Overview and Results
The CORE and CORE2 trials involved a total of 1,063 participants, with 617 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. A subsequent random assignment within each cohort allocated patients to receive either olezarsen or a matching placebo, administered subcutaneously every four weeks. Each trial lasted for a year and included a substudy using MRI to assess changes in hepatic fat over the same period.
The median age of participants across both trials was 54 years, with a median TG level of 794 mg/dl. Notably, 43% of the patients had TG levels of 880 mg/dl or higher, while 18% had a history of pancreatitis. A total of 333 patients participated in the hepatic MRI substudy, which further enriched the data collected during these trials.
Olezarsen achieved a placebo-adjusted mean reduction in fasting TG levels of up to 72% at the six-month mark, a figure that remained consistent throughout the 12-month study period. In addition, the trials reported an impressive 85% reduction in adjudicated acute pancreatitis events at the 12-month evaluation point. Following the trials, over 90% of patients who completed CORE and CORE2 opted to continue into the extension phase.
The findings from these trials not only highlight the effectiveness of olezarsen but also underscore the potential for significant advancements in the management of severe hypertriglyceridemia, a condition often associated with serious health risks, including acute pancreatitis. As the medical community continues to seek more effective treatment options, olezarsen emerges as a promising candidate that could reshape the therapeutic landscape for patients affected by this challenging condition.
