Olezarsen reduces triglycerides, pancreatitis risk in severe hypertriglyceridaemia

Treatment with olezarsen significantly reduced triglyceride levels and the risk of acute pancreatitis in patients with severe hypertriglyceridaemia, according to the primary results of the CORE-TIMI 72a and CORE2-TIMI 72b trials presented at AHA 2025.

Dr Nicholas Martson, lead author from Brigham and Women’s Hospital in Boston, Massachusetts, US, stated that treatment with olezarsen “resulted in >85 percent of patients achieving levels <500 mg/dL, bringing them out of the severe range.”

Olezarsen also “reduced the risk of acute pancreatitis by 85 percent, which is a first in the severe hypertriglyceridaemia population,” Martson added.

CORE-TIMI 72a and CORE2-TIMI 72b trials included 1,063 patients (mean age 54 years, 24 percent female) with severe hypertriglyceridaemia whose baseline median triglycerides were 832 and 748 mg/dL, respectively. Participants were randomized in a 1:1:1 ratio to receive olezarsen 50 mg (n=354) or 80 mg (n=351) or placebo (n=358) every 4 weeks for 12 months. [AHA 2025, abstract LBS.01]

At 6 months, olezarsen 50 mg significantly reduced triglycerides by 62.9 percent in the CORE-TIMI 72a trial and by 49.2 percent in the CORE2-TIMI 72b trial (p<0.001 for both) compared with placebo.

Treatment with olezarsen 80 mg vs placebo also showed significant reductions in triglyceride levels at 6 months in both trials (-72.2 percent in CORE-TIMI 72a and -54.5 percent in CORE2-TIMI 72b; p<0.001 for both).

Martson noted that the triglyceride levels achieved at 6 months were sustained through 12 months.

Additionally, in both trials, treatment with either dose of olezarsen was associated with significant reductions in apolipoprotein C-III (ranging from -57 percent to -77 percent), remnant cholesterol (ranging from -51 percent to -70 percent), and non-high-density lipoprotein cholesterol (ranging from -19 percent to -33 percent) at 6 months compared with placebo (p<0.001 for all).

The incidence of acute pancreatitis was lower in the olezarsen group than in the placebo group (mean rate ratio, 0.15), with an absolute risk reduction of 5.2 percent. The number needed to treat to prevent one episode at 1 year was 20.

Safety endpoints

Rates of treatment-emergent adverse events were similar between the olezarsen groups (75 percent [50 mg] and 75 percent [80 mg]) and the placebo group (75 percent).

However, injection site reactions were more common with olezarsen than with placebo (10 percent [50 mg] and 17 percent [80 mg] vs 1 percent). These reactions were mostly mild, with no severe events reported, Martson noted.

“Olezarsen was generally well-tolerated, with ongoing monitoring in an open-label extension,” he said.