Olezarsen Cuts Triglycerides, Pancreatitis Risk in Severe Hypertriglyceridemia

NEW ORLEANS, LA—Patients with severe hypertriglyceridemia treated with olezarsen (Tryngolza; Ionis Pharmaceuticals) have a significant reduction in triglyceride levels by 6 months, as well as a lower risk of acute pancreatitis, compared with those given placebo, according to results from two phase III randomized trials presented recently at the American Heart Association 2025 Scientific Sessions.

In CORE-TIMI 72a and CORE2-TIMI 72b, which were published as a single paper in the New England Journal of Medicine, treatment with olezarsen 50 mg reduced triglyceride levels by as much as 63%, while the 80-mg dose led to a reduction as high as 72%.

Olezarsen “resulted in over 85% of patients achieving levels below 500 mg/dL, bringing them out of the severe range, and it reduced the risk of acute pancreatitis by 85%, which is a first in the severe hypertriglyceridemia population,” said lead researcher Nicholas A. Martson, MD (Brigham and Women’s Hospital, Boston, MA), last week during a late-breaking science presentation.

Robert Rosenson, MD (Icahn School of Medicine at Mount Sinai, New York, NY), the discussant following the presentation, said the decrease in acute pancreatitis was striking and noted that it was also observed in high-risk patients, defined as those with baseline triglyceride levels of 880 mg/dL or higher and a history of acute pancreatitis. The reduction in this group was more than would have been anticipated based on the observational data, he said.

“This trial is important because it extends the benefits of apolipoprotein C-III [APOC3] inhibition, and of lowering the risk of acute pancreatitis, to a population that is more commonly encountered in clinical practice and beyond the [familial chylomicronemia syndrome] patients,” he said.

CORE-TIMI 72a and CORE2-TIMI 72b

Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III messenger RNA, is currently approved as a treatment for patients familial chylomicronemia syndrome (FCS), a genetic form of severe hypertriglyceridemia that can lead to acute pancreatitis. While severe hypertriglyceridemia can lead to acute pancreatitis, olezarsen is not approved for lowering triglyceride levels when they’re elevated. The CORE-TIMI 72a and CORE2-TIMI 72b trials (n = 617 and n = 446, respectively) were designed to test the safety and efficacy of olezarsen in this population.

Both studies, which were identical in design, included patients with fasting triglyceride levels of 500 mg/dL or higher. Patients with FCS and those with acute pancreatitis at the time of screening, or within 4 weeks of screening, were excluded from the studies. In both trials, patients were randomized to olezarsen 50 mg, 80 mg, or placebo. The median age of patients was 54 years, and 23.6% were female.

Treatment with olezarsen 50 mg reduced triglyceride levels 49.2% and 62.9% from baseline in CORE-TIMI 72a and CORE2-TIMI 72b, respectively. These decreases were statistically significant compared with placebo. The 80-mg dose resulted in reductions of 54.5% and 72.2%, respectively, which were also significant compared with placebo. Apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol levels were also dropped with treatment.

There were 29 cases of acute pancreatitis in 22 patients in both studies. In the pooled olezarsen group, there were seven events in five patients (incidence 1.01 events per 100 patient-years), whereas there were 22 events in 17 patients given placebo (incidence 6.23 events per 100 patient-years), which translated into a mean rate ratio of 0.15 (95% CI 0.05-0.40) favoring olezarsen. The majority (25 cases) of acute pancreatitis occurred in the high-risk patients, and in this high-risk group, the number needed to treat to prevent a single case of acute pancreatitis was 4.  

In a substudy of patients who had a liver MRI at baseline and 12 months, hepatic fat levels increased in those taking olezarsen. Overall, there was a dose-dependent increase in the hepatic fat fraction with treatment, with an absolute increase of 5 or more percentage points in 27% of those taking the 50-mg dose and 40% of those taking the 80-mg dose. A hepatic fat fraction of less than 5% is considered normal. There was also a small, but significant, increase in HbA1c of roughly 0.25% with olezarsen.

Consequences of Hepatic Fat Change

Investigators say the clinical significance of the change in hepatic fat fraction is not known. At 3 times the upper limit of normal, increases in liver enzymes were more common with the 80-mg dose. There was no significant increase in liver enzymes above 5 times the upper limit of normal between the olezarsen- and placebo-treated patients.  

For Rosenson, the findings raise some questions, particularly around the long-term consequences of an increase in hepatic fat fraction.

“Is this a compound-specific or a class effect of the therapy?” he wondered. In the SHASTA-2 study of patients with severe hypertriglyceridemia, plozasiran (Arrowhead Pharmaceuticals), a small interfering RNA designed to reduce APOC3 in the liver, did not result in a significant increase in hepatic fat, he noted.

The long-term implications of an increase in HbA1c with olezarsen aren’t known either, Rosenson said, although he added that this trend has been reported in most trials that lower triglycerides.

“Typically, this is seen in the individuals with the most poorly controlled diabetes at baseline and at the highest dose of the therapy,” he said. “We need to do a better job controlling the diabetes before patients get into these trials, and maybe lowering HbA1c inclusion criteria might be appropriate going forward to assess these agents. Of course, after the trial is done, the opportunity to adjust background antidiabetic therapy is certainly an approach because the benefit is greater in people that have established pancreatitis.”