Monthly injections of olezarsen demonstrated substantial triglyceride reduction in patients with moderate hypertriglyceridemia and elevated cardiovascular risk, according to results from the phase 3 ESSENCE-TIMI 73b trial presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine.
The antisense oligonucleotide, which targets messenger RNA for apolipoprotein C-III, reduced triglyceride levels by up to 60% at 6 months compared to placebo. More than 80% of patients treated with olezarsen achieved normal triglyceride levels, defined as less than 150 mg/dL, at both 6 and 12 months.
Superior Efficacy Over Current Therapies
"This triglyceride effect was greater than is possible with current standard of care therapies," said Dr. Brian A. Bergmark from the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women's Hospital and Harvard Medical School during a press conference. "These findings support the efficacy and safety of olezarsen for triglyceride lowering in a broad population of patients with moderately elevated triglycerides."
The double-blind, randomized, placebo-controlled trial included 1,349 patients with moderate hypertriglyceridemia (150-499 mg/dL) and elevated cardiovascular risk due to established atherosclerotic cardiovascular disease or type 2 diabetes plus age of at least 55 years. The median age was 64 years, 40% were women, and the median baseline triglyceride level was 238.5 mg/dL.
Dose-Dependent Triglyceride Reduction
Patients were randomly assigned to receive olezarsen 50 mg, olezarsen 80 mg, or placebo administered every 4 weeks via subcutaneous injection for 12 months. The primary endpoint was the percent change in triglyceride levels from baseline to 6 months.
At 6 months, the placebo-adjusted least-squares mean change in triglyceride levels was -58.4 percentage points for olezarsen 50 mg (P < .001) and -60.6 percentage points for olezarsen 80 mg (P < .001) compared to placebo.
Among patients with moderate hypertriglyceridemia, only 12.5% in the placebo group achieved normal triglyceride levels at 6 months, compared with 85% in the olezarsen 50 mg group and 88.7% in the 80 mg group (P < .001 for both versus placebo). At 12 months, the proportions were 20.6%, 82.8%, and 85.0% for placebo, olezarsen 50 mg, and olezarsen 80 mg, respectively.
Comprehensive Lipid Profile Improvements
Beyond triglyceride reduction, olezarsen treatment resulted in significant improvements across multiple lipid parameters. Reductions included up to 22% for non-HDL cholesterol, 57% for VLDL cholesterol, 68% for remnant cholesterol, and 15% for apolipoprotein B. Notably, there was no change in LDL cholesterol with either dose compared to placebo.
Favorable Safety Profile
The trial demonstrated no major safety concerns with olezarsen treatment. Adverse event rates were similar between treatment groups, with 72.8%-76.7% experiencing adverse events with olezarsen versus 72.1% with placebo. Serious adverse event rates were 9.4%-13.6% with olezarsen compared to 11.4% with placebo.
Liver transaminase elevations above the upper limit of normal were more common with olezarsen 50 mg (34.2%) and 80 mg (38.3%) than with placebo (17.6%), but clinically meaningful increases were rare and consistent across treatment groups. Injection-site reactions were more frequent with olezarsen treatment.
Addressing Unmet Medical Need
Elevated triglyceride levels represent an important risk factor for atherosclerotic cardiovascular disease, but highly effective therapies have been lacking. Olezarsen, already approved by the FDA in 2024 for familial chylomicronemia syndrome, works by targeting apolipoprotein C-III, which inhibits triglyceride clearance.
"High levels of triglycerides are an important risk factor for atherosclerotic cardiovascular disease and yet the effects of current therapies are modest," Bergmark explained. The ESSENCE-TIMI 73b trial was designed to investigate olezarsen's efficacy and safety in a broader population of patients with hypertriglyceridemia and elevated cardiovascular risk.
The researchers noted that determining whether these lipid profile changes would translate into clinical cardiovascular benefit would require a dedicated outcomes trial. The current results establish olezarsen as a potentially transformative therapy for triglyceride management in high-risk cardiovascular patients.
