Triglyceride levels substantially reduced with olezarsen compared to placebo

Olezarsen decreased levels of triglycerides compared with placebo in patients with moderate hypertriglyceridemia and elevated cardiovascular risk, according to a late-breaking trial presented in a Hot Line session today at ESC Congress 2025 and simultaneously published in New England Journal of Medicine.

High levels of triglycerides are an important risk factor for atherosclerotic cardiovascular disease (ASCVD) and yet the effects of current therapies are modest. Olezarsen targets the mRNA of apolipoprotein C-III, which inhibits triglyceride clearance. Olezarsen has been shown to lower triglyceride levels in small phase II trials and in patients with very high triglyceride levels. We investigated the efficacy and safety of olezarsen in patients with moderate hypertriglyceridemia at high ASCVD risk in the ESSENCE-TIMI 73b trial."

Doctor Brian Bergmark, Principal Investigator, from the TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, USA

The placebo-controlled, double-blind phase III ESSENCE-TIMI 73b trial was conducted at 160 sites in North America and Europe. The trial included adult patients with moderate hypertriglyceridemia (triglycerides 150−499 mg/dL) and elevated cardiovascular risk due to an established diagnosis of ASCVD or increased ASCVD risk as a result of type 2 diabetes mellitus and age ≥55 years. Patients were expected to be on optimised stable low-density lipoprotein-cholesterol (LDL-C)-lowering therapy at enrolment. The ESSENCE-TIMI 73b trial also included patients with severe hypertriglyceridemia (triglycerides ≥500 mg/dL). The primary analytic cohort was patients with moderate hypertriglyceridemia as patients with severe hypertriglyceridemia are being studied in dedicated, separate trials.

The primary analysis population included 1,349 patients with moderate hypertriglyceridemia and elevated cardiovascular risk who were randomised to olezarsen 50 mg (n=254), olezarsen 80 mg (n=766) or placebo (n=329) given every 4 weeks via subcutaneous injection for 12 months. The primary endpoint was the percent change from baseline in triglyceride levels at 6 months compared with placebo.

The primary analysis population had a median age of 64 years and 40% were women. The median triglyceride level at baseline was 238.5 mg/dL.

At 6 months, olezarsen significantly reduced levels of triglycerides: the placebo-adjusted least-squares mean difference in percent change from baseline was −58.4 percentage points for olezarsen 50 mg and −60.6 percentage points for olezarsen 80 mg (both p<0.001 vs. placebo).

In the placebo group, 12.5% of patients had triglyceride levels <150 mg/dL at 6 months, compared with 85.0% of patients on olezarsen 50 mg and 88.7% on olezarsen 80 mg (p<0.001 for both). At 12 months, the proportions were 20.6%, 82.8% and 85.0% for placebo, olezarsen 50 mg and olezarsen 80 mg, respectively (p<0.001 for both vs. placebo). Olezarsen significantly reduced levels of other lipoproteins − remnant cholesterol, non-high-density lipoprotein cholesterol and apolipoprotein B - with no significant effect on LDL-C.

The incidence of serious adverse events appeared similar: 9% with olezarsen 50 mg, 14% with olezarsen 80 mg and 11% with placebo. Liver transaminase elevations to any degree above the upper limit of the normal range were more common with olezarsen 50 mg (34.2%) and olezarsen 80 mg (38.3%) than with placebo (17.6%) (both p<0.001); however, clinically meaningful increases were rare and similar across groups.

Summarising, Doctor Bergmark said: "In a population with moderate hypertriglyceridemia and elevated cardiovascular risk, monthly olezarsen resulted in substantial triglyceride lowering greater than would be expected from currently available therapies, with more than 80% of patients treated with olezarsen achieving normal triglyceride levels."