Olezarsen lowers triglycerides in patients with moderate HTG, high CV risk

Treatment with olezarsen 50 or 80 mg significantly reduced triglyceride levels in patients with moderate hypertriglyceridaemia (HTG) and elevated cardiovascular (CV) risk compared with placebo, according to the Essence-TIMI 73b trial presented at ESC 2025.

“High levels of triglycerides are an important risk factor for atherosclerotic cardiovascular disease and yet the effects of current therapies are modest,” said lead author Dr Brian Bergmark from Brigham and Women's Hospital in Boston, Massachusetts, US.

“Olezarsen targets the mRNA of apolipoprotein C-III (apoC-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,” he noted. “However, the efficacy and safety of olezarsen in a broader population of patients with HTG and elevated CV risk are not established.”

Hence, the researchers conducted a phase III, international, double-blind, placebo-controlled trial involving 1,349 patients (mean age 64 years, 40 percent female) with moderate HTG (median triglyceride level 238.5 mg/dL) who are at high CV risk.

The participants were randomized in a 3:1 ratio to receive subcutaneous injections of olezarsen at 50 mg (n=254) or 80 mg (n=766) or placebo (n=329) every 4 weeks for 12 months. At baseline, 96 percent of patients received lipid-lowering therapy, primarily statins (81 percent), followed by fibrates (23 percent) and ezetimibe (17 percent).

From baseline to 6 months, patients treated with either dose of olezarsen had significant reductions in triglycerides, with a 58.4-percent decrease in the 50-mg group and a 60.6-percent decrease in the 80-mg group (p<0.001 for both) compared with placebo. [Bergmark B, et al, ESC 2025]

At 6 months, a significantly higher proportion of olezarsen-treated patients achieved a normal triglyceride level of <150 mg/dL (1.69 mmol/L) than placebo-treated patient (85 percent [50 mg] and 88.7 percent [80 mg] vs 12.5 percent; p<0.001 for both).

“Both doses of olezarsen led to rapid and sustained reductions in triglyceride levels,” said Bergmark.

Additional lipid parameters

Compared with placebo, both doses of olezarsen significantly reduced levels of apoC-III (up to -69.8 percent), non-HDL-C* (up to -21 percent), VLDL-C** (up to -57 percent), remnant cholesterol (up to -68 percent), and apolipoprotein B (up to -14 percent).

No significant change in LDL-C⁺ was observed between the olezarsen and placebo groups.

HDL-C*** levels increased significantly by 45.5 percent [50 mg] and 47.6 percent [80 mg] (p<0.001) with olezarsen compared with placebo.

Safety

The rate of treatment-emergent adverse events was similar across the olezarsen arms (73 percent [50 mg] and 77 percent [80 mg]) and the placebo arm (72 percent), as was the serious AEs (9 percent [50 mg], 14 percent [80 mg], and 11 percent [placebo]).

Injection site reactions occurred more frequently in the olezarsen arm than the placebo arm (13 percent [50 mg] and 15 percent [80 mg] vs 2 percent), but all were classified as mild.

The incidence of elevated ALT or AST levels, as well as infrequent renal abnormalities and reductions in platelet count was similar in both groups, Bergmark noted.

“Overall, in patients with moderate HTG and heightened CV risk, … monthly olezarsen resulted in substantial triglyceride lowering greater than would be expected from currently available therapies, with more than 80 percent of patients treated with olezarsen achieving normal triglyceride levels,” said Bergmark.