Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia

N Engl J Med. 2025 Oct 2;393(13):1279-1291. doi: 10.1056/NEJMoa2507227. Epub 2025 Aug 30.

Abstract

Background: Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an N-acetylgalactosamine-conjugated antisense oligonucleotide that targets the messenger RNA of apolipoprotein C-III, which inhibits triglyceride clearance.

Methods: In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change).

Results: A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups.

Conclusions: Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.).

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Clinical Trial, Phase III

MeSH terms

  • Aged
  • Apolipoprotein C-III* / antagonists & inhibitors
  • Apolipoprotein C-III* / genetics
  • Apolipoprotein C-III* / metabolism
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control
  • Double-Blind Method
  • Female
  • Humans
  • Hypertriglyceridemia* / blood
  • Hypertriglyceridemia* / complications
  • Hypertriglyceridemia* / diagnosis
  • Hypertriglyceridemia* / drug therapy
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Oligonucleotides* / administration & dosage
  • Oligonucleotides* / adverse effects
  • Oligonucleotides, Antisense* / administration & dosage
  • Oligonucleotides, Antisense* / adverse effects
  • Severity of Illness Index
  • Treatment Outcome
  • Triglycerides* / blood
  • Triglycerides* / metabolism

Substances

  • APOC3 protein, human
  • Apolipoprotein C-III
  • olezarsen
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Triglycerides

Associated data

  • ClinicalTrials.gov/NCT05610280