Study title: Olezarsen in patients with hypertriglyceridemia at high cardiovascular risk: Rationale and design of Essence-TIMI 73b trial

Presented at: ESC Congress 2025

Link: https://esc365.escardio.org/presentation/312173

Prepared by: Dr. Simay Erdal Sayın

Background:
Elevated triglyceride levels constitute an important risk factor for atherosclerosis. However, the magnitude of triglyceride reduction achieved with currently available therapies is limited, and the impact of triglyceride lowering on atherosclerosis remains uncertain. Olezarsen is an antisense oligonucleotide targeting the mRNA of apolipoprotein C-III (ApoC-III), an inhibitor of triglyceride clearance. ApoC-III increases circulating triglyceride levels through lipoprotein lipase inhibition and other mechanisms. Its inhibition leads to reductions in triglycerides, triglyceride-rich lipoproteins (TRLs), and apolipoprotein B, thereby being associated with reduced cardiovascular risk.

Objective:
To evaluate the efficacy and safety of olezarsen in reducing triglyceride levels over time and its impact on coronary plaque burden and characteristics in patients with moderate hypertriglyceridemia (200-499 mg/dL) and cardiovascular risk factors, as well as those with severe hypertriglyceridemia (≥500 mg/dL).

Methods:
Essence-TIMI 73b is a randomized, double-blind, placebo-controlled phase 3 trial. A total of 1,478 patients were randomized across 160 centers in North America and Europe. The study employed a two-stage randomization approach: patients were first randomized in a 1:3 ratio to 50 mg or 80 mg olezarsen cohorts, then within each cohort, randomized 3:1 to receive olezarsen or placebo. Treatment duration was 12 months with subcutaneous injections administered every 4 weeks, followed by a 13-week safety follow-up period. The primary endpoint was the percent change in triglyceride levels from baseline to 6 months. A coronary computed tomography angiography (CTA) substudy in approximately 1,000 patients evaluated changes in noncalcified plaque volume at 12 months.

Results:
The study population had a median age of 63 years, with 39% being female and 71% non-Hispanic white. Diabetes mellitus was present in 60% of patients, and 42% had atherosclerotic cardiovascular disease. The median baseline triglyceride level was 249 mg/dL, with 9% of patients having triglyceride levels ≥500 mg/dL. Lipid-lowering therapy was utilized by 97% of patients, with 82% receiving statin therapy. Among the 1,000 patients who underwent coronary CTA, 555 (55%) had quantifiable noncalcified coronary plaque.

Conclusions:
The Essence-TIMI 73b trial established endpoints across three main categories. The primary endpoint assessed the percent change in triglyceride levels at 6 months between olezarsen and placebo groups. Secondary endpoints encompassed the proportion of patients achieving triglyceride levels <150 mg/dL at 6 and 12 months, and changes in various lipid parameters (apoC-III, VLDL-C, remnant cholesterol, non-HDL-C, HDL-C, apoB, LDL-C). Exploratory endpoints included cardiovascular events (cardiovascular death, myocardial infarction, ischemic stroke, and any arterial revascularization), glycemic measures, and changes in non-calcified coronary plaque volume on coronary CTA. However, detailed results for these outcomes have not yet been fully reported.

Commentary:
While contemporary LDL-lowering agents enable reduction of atherosclerotic cardiovascular disease risk, residual risk persists due to triglyceride-rich lipoproteins (TRLs). Targeting apoC-III to facilitate clearance of triglyceride-rich lipoproteins represents a promising therapeutic strategy for lowering triglyceride levels and reducing cardiovascular risk. Prior phase 2 studies demonstrated substantial triglyceride reduction with olezarsen at 6 and 12 months. Additional studies showed that both olezarsen and plozasiran significantly reduced apolipoprotein B (ApoB), thereby facilitating clearance of atherogenic particles. Coronary CTA enables assessment of both coronary plaque burden and plaque characteristics. This study represents a pivotal RNA-targeted therapy trial for triglyceride metabolism and is significant for evaluating whether olezarsen can decelerate atherosclerosis progression and improve clinical outcomes. This research holds potential for providing important evidence regarding the cardiovascular clinical benefits of olezarsen.