Journal Article

Olezarsen in patients with hypertriglyceridemia at high cardiovascular risk: Rationale and design of the Essence–TIMI 73b trial

Murphy, Sabina A., Marston, Nicholas A., Alexander, Veronica J., Kang, Yu Mi, Giugliano, Robert P., Zhang, Shuanglu, Tsimikas, Sotirios, Prohaska, Thomas A., Lu, Michael T., Sabatine, Marc S., Bergmark, Brian A., Zimerman, Andre, Moura, Filipe A., Karwatowska-Prokopczuk, Ewa

2025

Overview

Elevated triglycerides are an important risk factor for atherosclerosis. However, the magnitude of triglyceride lowering with currently available therapies is modest and the impact of triglyceride-lowering on atherosclerosis remains undefined. Olezarsen is an antisense oligonucleotide (ASO) targeting mRNA for apolipoprotein C-III (apoC-III), an inhibitor of triglyceride clearance. The Essence–TIMI 73b trial (NCT05610280) is a randomized, double-blind, placebo-controlled phase 3 trial of olezarsen 50 mg or 80 mg every 4 weeks compared with placebo. The trial enrolled adults with either moderate hypertriglyceridemia (200-499 mg/dL) plus increased cardiovascular risk, or severe hypertriglyceridemia (≥500 mg/dL). The primary endpoint is the percent change in triglyceride levels from baseline to 6 months, reported as the difference between each olezarsen dose group and pooled placebo. A coronary computed tomography angiography (CTA) substudy will examine changes in noncalcified plaque volume from baseline to 12 months. A total of 1,478 patients were randomized at 160 sites in North America and Europe. The median age is 63 (IQR 56-69) years, 39% are women, and 71% are non-Hispanic White. Overall, 60% of patients have diabetes, and 42% have atherosclerotic cardiovascular disease. At randomization, 97% were receiving lipid-lowering therapies, including 82% on a statin. The median baseline triglyceride level was 249 (195-339) mg/dL and 9% of patients had triglycerides ≥500 mg/dL at enrollment. Approximately 1000 patients completed a baseline CTA, of whom 555 (55%) had measurable noncalcified coronary plaque and continued in the substudy. Targeting apoC-III to facilitate clearance of triglyceride-rich lipoproteins is a potential therapeutic strategy for lowering triglyceride levels, regressing atherosclerosis, and reducing cardiovascular risk. The phase 3 Essence–TIMI 73b trial, which has enrolled nearly 1,500 patients, including over 550 in a coronary CTA substudy, should provide key insights into the efficacy and safety of olezarsen in patients with largely moderate hypertriglyceridemia and elevated cardiovascular risk. Clinicaltrials.gov: NCT05610280

• Publisher: Elsevier Inc,Elsevier Limited
• Subject: Aged / Angiography / Antisense oligonucleotides / Antisense RNA / Apolipoprotein C-III / Apolipoprotein C-III - antagonists & inhibitors / Apolipoprotein C-III - genetics / Apolipoproteins / Arteriosclerosis / Atherosclerosis / Cardiovascular diseases / Cardiovascular Diseases - etiology / Cardiovascular Diseases - prevention & control / Cholesterol / Clinical Trials, Phase III as Topic / Computed tomography / Computed Tomography Angiography / Coronary Angiography / Diabetes / Diabetes mellitus / Double-Blind Method / Drug dosages / Female / Health risks / Heart attacks / Heart Disease Risk Factors / High density lipoprotein / Humans / Hypertriglyceridemia / Hypertriglyceridemia - blood / Hypertriglyceridemia - complications / Hypertriglyceridemia - drug therapy / Lipids / Lipoproteins / Male / Middle Aged / mRNA / Oligonucleotides - administration & dosage / Oligonucleotides - therapeutic use / Oligonucleotides, Antisense - administration & dosage / Oligonucleotides, Antisense - therapeutic use / Pancreatitis / Patients / Placebos / Randomization / Randomized Controlled Trials as Topic / Risk factors / Triglycerides / Triglycerides - blood