Olezarsen in patients with hypertriglyceridemia at high cardiovascular risk: Rationale and design of the Essence–TIMI 73b trial - 04/04/25

Doi : 10.1016/j.ahj.2025.02.022

Brian A. Bergmark, MD ^a,^b,^⁎ , Nicholas A. Marston, MD, MPH ^a,^b, Thomas A. Prohaska, MD, PhD ^c, Veronica J. Alexander, PhD ^c, Andre Zimerman, MD, PhD ^d, Filipe A. Moura, MD, PhD ^e,^f, Yu Mi Kang, MD, PhD ^a,^g, Sabina A. Murphy, MPH ^a,^b, Shuanglu Zhang, MPH ^a,^b, Michael T. Lu, MD, MPH ^b,^h, Ewa Karwatowska-Prokopczuk, MD, PhD ^c, Sotirios Tsimikas, MD ^c,ⁱ, Robert P. Giugliano, MD, SM ^a,^b, Marc S. Sabatine, MD, MPH ^a,^b
^a TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA
^b Harvard Medical School, Boston, MA
^c Ionis Pharmaceuticals, Carlsbad, CA
^d Clinical Trials Unit, Hospital Moinhos de Vento, Moinhos de Vento College of Health Sciences, Porto Alegre, Brazil
^e Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT
^f VA Connecticut Healthcare System, West Haven, CT
^g Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA
^h Cardiovascular Imaging Research Center, Massachusetts General Hospital, Boston, MA
ⁱ Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA

^⁎Reprint requests: Brian A. Bergmark, MD, TIMI Study Group, 60 Fenwood Rd, Suite 7022, Boston, MA, 02115.TIMI Study Group60 Fenwood Rd, Suite 7022BostonMA02115

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ABSTRACT

Background

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.

Methods

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.

Results

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.

Discussion

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.