2. Academic Validation
  3. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk

  • Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820.
Jean-Claude Tardif 1,  Ewa Karwatowska-Prokopczuk 2,  Eric St Amour 3,  Christie M Ballantyne 4,  Michael D Shapiro 5,  Patrick M Moriarty 6,  Seth J Baum 7,  Eunju Hurh 2,  Victoria J Bartlett 2,  Joyce Kingsbury 2,  Amparo L Figueroa 2,  Veronica J Alexander 8,  Joseph Tami 8,  Joseph L Witztum 9,  Richard S Geary 8,  Louis St L O'Dea 2,  Sotirios Tsimikas 8 10,  Daniel Gaudet 11
Affiliations

Affiliations

  • 1 Jean-Claude Tardif MD Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, PQ H1T1C8, Canada.
  • 2 Akcea Therapeutics, 55 Cambridge Parkway Suite 100 Cambridge, Boston, MA 02142, USA.
  • 3 Eric St-Amour, MD 214 Cite des jeunes Gatineau, QC J8Y 6S8, Canada.
  • 4 Department of Medicine, Baylor College of Medicine, One Baylor Plaza, MS BCM285, Houston, TX 77030, USA.
  • 5 Wake Forest University School of Medicine, Section on Cardiovascular Medicine 1, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
  • 6 Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
  • 7 Clinical Affiliate Professor of Cardiology, Department of Integrated Medical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, 777 Glades Road, BC-71 Boca Raton, FL 33431, USA.
  • 8 Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • 9 Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, BSB1080 La Jolla, CA 92093-0682, USA.
  • 10 Division of Cardiovascular Medicine, University of California, San Diego, 9500 Gilman Drive, BSB1080 La Jolla, CA 92093-0682, USA.
  • 11 Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Chicoutimi, QC, Canada.
PMID: 35025993 DOI: 10.1093/eurheartj/ehab820
Abstract

Aims: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic apoC3 mRNA to inhibit Apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established Cardiovascular Disease.

Methods and results: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein Cholesterol, non-high-density lipoprotein Cholesterol, and Apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site.

Conclusion: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established Cardiovascular Disease.

Trial registration number: NCT03385239.

Keywords

Antisense; Atherosclerosis; Cardiovascular disease; Cardiovascular risk factors; Hypertriglyceridaemia; apoC-III.

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