Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia

  • J Clin Lipidol. 2022 Sep-Oct;16(5):617-625. doi: 10.1016/j.jacl.2022.06.005.
Ewa Karwatowska-Prokopczuk  1 ,  Jean-Claude Tardif  2 ,  Daniel Gaudet  3 ,  Christie M Ballantyne  4 ,  Michael D Shapiro  5 ,  Patrick M Moriarty  6 ,  Seth J Baum  7 ,  Eric St Amour  8 ,  Veronica J Alexander  1 ,  Shuting Xia  1 ,  James D Otvos  9 ,  Joseph L Witztum  10 ,  Sotirios Tsimikas  11 ,  Olezarsen Trial Investigators
Affiliations
  • 1. Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA 92010 (EK-P, VJA, SX, ST).
  • 2. Montreal Heart Institute, Université de Montréal, Montreal, QC, QC H1T 1C8 Canada (J-CT).
  • 3. Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Chicoutimi, QC, G7H 7K9 Canada (DG).
  • 4. Baylor College of Medicine, Sections of Cardiology and Cardiovascular Research, Houston, TX, USA 77030, (CMB).
  • 5. Section on Cardiovascular Medicine, Wake Forest University School of Medicine, Winston Salem, NC 27157 (MDS).
  • 6. Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO USA 66160 (PMM).
  • 7. Excel Medical Clinical Trials, Boca Raton, FL, USA 33434 (SJB).
  • 8. Q and T Research Outaouais Inc., Gatineau, QC, J8Y 6S8 Canada (EStA).
  • 9. LabCorp, Morrisville, NC USA 27560 (JO).
  • 10. University of California San Diego, La Jolla, California, USA 92093-0682 (JLW, ST).
  • 11. Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA 92010 (EK-P, VJA, SX, ST); University of California San Diego, La Jolla, California, USA 92093-0682 (JLW, ST). Electronic address: [email protected].
PMID: 35902351 DOI: 10.1016/j.jacl.2022.06.005
Abstract

Background: Olezarsen is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of Apolipoprotein C-III (apoC-III) and triglyceride-rich lipoproteins (TRLs).

Objective: To define the effect of olezarsen on NMR-derived lipoprotein particle size and concentration.

Methods: Patients (n=114) with or at risk for atherosclerotic Cardiovascular Disease and fasting triglycerides ≥200 and <500 mg/dL 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. NMR LipoProfile® analysis was performed in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months.

Results: A dose-dependent relationship was generally noted with increasing cumulative doses of olezarsen in TRL particle (TRLP), LDL particle (LDL-P) and HDL (HDL-P) particle concentrations. In the 50 mg every 4 weeks dose, compared to placebo, olezarsen resulted in a significant reduction in total TRL-P (51%, P<0.0001) with largest reductions in large-size (68%, P<0.0001) and medium-size (63%, P<0.0001) TRL-P. Total LDL-P concentration was not changed, but large LDL-P increased by 186% (p=0.0034), and small LDL-P decreased by 39% (p=0.0713). Total HDL-P concentration increased by 15% (P=0.0006), driven primarily by a 32% increase in small HDL subspecies (diameters <8.3 nm) (P=0.0008).

Conclusion: Olezarsen results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDL-P. These findings suggest that apoC-III inhibition improves the overall atherogenic risk profile.

Keywords
Antisense; ApoCIII; Cardiovascular disease; Cholesterol; Therapy.
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