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. 2022 Sep-Oct;16(5):617-625.
doi: 10.1016/j.jacl.2022.06.005. Epub 2022 Jun 23.

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

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
Free article

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

Ewa Karwatowska-Prokopczuk et al. J Clin Lipidol. 2022 Sep-Oct.
Free article

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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Conflict of interest statement

Disclosures EKP, VJB, SX, and ST are employees of Ionis Pharmaceuticals. J-C T received research grants from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Pfizer and Servier; honoraria from Amarin, DalCor, Pfizer, Sanofi and Servier; minor equity interest in DalCor. DG reports grants and personal fees from Akcea Therapeutics, Ionis Pharmaceuticals during the conduct of the study, Arrowhead and Regeneron, and grants from Kowa and Acasti and grants from Uniqure outside the submitted work. CMB has received grant/research support (to his institution) from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostic, and has been a consultant for Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma Inc, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. MDS serves on scientific advisory boards: Amgen, Esperion, Novartis. PMM is a consultant, speaker, or received Research grants from Amgen, Esperion, Kaneka, Amarin, Stage II Innovations/Renew, Novartis, Ionis, FH Foundation, GB Life Sciences, Aegerion. SJB is consultant on scientific advisory board or speaker for Altimmune, Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, Axcella, Eli Lilly, Esperion, Madrigal, Novartis, Regeneron, Sanofi. JDO is an employee of LabCorp. JLW is a consultant to Ionis. JLW and ST are co-inventors and receive royalties from patents owned by UCSD on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins and are co-founders and have an equity interest in Oxitope, Inc and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics, LLC (“Kleanthi”). ST is a co-founder of Covicept Therapeutics. Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. The other authors have no disclosures. All authors have approved the final article should be true and included in the disclosure.

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