Patient-Oriented and Epidemiological Research
Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results1

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Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100–300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose; P < 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.

hypertriglyceridemia
triglycerides
remnant lipoproteins
antisense oligonucleotides
cardiovascular disease
familial chylomicronemia syndrome
apolipoprotein C-III

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This work was supported by National Institutes of Health Grants R01-HL119828, P01-HL088093, P01-HL055798, R01-HL124174, and R01-HL086599 (Y.I.M., J.L.W., S.T.). Ionis Pharmaceuticals provided funding via a lab service contract to University of California San Diego to perform the apoC-III-lipoprotein assay measurements. S.T. and J.L.W. are co-inventors of and receive royalties from patents or patent applications owned by the University of California San Diego on oxidation-specific and other antibodies and apoC-III-lipoprotein assays. S.T. has a dual appointment at University of California San Diego and Ionis Pharmaceuticals, Inc. A.D. is a full-time employee of Akcea Therapeutics. J.L.W. has received honoraria for consulting for Ionis, CymaBay, Intercept, and Prometheus Pharmaceuticals. V.J.A. and Q.Y. are employees of Ionis Pharmaceuticals. The other authors report no conflicts of interest. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Abbreviations:

    CHD

    coronary heart disease

    FCS

    familial chylomicronemia syndrome

    HDL-C

    HDL cholesterol

    IQR

    interquartile range

    LDL-C

    LDL cholesterol

    Lp(a)

    lipoprotein (a)

    nonHDL-C

    total cholesterol – HDL cholesterol

    RLU

    relative light units

    TRL

    triglyceride-rich lipoprotein

    VLDL-C

    VLDL cholesterol

1

Guest editor for this article was Alan M. Fogelman, David Geffen School of Medicine at UCLA.