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Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy

Published:September 21, 2022DOI:https://doi.org/10.1016/j.jacl.2022.06.011

      Highlights

      • Volanesorsen suppressed apolipoprotein C-III (apo C-III) in partial lipodystrophy.
      • Lowering of apo C-III increased lipoprotein lipase (LPL) activity.
      • Volanesorsen lowered serum triglycerides, likely by activating LPL.
      • Peripheral, hepatic, and adipose insulin sensitivity increased after volanesorsen.

      Abstract

      Background

      Partial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL).

      Objective

      We hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL.

      Methods

      Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension.

      Results

      Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25th, 75th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects’ serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets.

      Conclusions

      In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.

      Keywords

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      References

        • Garg A.
        Clinical review#: Lipodystrophies: genetic and acquired body fat disorders.
        J Clin Endocrinol Metab. 2011; 96: 3313-3325
        • Lightbourne M
        • Brown RJ.
        Genetics of Lipodystrophy.
        Endocrinol Metab Clin North Am. 2017; 46: 539-554
        • Brown RJ
        • Araujo-Vilar D
        • Cheung PT
        • et al.
        The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline.
        J Clin Endocrinol Metab. 2016; 101: 4500-4511
        • Chan JL
        • Oral EA.
        Clinical classification and treatment of congenital and acquired lipodystrophy.
        Endocr Pract. 2010; 16: 310-323
        • Garg A
        • Speckman RA
        • Bowcock AM.
        Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene.
        Am J Med. 2002; 112: 549-555
        • Diker-Cohen T
        • Cochran E
        • Gorden P
        • Brown RJ.
        Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin.
        J Clin Endocrinol Metab. 2015; 100: 1802-1810
      1. Agency EM. Myalepta Vol 2021. European Medicines Agency Science Medicines Health Website: European Medicines Agency Science Medicines Health 2018.

        • Ooi EM
        • Barrett PH
        • Chan DC
        • Watts GF.
        Apolipoprotein C-III: understanding an emerging cardiovascular risk factor.
        Clin Sci (Lond). 2008; 114: 611-624
        • Chan DC
        • Chen MM
        • Ooi EM
        • Watts GF.
        An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk factor?.
        Int J Clin Pract. 2008; 62: 799-809
        • Lemieux I
        • Salomon H
        • Despres JP.
        Contribution of apo CIII reduction to the greater effect of 12-week micronized fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients.
        Ann Med. 2003; 35: 442-448
        • Gordts PL
        • Nock R
        • Son NH
        • et al.
        ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors.
        J Clin Invest. 2016; 126: 2855-2866
        • Petersen KF
        • Dufour S
        • Hariri A
        • et al.
        Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.
        N Engl J Med. 2010; 362: 1082-1089
        • Jorgensen AB
        • Frikke-Schmidt R
        • Nordestgaard BG
        • Tybjaerg-Hansen A.
        Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.
        N Engl J Med. 2014; 371: 32-41
        • Pollin TI
        • Damcott CM
        • Shen H
        • et al.
        A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.
        Science. 2008; 322: 1702-1705
        • Gaudet D
        • Alexander VJ
        • Baker BF
        • et al.
        Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia.
        N Engl J Med. 2015; 373: 438-447
        • Gaudet D
        • Brisson D
        • Tremblay K
        • et al.
        Targeting APOC3 in the familial chylomicronemia syndrome.
        N Engl J Med. 2014; 371: 2200-2206
        • Witztum JL
        • Gaudet D
        • Freedman SD
        • et al.
        Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome.
        N Engl J Med. 2019; 381: 531-542
        • Digenio A
        • Dunbar RL
        • Alexander VJ
        • et al.
        Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes.
        Diabetes Care. 2016; 39: 1408-1415
        • Kassai A
        • Muniyappa R
        • Levenson AE
        • et al.
        Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy.
        J Clin Endocrinol Metab. 2016; 101: 1790-1797
        • Herdman M
        • Gudex C
        • Lloyd A
        • et al.
        Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).
        Qual Life Res. 2011; 20: 1727-1736
        • Brazier JE
        • Harper R
        • Jones NM
        • et al.
        Validating the SF-36 health survey questionnaire: new outcome measure for primary care.
        BMJ. 1992; 305: 160-164
        • Yu RZ
        • Baker B
        • Chappell A
        • Geary RS
        • Cheung E
        • Levin AA.
        Development of an ultrasensitive noncompetitive hybridization-ligation enzyme-linked immunosorbent assay for the determination of phosphorothioate oligodeoxynucleotide in plasma.
        Analytical biochemistry. 2002; 304: 19-25
        • Brown RJ
        • Valencia A
        • Startzell M
        • et al.
        Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy.
        J Clin Invest. 2018; 128: 3504-3516
        • Ouwerkerk R
        • Pettigrew RI
        • Gharib AM.
        Liver metabolite concentrations measured with 1H MR spectroscopy.
        Radiology. 2012; 265: 565-575
        • Duncan GE
        • Perri MG
        • Theriaque DW
        • Hutson AD
        • Eckel RH
        • Stacpoole PW.
        Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults.
        Diabetes Care. 2003; 26: 557-562
        • Kinnunen PK
        • Ehnolm C.
        Effect of serum and C-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase.
        FEBS Lett. 1976; 65: 354-357
        • Mendivil CO
        • Zheng C
        • Furtado J
        • Lel J
        • Sacks FM.
        Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins.
        Arterioscler Thromb Vasc Biol. 2010; 30: 239-245
        • Brown RJ
        • Lagor WR
        • Sankaranaravanan S
        • et al.
        Impact of combined deficiency of hepatic lipase and endothelial lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins.
        Circ Res. 2010; 107: 357-364
        • Ito Y
        • Azrolan N
        • O'Connell A
        • Walsh A
        • Breslow JL.
        Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice.
        Science. 1990; 249: 790-793
        • Mann CJ
        • Troussard AA
        • Yen FT
        • et al.
        Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of triglyceride-rich lipoproteins to the lipolysis-stimulated receptor.
        J Biol Chem. 1997; 272: 31348-31354
        • Avall K
        • Ali Y
        • Leibiger IB
        • et al.
        Apolipoprotein CIII links islet insulin resistance to beta-cell failure in diabetes.
        Proc Natl Acad Sci U S A. 2015; 112: E2611-E2619
      2. Akcea Therapeutics I. Akcea and Ionis report top-line results from the BROADEN Study with WAYLIVRA® (volanesorsen) in patients with familial partial lipodystrophy 2019.

        • Oral EA
        • Garg A
        • Tami J
        • Huang EA
        • O'Dea Louis St.L.
        • Schmidt H
        • Tiulpakov A
        • Mertens A
        • Alexander VJ
        • Watts L
        • Hurh E
        • Witztum JL
        • Geary RS
        • Tsimikas S
        Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study.
        J. Clin. Lipidol. 2022;

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