Evaluation of efficacy and safety of antisense inhibition of apolipoprotein C-III with volanesorsen in patients with severe hypertriglyceridemia

References

• Laufs U, Parhofer KG, Ginsberg HN, et al. Clinical review on triglycerides. Eur Heart J. 2020 Jan 1;41(1):99-109c.
   Web of Science ®Google Scholar
• Pedersen SB, Langsted A, Nordestgaard BG. Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis. JAMA Intern Med. 2016 Dec 1;176(12):1834–1842.
   PubMed Web of Science ®Google Scholar
• Hegele RA, Berberich AJ, Ban MR, et al. Clinical and biochemical features of different molecular etiologies of familial chylomicronemia. J Clin Lipidol. 2018 Aug;12(4):920–927.e4.
   PubMed Web of Science ®Google Scholar
• Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014 Aug;2(8):655–666.
   PubMed Web of Science ®Google Scholar
• D’Erasmo L, Di Costanzo A, Cassandra F, et al. Spectrum of mutations and long-term clinical outcomes in genetic chylomicronemia syndromes. Arterioscler Thromb Vasc Biol. 2019 Dec;39(12):2531–2541.
   PubMed Web of Science ®Google Scholar
• Hegele RA, Borén J, Ginsberg HN, et al. Rare dyslipidaemias, from phenotype to genotype to management: a European atherosclerosis society task force consensus statement. Lancet Diabetes Endocrinol. 2020 Jan 1;8(1):50–67.
   PubMed Web of Science ®Google Scholar
• Brahm AJ, Hegele RA. Chylomicronaemia–current diagnosis and future therapies. Nat Rev Endocrinol. 2015 Jun;11(6):352–362.
   PubMed Web of Science ®Google Scholar
• Moulin P, Dufour R, Averna M, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an “FCS score.”. Atherosclerosis. 2018;275:265–272.
   PubMed Web of Science ®Google Scholar
• Gaudet D, Blom D, Bruckert E, et al. Acute pancreatitis is highly prevalent and complications can be fatal in patients with familial chylomicronemia: results from a survey of lipidologist. J Clin Lipidol. 2016 May 1;10(3):680–681.
   Google Scholar
• Valdivielso P, Ramírez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med. 2014 Oct;25(8):689–694.
   PubMed Web of Science ®Google Scholar
• Davidson M, Stevenson M, Hsieh A, et al. The burden of familial chylomicronemia syndrome: results from the global IN-FOCUS study. J Clin Lipidol. 2018 Aug;12(4):898–907.e2.
   PubMed Web of Science ®Google Scholar
• Stroes E, Moulin P, Parhofer KG, et al. Diagnostic algorithm for familial chylomicronemia syndrome. Atheroscler Suppl. 2017 Jan;23:1–7.
   PubMed Web of Science ®Google Scholar
• Garg A. Clinical review#: lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011 Nov;96(11):3313–3325.
   PubMed Web of Science ®Google Scholar
• Hussain I, Patni N, Garg A. Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease. Pathology. 2019 Feb;51(2):202–212.
   PubMed Web of Science ®Google Scholar
• Falko JM. Familial chylomicronemia syndrome: A clinical guide for endocrinologists. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2018;24(8):756–763.
   Google Scholar
• Williams L, Rhodes KS, Karmally W, et al. Familial chylomicronemia syndrome: bringing to life dietary recommendations throughout the life span. J Clin Lipidol. 2018 Aug;12(4):908–919.
   PubMed Web of Science ®Google Scholar
• Fitts E, Lee PDK, Yates SG. Efficacy of therapeutic plasma exchange in reducing the incidence of recurrent pancreatitis related to familial chylomicronemia. Transfusion (Paris). 2019 Nov;59(11):3324–3328.
   Web of Science ®Google Scholar
• Chaudhry R, Viljoen A, Wierzbicki AS. Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome. Expert Rev Clin Pharmacol. 2018 Jun 3;11(6):589–598.
   PubMed Web of Science ®Google Scholar
• Berberich AJ, Ziada A, Zou GY, et al. Conservative management in hypertriglyceridemia-associated pancreatitis. J Intern Med. 2019 Dec;286(6):644–650.
   PubMed Web of Science ®Google Scholar
• Bryant LM, Christopher DM, Giles AR, et al. Lessons learned from the clinical development and market authorization of Glybera. Hum Gene Ther Clin Dev. 2013 Jun;24(2):55–64.
   PubMed Web of Science ®Google Scholar
• Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol. 2019 Jun 25;73(24):e285–350.
   PubMed Web of Science ®Google Scholar
• Connor WE, DeFrancesco CA, Connor SL. N-3 fatty acids from fish oil. Effects on plasma lipoproteins and hypertriglyceridemic patients. Ann N Y Acad Sci. 1993 Jun 14;683:16–34.
   PubMed Web of Science ®Google Scholar
• Ahmad Z, Wilson DP. Familial chylomicronemia syndrome and response to medium-chain triglyceride therapy in an infant with novel mutations in GPIHBP1. J Clin Lipidol. 2014 Dec;8(6):635–639.
   PubMed Web of Science ®Google Scholar
• Sahebkar A, Simental-Mendía LE, Katsiki N, et al. Effect of fenofibrate on plasma apolipoprotein C-III levels: a systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open. 2019 22; 8(11): e021508.
   PubMed Web of Science ®Google Scholar
• Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovasc Diabetol. 2012 Oct 11;11:125.
   PubMed Web of Science ®Google Scholar
• Gryn SE, Hegele RA. Novel therapeutics in hypertriglyceridemia. Curr Opin Lipidol. 2015 Dec;26(6):484–491.
   PubMed Web of Science ®Google Scholar
• Chyzhyk V, Brown AS. Familial chylomicronemia syndrome: A rare but devastating autosomal recessive disorder characterized by refractory hypertriglyceridemia and recurrent pancreatitis. Trends Cardiovasc Med. 2020;30(2):80-85.
   PubMed Web of Science ®Google Scholar
• Brewer HB, Shulman R, Herbert P, et al. The complete amino acid sequence of alanine apolipoprotein (apoC-3), and apolipoprotein from human plasma very low density lipoproteins. J Biol Chem. 1974 Aug 10;249(15):4975–4984.
   PubMed Web of Science ®Google Scholar
• Yassine HN, Trenchevska O, Ramrakhiani A, et al. The association of human apolipoprotein C-III sialylation proteoforms with plasma triglycerides. PloS One. 2015;10(12):e0144138.
   PubMed Web of Science ®Google Scholar
• Vaith P, Assmann G, Uhlenbruck G. Characterization of the oligosaccharide side chain of apolipoprotein C-III from human plasma very low density lipoproteins. Biochim Biophys Acta. 1978 Jun 15;541(2):234–240.
   PubMedGoogle Scholar
• Yao Z. Human apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. Cardiovasc Hematol Disord Drug Targets. 2012 Dec;12(2):133–140.
   PubMedGoogle Scholar
• Norum RA, Lakier JB, Goldstein S, et al. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N Engl J Med. 1982 Jun 24;306(25):1513–1519.
   PubMed Web of Science ®Google Scholar
• 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 Dec 12;322(5908):1702–1705.
   PubMed Web of Science ®Google Scholar
• Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014 Jul 3;371(1):32–41.
   PubMed Web of Science ®Google Scholar
• Saleheen D, Natarajan P, Armean IM, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 12; 544(7649): 235–239.
   PubMed Web of Science ®Google Scholar
• Crosby J, Peloso GM, Auer PL, et al. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014 Jul 3;371(1):22–31.
   PubMed Web of Science ®Google Scholar
• Martinelli N, Baroni M, Castagna A, et al. Apolipoprotein C-III strongly correlates with activated factor VII-anti-thrombin complex: an additional link between plasma lipids and coagulation. Thromb Haemost. 2019 Feb;119(2):192–202.
   PubMed Web of Science ®Google Scholar
• Sacks FM. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia. Curr Opin Lipidol. 2015 Feb;26(1):56–63.
   PubMed Web of Science ®Google Scholar
• Reyes-Soffer G, Sztalryd C, Horenstein RB, et al. Effects of APOC3 heterozygous deficiency on plasma lipid and lipoprotein metabolism. Arterioscler Thromb Vasc Biol. 2019;39(1):63–72.
   PubMed Web of Science ®Google Scholar
• Reyes-Soffer G, Ginsberg HN. Life is complicated: so is apoCIII. J Lipid Res. 2019 Aug;60(8):1347–1349.
   PubMed Web of Science ®Google Scholar
• Macchi C, Sirtori CR, Corsini A, et al. A new dawn for managing dyslipidemias: the era of RNA-based therapies. Pharmacol Res. 2019 Dec;150:104413.
   PubMed Web of Science ®Google Scholar
• Norata GD, Tsimikas S, Pirillo A, et al. Apolipoprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci. 2015 Oct;36(10):675–687..
   PubMed Web of Science ®Google Scholar
• Gouni-Berthold I, Berthold HK. Antisense oligonucleotides for the treatment of dyslipidemia. Curr Pharm Des. 2011;17(9):950–960.
   PubMed Web of Science ®Google Scholar
• Ito MK. ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense? Ann Pharmacother. 2007 Oct;41(10):1669–1678.
   PubMed Web of Science ®Google Scholar
• Aboul-Fadl T. Antisense oligonucleotides: the state of the art. Curr Med Chem. 2005;12(19):2193–2214.
   PubMed Web of Science ®Google Scholar
• Chan JHP, Lim S, Wong WSF. Antisense oligonucleotides: from design to therapeutic application. Clin Exp Pharmacol Physiol. 2006 Jun;33(5–6):533–540.
   PubMed Web of Science ®Google Scholar
• Graham MJ, Lee RG, Bell TA, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013 May 24;112(11):1479–1490..
   PubMed Web of Science ®Google Scholar
• Jensen MK, Rimm EB, Furtado JD, et al. Apolipoprotein C-III as a potential modulator of the association between HDL-cholesterol and incident coronary heart disease. J Am Heart Assoc. 2012 Apr;1(2). DOI:10.1161/JAHA.111.000232.
   PubMed Web of Science ®Google Scholar
• Kawakami A, Aikawa M, Alcaide P, et al. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006 Aug 15;114(7):681–687.
   PubMed Web of Science ®Google Scholar
• Kawakami A, Aikawa M, Libby P, et al. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation. 2006 Feb 7;113(5):691–700.
   PubMed Web of Science ®Google Scholar
• Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014 Dec 4;371(23):2200–2206.
   PubMed Web of Science ®Google Scholar
• Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol [Internet]. 2018 Nov 10 [cited 2019 May 8]. Available from: http://www.sciencedirect.com/science/article/pii/S073510971839034X
   Google Scholar
• Ramms B, Gordts PLSM. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol. 2018;29(3):171–179.
   PubMed Web of Science ®Google Scholar
• Gordts PLSM, Nock R, Son N-H, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016 01; 126(8): 2855–2866..
   PubMed Web of Science ®Google Scholar
• Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015 Jul 30;373(5):438–447.
   PubMed Web of Science ®Google Scholar
• 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 Aug;39(8):1408–1415..
   PubMed Web of Science ®Google Scholar
• The APPROACH study: a study of volanesorsen (Formerly IONIS-APOCIIIRx) in patients with familial chylomicronemia syndrome - full text view - ClinicalTrials.gov [Internet]. [cited 2019 Dec 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT02211209
   Google Scholar
• The COMPASS study: a study of volanesorsen (Formally ISIS-APOCIIIRx) in patients with hypertriglyceridemia - full text view - ClinicalTrials.gov [Internet]. [cited 2019 Dec 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT02300233
   Google Scholar
• Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 2019 08; 381(6): 531–542..
   PubMed Web of Science ®Google Scholar
• Arca M, Hsieh A, Soran H, et al. The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS study. Expert Rev Cardiovasc Ther. 2018 Jul;16(7):537–546.
   PubMed Web of Science ®Google Scholar
• Gelrud A, Digenio A, Alexander V, et al. Treatment with volanesorsen (VLN) reduced triglycerides and pancreatitis in patients with FCS and sHTG vs placebo: results of the APPROACH and COMPASS †. J Clin Lipidol. 2018 Mar 1;12(2):537.
   Google Scholar
• Khetarpal SA, Wang M, Khera AV. Volanesorsen, familial chylomicronemia syndrome, and thrombocytopenia. N Engl J Med. 2019. 26. 381(26):2582–2584.
   PubMed Web of Science ®Google Scholar
• Witztum JL, Geary RS, O’Dea L. Volanesorsen, familial chylomicronemia syndrome, and thrombocytopenia reply. N Engl J Med. 2019 26;381(26):2584.
   PubMed Web of Science ®Google Scholar
• Crooke ST, Baker BF, Witztum JL, et al. The effects of 2ʹ-O-methoxyethyl containing antisense oligonucleotides on platelets in human clinical trials. Nucleic Acid Ther. 2017 Jun;27(3):121–129..
   PubMed Web of Science ®Google Scholar
• The BROADEN study: a study of volanesorsen (Formerly ISIS-APOCIIIRx) in patients with familial partial lipodystrophy - full text view - ClinicalTrials.gov [Internet]. [cited 2019 Dec 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT02527343
   Google Scholar
• Anonymous. Waylivra [Internet]. European Medicines Agency. 2018 [cited 2020 Mar 31]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/waylivra
   Google Scholar
• Wang Y, Yu RZ, Henry S, et al. Pharmacokinetics and clinical pharmacology considerations of GalNAc3-conjugated antisense oligonucleotides. Expert Opin Drug Metab Toxicol. 2019 Jun;15(6):475–485.
   PubMed Web of Science ®Google Scholar
• Alexander VJ, Xia S, Hurh E, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 2019 Sep 1;40(33):2785–2796.
   PubMed Web of Science ®Google Scholar
• Study of ISIS 678354 (AKCEA-APOCIII-LRx) in Patients With Hypertriglyceridemia and Established Cardiovascular Disease (CVD) - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 Dec 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT03385239
   Google Scholar
• Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation. 2019 Aug 6;140(6):470–486.
   PubMed Web of Science ®Google Scholar
• A multiple ascending dose study of BIO89-100 in subjects with biopsy confirmed NASH or NAFLD and at high risk of NASH - full text view - ClinicalTrials.gov [Internet]. cited 2020 Jun 16. Available from: https://clinicaltrials.gov/ct2/show/NCT04048135
   Google Scholar
• Arrowhead Pharmaceuticals. A phase 1 single and multiple dose-escalating study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamic effects of ARO-APOC3 in adult healthy volunteers as well as in severely hypertriglyceridemic patients and patients with familial chylomicronemia syndrome [Internet]. clinicaltrials.gov. Report No.: NCT03783377. 2020 May [cited 2020 Jun 15]. Available from: https://clinicaltrials.gov/ct2/show/NCT03783377
   Google Scholar