Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.
Abstract
Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.
참고문헌 (91)
- Mach F, "2019 ESC", EAS Guidelines for the management of dyslipidaemias : lipid modification to reduce cardiovascular risk, 2020, pp.41, 111~188
- Ference BA, "Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel", Eur Heart J, 38, pp.2459~2472 (2017)
- Grundy SM, "2018 AHA", ACC, AAPA, pp.ABC, ACPM[DOI]
- Nissen SE, "Bempedoic acid and cardiovascular outcomes in statin-intolerant patients", N Engl J Med, 388, pp.1353~1364 (2023)
- Tokgözoğlu L, "The dawn of a new era of targeted lipid-lowering therapies", Eur Heart J, 43, pp.3198~3208 (2022)
- Laufs U, "Clinical review on triglycerides", Eur Heart J, 41, pp.99~109 (2020)
- Ginsberg HN, "Triglyceride-rich lipoproteins and their remnants : metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society", Eur Heart J, 42, pp.4791~4806 (2021)
- Ference BA, "Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease", JAMA, 321, pp.364~373 (2019)
- Marston NA, "Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes : a systematic review and meta-regression analysis of randomized controlled trials", Circulation, 140, pp.1308~1317 (2019)
- Bhatt DL, "Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia", N Engl J Med, 380, pp.11~22 (2019)
- Grundy SM, "2018 AHA", ACC, AAPA, pp.ABC, ACPM[DOI]
- Tall AR, "Addressing dyslipidemic risk beyond LDL-cholesterol", J Clin Invest, 132, pp.e148559~ (2022)
- Conklin D, "Identification of a mammalian angiopoietin-related protein expressed specifically in liver", Genomics, 62, pp.477~482 (1999)
- Shimizugawa T, "ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase", J Biol Chem, 277, pp.33742~33748 (2002)
- Shimamura M, "Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase", Arterioscler Thromb Vasc Biol, 27, pp.366~372 (2007)
- Adam RC, "Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance", J Lipid Res, 61, pp.1271~1286 (2020)
- Wu L, "LDL-cholesterol reduction by ANGPTL3 inhibition in mice is dependent on endothelial lipase", Circ Res, 127, pp.1112~1114 (2020)
- Thomas DG, "Lipid and metabolic syndrome traits in coronary artery disease : a Mendelian randomization study", J Lipid Res, 62, pp.100044~ (2021)
- Ruppert PM, "Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue", Mol Metab, 40, pp.101033~ (2020)
- Chen YQ, "Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids", J Lipid Res, 61, pp.1203~1220 (2020)
- Athyros VG, "Drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease : from PCSK9 inhibition to ANGPTL3 inactivation", Curr Pharm Des, 24, pp.3638~3646 (2018)
- Dewey FE, "Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease", N Engl J Med, 377, pp.211~221 (2017)
- Dewey FE, "Inactivating variants in ANGPTL4 and risk of coronary artery disease", N Engl J Med, 374, pp.1123~1133 (2016)
- Desai U, "Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice", Proc Natl Acad Sci U S A, 104, pp.11766~11771 (2007)
- Gusarova V, "ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice", Endocrinology, 158, pp.1252~1259 (2017)
- Chen PY, "Angiopoietin-like protein 3(ANGPTL3)modulates lipoprotein metabolism and dyslipidemia", Int J Mol Sci, 22, pp.7310~ (2021)
- Murphy AJ, "Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice", Proc Natl Acad Sci U S A, 111, pp.5153~5158 (2014)
- Gusarova V, "ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys", J Lipid Res, 56, pp.1308~1317 (2015)
- Ahmad Z, "Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia", Circulation, 140, pp.470~486 (2019)
- Harada-Shiba M, "A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects", Atherosclerosis, 314, pp.33~40 (2020)
- Gaudet D, "ANGPTL3 inhibition in homozygous familial hypercholesterolemia", N Engl J Med, 377, pp.296~297 (2017)
- Rosenson RS, "Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations : a phase 2 randomized trial", Nat Med, 29, pp.729~737 (2023)
- Raal FJ, "Evinacumab for homozygous familial hypercholesterolemia", N Engl J Med, 383, pp.711~720 (2020)
- Rosenson RS, "Evinacumab in patients with refractory hypercholesterolemia", N Engl J Med, 383, pp.2307~2319 (2020)
- Banerjee P, "Functional analysis of LDLR(low-density lipoprotein receptor)variants in patient lymphocytes to assess the effect of evinacumab in homozygous familial hypercholesterolemia patients with a spectrum of LDLR activity", Arterioscler Thromb Vasc Biol, 39, pp.2248~2260 (2019)
- Kuehn BM, "Evinacumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag", Circulation, 143, pp.2494~2496 (2021)
- Reeskamp LF, "ANGPTL3 inhibition with evinacumab results in faster clearance of IDL and LDL apoB in patients with homozygous familial hypercholesterolemia-brief report", Arterioscler Thromb Vasc Biol, 41, pp.1753~1759 (2021)
- Reeskamp LF, "Marked plaque regression in homozygous familial hypercholesterolemia", Atherosclerosis, 327, pp.13~17 (2021)
- Jin M, "Efficacy and safety of evinacumab for the treatment of hypercholesterolemia : a meta-analysis", J Cardiovasc Pharmacol, 78, pp.394~402 (2021)
- Ruscica M, "Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors : New therapeutic approaches for the treatment of atherogenic dyslipidemia", Pharmacol Res, 153, pp.104653~ (2020)
- Brandt TA, "ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and in healthy human volunteers", Atherosclerosis, 241, pp.e30~ (2015)
- Graham MJ, "Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides", N Engl J Med, 377, pp.222~232 (2017)
- Gaudet D, "Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia", Eur Heart J, 41, pp.3936~3945 (2020)
- Bergmark BA, "Effect of vupanorsen on non-high-density lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol : TRANSLATE-TIMI 70", Circulation, 145, pp.1377~1386 (2022)
- "Pfizer and Ionis Announce Discontinuation of Vupanorsen Clinical Development Program" (2022)[URL]
- Watts GF, "RNA interference targeting hepatic angiopoietin-like protein 3 results in prolonged reductions in plasma triglycerides and LDL-C in human subjects", Circulation, 140, pp.E987~988 (2019)
- Watts GF, "RNAi inhibition of angiopoietin-like protein 3(ANGPTL3)with ARO-ANG3 mimics the lipid and lipoprotein profile of familial combined hypolipidemia", Eur Heart J, 41(Suppl 2), pp.ehaa946.3331~ (2020)
- Watts GF, "Abstract 15751: pharmacodynamic effect of ARO-ANG3, an investigational RNA interference targeting hepatic angiopoietin-like protein 3, in patients with hypercholesterolemia", Circulation, 142(Suppl 3), pp.A15751~ (2020)
- "ARO-ANG3, an Investigational RNAi Therapeutic, Decreases Serum LDL-Cholesterol, Apolipoprotein B, and Angiopoietin-like Protein 3 in Patients with Homozygous Familial Hypercholesterolaemia" (2023)[URL]
- "Medicines in Development" (2023)[URL]
- "Kyttaro Announces Worldwide Exclusive Licensing Agreement with Lilly for Antibody Therapeutic Program" (2023)[URL]
- Balasubramaniam D, "An anti-ANGPTL3", 8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif, 2022, pp.63, 100198~
- Fowler A, "A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice", Vaccine, 39, pp.5780~5786 (2021)
- Fukami H, "Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia", Cell Rep Med, 2, pp.100446~ (2021)
- Chadwick AC, "Reduced blood lipid levels with in vivo CRISPR-Cas9 base editing of ANGPTL3", Circulation, 137, pp.975~977 (2018)
- Qiu M, "Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3", Proc Natl Acad Sci U S A, 118, pp.e2020401118~ (2021)
- Li WW, "Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia", J Clin Invest, 96, pp.2601~2605 (1995)
- Caron S, "Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia", Arterioscler Thromb Vasc Biol, 31, pp.513~519 (2011)
- Forcheron F, "Mechanisms of the triglyceride-and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients", Diabetes, 51, pp.3486~3491 (2002)
- Gibson WT, "Beneficial metabolic phenotypes caused by loss-of-function APOC3 mutations", Clin Genet, 87, pp.31~32 (2015)
- Jørgensen AB, "Loss-of-function mutations in APOC3 and risk of ischemic vascular disease", N Engl J Med, 371, pp.32~41 (2014)
- Natarajan P, "Association of APOC3 loss-of-function mutations with plasma lipids and subclinical atherosclerosis : the multi-ethnic bioimage study", J Am Coll Cardiol, 66, pp.2053~2055 (2015)
- Crosby J, "Loss-of-function mutations in APOC3, triglycerides, and coronary disease", N Engl J Med, 371, pp.22~31 (2014)
- Wulff AB, "APOC3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk : mediation-and meta-analyses of 137 895 individuals", Arterioscler Thromb Vasc Biol, 38, pp.660~668 (2018)
- Gordts PL, "ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors", J Clin Invest, 126, pp.2855~2866 (2016)
- Ramms B, "ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance", J Lipid Res, 60, pp.1379~1395 (2019)
- Gugliucci A, "Triglyceride-rich lipoprotein metabolism : key regulators of their flux", J Clin Med, 12, pp.4399~ (2023)
- Sundaram M, "Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions", J Lipid Res, 51, pp.150~161 (2010)
- Milonas D, "Experimental therapies targeting apolipoprotein C-III for the treatment of hyperlipidemia-spotlight on volanesorsen", Expert Opin Investig Drugs, 28, pp.389~394 (2019)
- Paik J, "Volanesorsen : first global approval", Drugs, 79, pp.1349~1354 (2019)
- "FDA Rejects Volanesorsen (Waylivra) for Rare Triglyceride Disorder" (2019)[URL]
- Graham MJ, "Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans", Circ Res, 112, pp.1479~1490 (2013)
- Gaudet D, "Targeting APOC3 in the familial chylomicronemia syndrome", N Engl J Med, 371, pp.2200~2206 (2014)
- Gaudet D, "Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia", N Engl J Med, 373, pp.438~447 (2015)
- Digenio A, "Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes", Diabetes Care, 39, pp.1408~1415 (2016)
- Witztum JL, "Volanesorsen and triglyceride levels in familial chylomicronemia syndrome", N Engl J Med, 381, pp.531~542 (2019)
- Gouni-Berthold I, "Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia(COMPASS) : a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial", Lancet Diabetes Endocrinol, 9, pp.264~275 (2021)
- Post N, "Metabolism and disposition of volanesorsen, a 2′-O-(2 methoxyethyl)antisense oligonucleotide, across species", Drug Metab Dispos, 47, pp.1164~1173 (2019)
- Witztum JL, "Volanesorsen and triglyceride levels in familial chylomicronemia syndrome : long-term efficacy and safety data from patients in an open-label extension trial", J Clin Lipidol, 17, pp.342~355 (2023)
- Davidson M, "The burden of familial chylomicronemia syndrome : Results from the global IN-FOCUS study", J Clin Lipidol, 12, pp.898~907 (2018)
- Arca M, "The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome : the results of the ReFOCUS study", Expert Rev Cardiovasc Ther, 16, pp.537~546 (2018)
- Jones A, "Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome(FCS)in the UK Early Access to Medicines Scheme(EAMS)", Atherosclerosis, 375, pp.67~74 (2023)
- Lightbourne M, "Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy", J Clin Lipidol, 16, pp.850~862 (2022)
- Oral EA, "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, 16, pp.833~849 (2022)
- Prohaska TA, "APOC3 inhibition with volanesorsen reduces hepatic steatosis in patients with severe hypertriglyceridemia", J Clin Lipidol, 17, pp.406~411 (2023)
- Alexander VJ, "N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels", Eur Heart J, 40, pp.2785~2796 (2019)
- Tardif JC, "Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk", Eur Heart J, 43, pp.1401~1412 (2022)
- Schwabe C, "RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency", Eur Heart J, 41, pp.ehaa946.3330~ (2020)
- Clifton P, "Abstract 12594 : pharmacodynamic effect of ARO-APOC3, an investigational hepatocyte-targeted RNA interference therapeutic targeting apolipoprotein C3, in patients with hypertriglyceridemia and multifactorial chylomicronemia", Circulation, 142(Suppl 3), pp.A12594~ (2020)
- Clifton P, "Abstract 10357 : ARO-APOC3, an investigational RNAi therapeutic, shows similar efficacy and safety in genetically confirmed FCS and non-FCS participants with severe hypertriglyceridemia", Circulation, 144(Suppl 1), pp.A10357~ (2021)
- Khetarpal SA, "A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels", Nat Med, 23, pp.1086~1094 (2017)
