1932

Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

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2017-01-06
2024-12-10
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Literature Cited

  1. Agarwal SK, Avery CL, Ballantyne CM, Catellier D, Nambi V. 1.  et al. 2011. Sources of variability in measurements of cardiac troponin T in a community-based sample: the Atherosclerosis Risk in Communities study. Clin. Chem. 57:891–97 [Google Scholar]
  2. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC. 2.  et al. 2012. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 307:1302–9 [Google Scholar]
  3. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ. 3.  et al. 2011. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ. Cardiovasc. Qual. Outcomes 4:337–45 [Google Scholar]
  4. Genser B, Marz W. 4.  2006. Low density lipoprotein cholesterol, statins and cardiovascular events: a meta-analysis. Clin. Res. Cardiol. 95:393–404 [Google Scholar]
  5. Avis HJ, Hutten BA, Gagne C, Langslet G, McCrindle BW. 5.  et al. 2010. Efficacy and safety of rosuvastatin therapy for children with familial hypercholesterolemia. J. Am. Coll. Cardiol. 55:1121–26 [Google Scholar]
  6. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA. 6.  et al. 2015. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372:2387–97 [Google Scholar]
  7. Needham M, Mastaglia FL. 7.  2014. Statin myotoxicity: a review of genetic susceptibility factors. Neuromuscul. Disord. 24:4–15 [Google Scholar]
  8. Abifadel M, Rabès JP, Devillers M, Munnich A, Erlich D. 8.  et al. 2009. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat. 30:520–29 [Google Scholar]
  9. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K. 9.  et al. 2003. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34:154–56 [Google Scholar]
  10. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. 10.  2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354:1264–72 [Google Scholar]
  11. Seidah NG, Awan Z, Chrétien M, Mbikay M. 11.  2014. PCSK9: a key modulator of cardiovascular health. Circ. Res. 114:1022–36 [Google Scholar]
  12. Chan JC, Piper DE, Cao Q, Liu D, King C. 12.  et al. 2009. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. PNAS 106:9820–25 [Google Scholar]
  13. Shimada YJ, Cannon CP. 13.  2015. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future. Eur. Heart. J. 36:2415–24 [Google Scholar]
  14. Seidah NG, Prat A. 14.  2012. The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discov. 11:367–83 [Google Scholar]
  15. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB. 15.  et al. 2003. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. PNAS 100:928–33 [Google Scholar]
  16. Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL. 16.  et al. 2007. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14:413–19 [Google Scholar]
  17. Horton JD, Cohen JC, Hobbs HH. 17.  2009. PCSK9: a convertase that coordinates LDL catabolism. J. Lipid Res. 50:Suppl.S172–97 [Google Scholar]
  18. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L. 18.  et al. 2004. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279:48865–75 [Google Scholar]
  19. Maxwell KN, Breslow JL. 19.  2004. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. PNAS 101:7100–5 [Google Scholar]
  20. Park SW, Moon YA, Horton JD. 20.  2004. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279:50630–38 [Google Scholar]
  21. Brown MS, Goldstein JL. 21.  1986. A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47 [Google Scholar]
  22. Holla OL, Cameron J, Berge KE, Ranheim T, Leren TP. 22.  2007. Degradation of the LDL receptors by PCSK9 is not mediated by a secreted protein acted upon by PCSK9 extracellularly. BMC Cell Biol. 8:9 [Google Scholar]
  23. Poirier S, Mayer G, Poupon V, McPherson PS, Desjardins R. 23.  et al. 2009. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J. Biol. Chem. 284:28856–64 [Google Scholar]
  24. Poupon V, Girard M, Legendre-Guillemin V, Thomas S, Bourbonniere L. 24.  et al. 2008. Clathrin light chains function in mannose phosphate receptor trafficking via regulation of actin assembly. PNAS 105:168–73 [Google Scholar]
  25. Saavedra YG, Day R, Seidah NG. 25.  2012. The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. J. Biol. Chem. 287:43492–501 [Google Scholar]
  26. Kosenko T, Golder M, Leblond G, Weng W, Lagace TA. 26.  2013. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J. Biol. Chem. 288:8279–88 [Google Scholar]
  27. Poirier S, Mayer G, Benjannet S, Bergeron E, Marcinkiewicz J. 27.  et al. 2008. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem. 283:2363–72 [Google Scholar]
  28. Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA. 28.  2008. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem. Biophys. Res. Commun. 375:69–73 [Google Scholar]
  29. Canuel M, Sun X, Asselin MC, Paramithiotis E, Prat A, Seidah NG. 29.  2013. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLOS ONE 8:e64145 [Google Scholar]
  30. Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A. 30.  et al. 2011. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler. Thromb. Vasc. Biol. 31:785–91 [Google Scholar]
  31. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV. 31.  et al. 2006. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79:514–23 [Google Scholar]
  32. Bonnefond A, Yengo L, Le May C, Fumeron F, Marre M. 32.  et al. 2015. The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. Diabetologia 58:2051–55 [Google Scholar]
  33. Demers A, Samami S, Lauzier B, Des Rosiers C, Sock ET. 33.  et al. 2015. PCSK9 induces CD36 degradation and affects long-chain fatty acid uptake and triglyceride metabolism in adipocytes and in mouse liver. Arterioscler. Thromb. Vasc. Biol. 35:2517–25 [Google Scholar]
  34. Zaid A, Roubtsova A, Essalmani R, Marcinkiewicz J, Chamberland A. 34.  et al. 2008. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology 48:646–54 [Google Scholar]
  35. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G. 35.  et al. 2015. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372:1489–99 [Google Scholar]
  36. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ. 36.  et al. 2015. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372:1500–9 [Google Scholar]
  37. Labonté P, Begley S, Guévin C, Asselin MC, Nassoury N. 37.  et al. 2009. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology 50:17–24 [Google Scholar]
  38. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG. 38.  et al. 2004. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 24:1454–59 [Google Scholar]
  39. Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW. 39.  2008. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid Res. 49:399–409 [Google Scholar]
  40. Horton JD, Goldstein JL, Brown MS. 40.  2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 109:1125–31 [Google Scholar]
  41. Browning JD, Horton JD. 41.  2010. Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J. Lipid Res. 51:3359–63 [Google Scholar]
  42. Persson L, Cao G, Stahle L, Sjoberg BG, Troutt JS. 42.  et al. 2010. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler. Thromb. Vasc. Biol. 30:2666–72 [Google Scholar]
  43. Horton JD, Cohen JC, Hobbs HH. 43.  2007. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32:71–77 [Google Scholar]
  44. Lagace TA. 44.  2014. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr. Opin. Lipidol. 25:387–93 [Google Scholar]
  45. Lambert G, Jarnoux AL, Pineau T, Pape O, Chetiveaux M. 45.  et al. 2006. Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor. Endocrinology 147:4985–95 [Google Scholar]
  46. Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. 46.  2012. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler. Thromb. Vasc. Biol. 32:1585–95 [Google Scholar]
  47. Li H, Dong B, Park SW, Lee HS, Chen W, Liu J. 47.  2009. Hepatocyte nuclear factor 1α plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J. Biol. Chem. 284:28885–95 [Google Scholar]
  48. Dong B, Wu M, Li H, Kraemer FB, Adeli K. 48.  et al. 2010. Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J. Lipid Res. 51:1486–95 [Google Scholar]
  49. Ai D, Chen C, Han S, Ganda A, Murphy AJ. 49.  et al. 2012. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J. Clin. Investig. 122:1262–70 [Google Scholar]
  50. Hussain Y, Ding Q, Connelly PW, Brunt JH, Ban MR. 50.  et al. 2015. G-protein estrogen receptor as a regulator of low-density lipoprotein cholesterol metabolism: cellular and population genetic studies. Arterioscler. Thromb. Vasc. Biol. 35:213–21 [Google Scholar]
  51. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. 51.  2012. Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. Arterioscler. Thromb. Vasc. Biol. 32:810–14 [Google Scholar]
  52. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW. 52.  et al. 2006. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Investig. 116:2995–3005 [Google Scholar]
  53. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S. 53.  et al. 2012. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 125:894–901 [Google Scholar]
  54. Al-Mashhadi RH, Sørensen CB, Kragh PM, Christoffersen C, Mortensen MB. 54.  et al. 2013. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci. Transl. Med. 5:166ra1 [Google Scholar]
  55. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y. 55.  et al. 2005. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. PNAS 102:5374–79 [Google Scholar]
  56. Ason B, van der Hoorn JWA, Chan J, Lee E, Pieterman EJ. 56.  et al. 2014. PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE. J. Lipid Res. 55:2370–79 [Google Scholar]
  57. Seidah NG, Poirier S, Denis M, Parker R, Miao B. 57.  et al. 2012. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLOS ONE 7:e41865 [Google Scholar]
  58. Le May C, Berger JM, Lespine A, Pillot B, Prieur X. 58.  et al. 2013. Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler. Thromb. Vasc. Biol. 33:1484–93 [Google Scholar]
  59. Mbikay M, Sirois F, Mayne J, Wang GS, Chen A. 59.  et al. 2010. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 584:701–6 [Google Scholar]
  60. Baass A, Dubuc G, Tremblay M, Delvin EE, O'Loughlin J. 60.  et al. 2009. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin. Chem. 55:1637–45 [Google Scholar]
  61. Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. 61.  2009. Genetic and metabolic determinants of plasma PCSK9 levels. J. Clin. Endocrinol. Metab. 94:2537–43 [Google Scholar]
  62. Richard C, Couture P, Desroches S, Benjannet S, Seidah NG. 62.  et al. 2012. Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome. Br. J. Nutr. 107:705–11 [Google Scholar]
  63. Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B. 63.  et al. 2006. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J. Biol. Chem. 281:6211–18 [Google Scholar]
  64. Berge KE, Ose L, Leren TP. 64.  2006. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler. Thromb. Vasc. Biol. 26:1094–100 [Google Scholar]
  65. Berthold HK, Seidah NG, Benjannet S, Gouni-Berthold I. 65.  2013. Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PLOS ONE 8:e60095 [Google Scholar]
  66. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L. 66.  et al. 2013. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart. J. 34:3478–90 [Google Scholar]
  67. Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC. 67.  et al. 1999. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am. J. Hum. Genet. 64:1378–87 [Google Scholar]
  68. Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL. 68.  et al. 2000. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler. Thromb. Vasc. Biol. 20:1089–93 [Google Scholar]
  69. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. 69.  2005. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37:161–65 [Google Scholar]
  70. Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL. 70.  et al. 2006. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78:410–22 [Google Scholar]
  71. Johansen CT, Hegele RA. 71.  2013. Using Mendelian randomization to determine causative factors in cardiovascular disease. J. Intern. Med. 273:44–47 [Google Scholar]
  72. Stender S, Tybjærg-Hansen A. 72.  2016. Using human genetics to predict the effects and side-effects of drugs. Curr. Opin. Lipidol. 27:105–11 [Google Scholar]
  73. Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M. 73.  et al. 2014. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr. Atheroscler. Rep. 16:439 [Google Scholar]
  74. Mayne J, Dewpura T, Raymond A, Bernier L, Cousins M. 74.  et al. 2011. Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin. Chem. 57:1415–23 [Google Scholar]
  75. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjærg-Hansen A. 75.  2010. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J. Am. Coll. Cardiol. 55:2833–42 [Google Scholar]
  76. Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD. 76.  et al. 2005. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler. Thromb. Vasc. Biol. 25:2654–60 [Google Scholar]
  77. Hopkins PN, Defesche J, Fouchier SW, Bruckert E, Luc G. 77.  et al. 2015. Characterization of autosomal dominant hypercholesterolemia caused by PCSK9 gain of function mutations and its specific treatment with alirocumab, a PCSK9 monoclonal antibody. Circ. Cardiovasc. Genet. 8:823–31 [Google Scholar]
  78. Alves AC, Etxebarria A, Medeiros AM, Benito-Vicente A, Thedrez A. 78.  et al. 2015. Characterization of the first PCSK9 gain of function homozygote. J. Am. Coll. Cardiol. 66:2152–54 [Google Scholar]
  79. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. 79.  2007. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193:445–48 [Google Scholar]
  80. Kühnast S, van der Hoorn JWA, Pieterman EJ, van den Hoek AM, Sasiela WJ. 80.  et al. 2014. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J. Lipid Res. 55:2103–12 [Google Scholar]
  81. Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W. 81.  et al. 2011. A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J. Lipid Res. 52:78–86 [Google Scholar]
  82. Zhang L, McCabe T, Condra JH, Ni YG, Peterson LB. 82.  et al. 2012. An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes. Int. J. Biol. Sci. 8:310–27 [Google Scholar]
  83. Lipovsek D. 83.  2011. Adnectins: engineered target-binding protein therapeutics. Protein Eng. Des. Sel. 24:3–9 [Google Scholar]
  84. Mitchell T, Chao G, Sitkoff D, Lo F, Monshizadegan H. 84.  et al. 2014. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J. Pharmacol. Exp. Ther. 350:412–24 [Google Scholar]
  85. Stein EA, Kasichayanula S, Turner T, Kranz T, Arumugam U. 85.  et al. 2014. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: results of a single ascending dose study. J. Am. Coll. Cardiol. 63:A1372 [Google Scholar]
  86. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B. 86.  et al. 2008. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. PNAS 105:11915–20 [Google Scholar]
  87. Lee HS, Seok H, Lee DH, Ham J, Lee W. 87.  et al. 2015. Abasic pivot substitution harnesses target specificity of RNA interference. Nat. Commun. 6:10154 [Google Scholar]
  88. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR. 88.  et al. 2014. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, Phase 1 trial. Lancet 383:60–68 [Google Scholar]
  89. Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP. 89.  et al. 2007. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48:763–67 [Google Scholar]
  90. Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C. 90.  et al. 2010. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLOS ONE 5:e10682 [Google Scholar]
  91. Lindholm MW, Elmen J, Fisker N, Hansen HF, Persson R. 91.  et al. 2012. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol. Ther. 20:376–81 [Google Scholar]
  92. McNutt MC, Kwon HJ, Chen C, Chen JR, Horton JD, Lagace TA. 92.  2009. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J. Biol. Chem. 284:10561–70 [Google Scholar]
  93. Alghamdi RH, O'Reilly P, Lu C, Gomes J, Lagace TA, Basak A. 93.  2015. LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153–421): design, synthesis and biochemical evaluation. Eur. J. Med. Chem. 92:890–907 [Google Scholar]
  94. Du F, Hui Y, Zhang M, Linton MF, Fazio S, Fan D. 94.  2011. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J. Biol. Chem. 286:43054–61 [Google Scholar]
  95. Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W. 95.  et al. 2014. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J. Biol. Chem. 289:942–55 [Google Scholar]
  96. Schroeder CI, Swedberg JE, Withka JM, Rosengren KJ, Akcan M. 96.  et al. 2014. Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Chem. Biol. 21:284–94 [Google Scholar]
  97. Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A. 97.  et al. 2011. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep 12:1300–5 [Google Scholar]
  98. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D. 98.  et al. 2012. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366:1108–18 [Google Scholar]
  99. Koren MJ, Kereiakes D, Pourfarzib R, Winegar D, Banerjee P. 99.  et al. 2015. Effect of PCSK9 inhibition by alirocumab on lipoprotein particle concentrations determined by nuclear magnetic resonance spectroscopy. J. Am. Heart. Assoc. 4:e002224 [Google Scholar]
  100. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. 100.  2012. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J. Am. Coll. Cardiol. 59:2344–53 [Google Scholar]
  101. Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B. 101.  et al. 2012. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J. Am. Coll. Cardiol. 60:1888–98 [Google Scholar]
  102. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U. 102.  et al. 2015. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann. Intern. Med. 163:40–51 [Google Scholar]
  103. Li C, Lin L, Zhang W, Zhou L, Wang H. 103.  et al. 2015. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials. J. Am. Heart. Assoc. 4:e001937 [Google Scholar]
  104. Zhang XL, Zhu QQ, Zhu L, Chen JZ, Chen QH. 104.  et al. 2015. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 13:123 [Google Scholar]
  105. Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T. 105.  et al. 2016. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur. Heart. J. 37:536–45 [Google Scholar]
  106. Kolodziejczak M, Navarese EP. 106.  2016. Role of PCSK9 antibodies in cardiovascular disease: critical considerations of mortality and neurocognitive findings from the current literature. Atherosclerosis 247:189–92 [Google Scholar]
  107. Sahebkar A, Di Giosia P, Stamerra CA, Grassi D, Pedone C. 107.  et al. 2016. Effect of monoclonal antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a meta-analysis of 16 randomized controlled treatment arms. Br. J. Clin. Pharmacol. 81:1175–90 [Google Scholar]
  108. Desai NR, Sabatine MS. 108.  2015. PCSK9 inhibition in patients with hypercholesterolemia. Trends Cardiovasc. Med. 25:567–74 [Google Scholar]
  109. Giugliano RP, Sabatine MS. 109.  2015. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field?. J. Am. Coll. Cardiol. 65:2638–51 [Google Scholar]
  110. Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM. 110.  2015. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation 132:1648–66 [Google Scholar]
  111. Farnier M. 111.  2015. An evaluation of alirocumab for the treatment of hypercholesterolemia. Expert Rev. Cardiovasc. Ther. 13:1307–23 [Google Scholar]
  112. Roth EM. 112.  2016. Alirocumab for hyperlipidemia: ODYSSEY Phase III clinical trial results and US FDA approval indications. Future Cardiol 12:115–28 [Google Scholar]
  113. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ. 113.  et al. 2015. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am. J. Cardiol. 115:1212–21 [Google Scholar]
  114. Raal F, Scott R, Somaratne R, Bridges I, Li G. 114.  et al. 2012. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 126:2408–17 [Google Scholar]
  115. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F. 115.  et al. 2015. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385:331–40 [Google Scholar]
  116. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R. 116.  et al. 2015. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart. J. 36:2996–3003 [Google Scholar]
  117. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F. 117.  et al. 2015. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 385:341–50 [Google Scholar]
  118. Hoe E, Hegele RA. 118.  2015. Lipid management in diabetes with a focus on emerging therapies. Can. J. Diabetes 39:S183–90 [Google Scholar]
  119. Sattar N, Preiss D, Robinson JG, Djedjos CS, Elliott M. 119.  et al. 2016. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol 4:403–10 [Google Scholar]
  120. Mancini GB, Tashakkor AY, Baker S, Bergeron J, Fitchett D. 120.  et al. 2013. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can. J. Cardiol. 29:1553–68 [Google Scholar]
  121. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS. 121.  et al. 2014. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled Phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. 63:2541–48 [Google Scholar]
  122. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J. 122.  et al. 2015. Efficacy and safety of alirocumab versus ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J. Clin. Lipidol. 9:758–69 [Google Scholar]
  123. Sabatine MS, Giugliano RP, Keech A, Honarpour N, Wang H. 123.  et al. 2016. Rationale and design of the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk trial. Am. Heart J. 173:94–101 [Google Scholar]
  124. Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V. 124.  et al. 2014. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am. Heart J. 168:682–89 [Google Scholar]
  125. Lepor NE, Kereiakes DJ. 125.  2015. The PCSK9 inhibitors: a novel therapeutic target enters clinical practice. Am. Health Drug Benefits 8:483–89 [Google Scholar]
  126. Tice JA, Kazi DS, Pearson SD. 126.  2016. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for treatment of high cholesterol levels: effectiveness and value. JAMA Intern. Med. 176:107–8 [Google Scholar]
  127. Puri R, Nissen SE, Somaratne R, Cho L, Kastelein JJP. 127.  et al. 2016. Impact of PCSK9 inhibition on coronary atheroma progression: rationale and design of GLAGOV (Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound). Am. Heart J. 176:83–92 [Google Scholar]
  128. Robinson JG, Heistad DD, Fox KA. 128.  2015. Atherosclerosis stabilization with PCSK-9 inhibition: an evolving concept for cardiovascular prevention. Atherosclerosis 243:593–97 [Google Scholar]
  129. Syed GH, Tang H, Khan M, Hassanein T, Liu J, Siddiqui A. 129.  2014. Hepatitis C virus stimulates low-density lipoprotein receptor expression to facilitate viral propagation. J. Virol. 88:2519–29 [Google Scholar]
  130. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE. 130.  et al. 2011. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 305:2556–64 [Google Scholar]
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