Anti-PCSK9 therapies for the treatment of hypercholesterolemia

Expert Opinion on Biological Therapy

Volumn 13, Issue 3, 2013, Pages 429-435

  Hooper, Amanda J ^a   Burnett, John R ^a,b  

^a ROYAL PERTH HOSPITAL   (Australia)

^b UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

Antibodies; Antisense oligonucleotides; Cholesterol; Hypercholesterolemia; LDL cholesterol; LDL receptor; Low density lipoprotein; Proprotein convertase subtilisin kexin type 9; Small interfering RNA

Indexed keywords

ALIROCUMAB; AMG 145; ANTILIPEMIC AGENT; ANTISENSE OLIGONUCLEOTIDE; ATORVASTATIN; BMS 962476; CHOLESTEROL; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LGT 209; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MONOCLONAL ANTIBODY; PF 04950615; PLACEBO; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 INHIBITOR; RG 7652; RN 316; ROSUVASTATIN; SERINE PROTEINASE INHIBITOR; SIMVASTATIN; SMALL INTERFERING RNA; SX PCK 9; UNCLASSIFIED DRUG;

CHOLESTEROL BLOOD LEVEL; DRUG EFFICACY; DRUG RESPONSE; DRUG SAFETY; DRUG TOLERABILITY; ENZYME INHIBITION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; INJECTION SITE REACTION; LIPID METABOLISM; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRURITUS; REVIEW;

EID: 84873927641     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.2012.748743     Document Type: Review

References (52)

1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78
2. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48:438-45
3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-7
4. Mills EJ, O'Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of > 40 000 patients. Eur Heart J 2011;32:1409-15
5. Mills EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65, 000 patients. J Am Coll Cardiol 2008;52:1769-81
6. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-32
7. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154-6
8. Naoumova RP, Tosi I, Patel D, et al. 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 2005;25:2654-60
9. Cameron J, Holla OL, Ranheim T, et al. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet 2006;15:1551-8
10. Denis M, Marcinkiewicz J, Zaid A, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 2012;125:894-901
11. Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006;116:2995-3005
12. Tibolla G, Norata GD, Artali R, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition. Nutr Metab Cardiovasc Dis 2011;21:835-43
13. Sun H, Samarghandi A, Zhang N, et al. 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 2012;32:1585-95
14. Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012;220:381-6
15. Costet P, Cariou B, Lambert G, et al. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 2006;281:6211-18
16. Chernogubova E, Strawbridge R, Mahdessian H, et al. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels. Arterioscler Thromb Vasc Biol 2012;32:1526-34
17. Alborn WE, Cao G, Careskey HE, et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin Chem 2007;53:1814-19
18. Homer VM, Marais AD, Charlton F, et al. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis 2008;196:659-66
19. Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc 2009;120:163-73
20. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004;24:1454-9
21. Konrad RJ, Troutt JS, Cao G. Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-C-lowering agents. Lipids Health Dis 2011;10:38
22. Huijgen R, Boekholdt SM, Arsenault BJ, et al. Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. J Am Coll Cardiol 2012;59:1778-84
23. Awan Z, Seidah NG, MacFadyen JG, et al. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem 2012;58:183-9
24. Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA 2005;102:5374-9
25. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72
26. Hooper AJ, Marais AD, Tanyanyiwa DM, et al. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007;193:445-8
27. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006;79:514-23
28. Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010;55:2833-42
29. Cariou B, Ouguerram K, Zair Y, et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 2009;29:2191-7
30. Marais DA, Blom DJ, Petrides F, et al. Proprotein convertase subtilisin/kexin type 9 inhibition. Curr Opin Lipidol 2012; In press
31. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 2012;11:367-83
32. Dias C, Shaywitz A, Cooke B, et al. Effects of AMG 145, a fully human monoclonal antibody against PCSK9, on low-density lipoprotein cholesterol in subjects taking statins: a phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. J Am Coll Cardiol 2012;59:E1379
33. Kohli P, Desai NR, Giugliano RP, et al. Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clin Cardiol 2012;35:385-91
34. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108-18
35. McKenney JM, Koren MJ, Kereiakes DJ, et al. 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 2012;59:2344-53
36. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36
37. Chaparro-Riggers J, Liang H, Devay RM, et al. Increasing serum half-life and extending cholesterol lowering in vivo by engineering an antibody with pH-sensitive binding to PCSK9. J Biol Chem 2012;287:11090-7
38. Graham MJ, Lemonidis KM, Whipple CP, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res 2007;48:763-7
39. Lindholm MW, Elmen J, Fisker N, et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther 2012;20:376-81
40. Ason B, Tep S, Davis HR Jr, et al. Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. J Lipid Res 2011;52:679-87
41. Alnylam reports positive clinical results for ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia. Available from: www.alnylam.com 2012
42. Fitzgerald K, Frank-Kamenetsky M, Mant T, et al. Phase I safety, pharmacokinetic, and pharmacodynamic results for ALN-PCS, a novel RNAi therapeutic for the treatment of hypercholesterolemia. Arterioscler Thromb Vasc Biol 2012;32:A67
43. Farnier M. The role of proprotein convertase subtilisin/kexin type 9 in hyperlipidemia: focus on therapeutic implications. Am J Cardiovasc Drugs 2011;11:145-52
44. Lambert G, Sjouke B, Choque B, et al. The PCSK9 decade. J Lipid Res 2012;53:2515-24
45. Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab Sci 2005;42:515-45
46. Sankatsing RR, Fouchier SW, de Haan S, et al. Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 2005;25:1979-84
47. Schonfeld G, Patterson BW, Yablonskiy DA, et al. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J Lipid Res 2003;44:470-8
48. Tanoli T, Yue P, Yablonskiy D, et al. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res 2004;45:941-7
49. Whitfield AJ, Barrett PHR, Robertson K, et al. Liver dysfunction and steatosis in familial hypobetalipoproteinemia. Clin Chem 2005;51:266-9
50. Tarugi P, Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. Adv Clin Chem 2011;54:81-107
51. Zamel R, Khan R, Pollex RL, et al. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis 2008;3:19
52. Duff CJ, Hooper NM. PCSK9: an emerging target for treatment of hypercholesterolemia. Expert Opin Ther Targets 2011;15:157-68