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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 2/2015

01-04-2015 | REVIEW ARTICLE

Update of Clinical Trials of Anti-PCSK9 Antibodies

Authors: Na-Qiong Wu, Sha Li, Jian-Jun Li

Published in: Cardiovascular Drugs and Therapy | Issue 2/2015

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Abstract

Hyperlipidemia is a predominant risk factor for cardiovascular disease (CVD). Statins have been successfully used to treat patients with dyslipidemia and decrease the events of CVD in addition to application of various other non-statin-lowering cholesterol agents, such as ezetimibe and niacin. However, there are still residual risks in patients with atherosclerotic CVD. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9), which was first identified in 2003, has been suggested to play an important role in the metabolism of low-density lipoprotein cholesterol (LDL-C). PCSK9 degrades the LDL-receptor, which may be pharmacologically targeted to improve the lipoprotein profile and future cardiovascular outcomes in patients with dyslipidemia. Several approaches to inhibiting PCSK9 activity have been theoretically proposed. Among them, monoclonal antibodies have been considered as the most promising strategy because of their large effect on lowering lipids as monotherapy and in combination with statins or ezetimibe. In this review, we mainly focus on the current status of monoclonal antibodies of PCSK9 and clinical trial results for an update on clinical application of monoclonal antibodies of PCSK9. The particular effects of monoclonal antibodies of PCSK9 on lipid profiles are also discussed.
Literature
1.
Robinson JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm. 2013;19:139–49.PubMed
2.
Chi MD, Vansomphone SS, Liu IL, Cheetham C, Green KR, Scott RD, et al. Adherence to statins and LDL-cholesterol goal attainment. Am J Manage Care. 2014;20:e105–12.
3.
Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. J Clin Lipidol. 2014;8:18–28.CrossRefPubMed
4.
Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S9–S17.CrossRefPubMed
5.
Liyanage KE, Burnett JR, Hooper AJ, van Bockxmeer FM. Familial hypercholesterolemia: epidemiology, neolithic origins and modern geographic distribution. Crit Rev Clin Lab Sci. 2011;48:1–18.CrossRefPubMed
6.
Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S1–8.CrossRefPubMed
7.
Wierzbicki AS, Humphries SE, Minhas R. Familial hypercholesterolaemia: summary of NICE guidance. BMJ. 2008;337:a1095.CrossRefPubMed
8.
9.
Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.CrossRef
10.
Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.CrossRefPubMed
11.
Cao G, Qian YW, Kowala MC, Konrad RJ. Further LDL cholesterol lowering through targeting PCSK9 for coronary artery disease. Endocr Metab Immune Disord Drug Targets. 2008;8:238–43.CrossRefPubMed
12.
Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50(Suppl):S172–7.PubMedCentralPubMed
13.
Seidah NG. PCSK9 as a therapeutic target of dyslipidemia. Expert Opin Ther Targets. 2009;13:19–28.CrossRefPubMed
14.
Lambert G, Krempf M, Costet P. PCSK9: a promising therapeutic target for dyslipidemias. Trends Endocrinol Metab. 2006;17:79–81.CrossRefPubMed
15.
Mousavi SA, Berge KE, Leren TP. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med. 2009;266:507–19.CrossRefPubMed
16.
Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab. 2009;94:2537–43.CrossRefPubMedCentralPubMed
17.
Persson L, Cao G, Ståhle L, Sjöberg BG, Troutt JS, Konrad RJ, et al. 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. 2010;30:2666–72.CrossRefPubMed
18.
Li J, Tumanut C, Gavigan JA, Huang WJ, Hampton EN, Tumanut R, et al. Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity. Biochem J. 2007;406:203–7.CrossRefPubMedCentralPubMed
19.
McNutt MC, Lagace TA, Horton JD. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J Biol Chem. 2007;282:20799–803.CrossRefPubMed
20.
Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282:18602–12.CrossRefPubMed
21.
McNutt MC, Kwon HJ, Chen C, Chen JR, Horton JD, Lagace TA. Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem. 2009;284:10561–70.CrossRefPubMedCentralPubMed
22.
Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009;106:9820–5.CrossRefPubMedCentralPubMed
23.
Duff CJ, Scott MJ, Kirby IT, Hutchinson SE, Martin SL, Hooper NM. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem J. 2009;419:577–84.CrossRefPubMedCentralPubMed
24.
Ni YG, Condra J, Orsatti L, Shen X, Di Marco S, Pandit S, et al. A proprotein convertase subtilisin-like/kexin type 9 (PCSK9)C-terminal domain antibody antigen binding fragment inhibits PCSK9 internalization and restores LDL-uptake. J Biol Chem. 2010;285:12882–91.CrossRefPubMedCentralPubMed
25.
Maxwell KN, Breslow JL. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr Opin Lipidol. 2005;16:167–72.CrossRefPubMed
26.
Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, 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.CrossRefPubMed
27.
Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005;26:497.CrossRefPubMed
28.
Humphries SE, Neely RD, Whittall RA, Troutt JS, Konrad RJ, Scartezini M, et al. Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin Chem. 2009;55:2153–61.CrossRefPubMed
29.
Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.CrossRefPubMed
30.
Fasano T, Cefalu AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, et al. A novel loss-of-function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol. 2007;27:677–81.CrossRefPubMed
31.
Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identifi cation of a compound heterozygote. Am J Hum Genet. 2006;79:514–23.CrossRefPubMedCentralPubMed
32.
Wu N-Q, Li J-J. PCSK9 gene mutations and low-density lipoprotein cholesterol. Clin Chim Acta. 2014;431:148–53.CrossRefPubMed
33.
Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546–7.CrossRefPubMedCentralPubMed
34.
Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–18.CrossRefPubMed
35.
Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS, et al. 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. 2012;60:1888–98.CrossRefPubMed
36.
Novartis Pharmaceuticals. Safety, pharmacokinetics and pharmacodynamics of LGT209 in healthy volunteers with elevated cholesterol and in hypercholesterolemic patients treated with statins. Available from: http://​clinicaltrials.​gov/​ct2/​show/​NCT01859455. NLM identifier: NCT 01859455. Accessed 12 Sept 2013.
37.
McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferramd AC, Stein EA. 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.CrossRefPubMed
38.
Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891–900.CrossRefPubMed
39.
Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, 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.CrossRefPubMed
40.
Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497–506.CrossRefPubMed
41.
Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. 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. 2012;126:2408–17.CrossRefPubMed
42.
Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006.CrossRefPubMed
43.
Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007–17.CrossRefPubMedCentralPubMed
44.
Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, Zhou J, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation. 2013;128:962–9.CrossRefPubMed
45.
Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014;129:234–43.CrossRefPubMed
46.
47.
48.
49.
50.
Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870–82.CrossRefPubMed
51.
Cho L, Rocco M, Colquhoun D, Sullivan D, Rosenson RS, Dent R, et al. Design and rationale of the GAUSS-2 Study Trial: a double-blind, ezetimibe-controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy. Clin Cardiol. 2014;37:131–9.CrossRefPubMed
52.
Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19.CrossRefPubMed
53.
54.
Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128:2113–20.CrossRefPubMed
55.
Jayasinghe R, Craig IH, Mohan RK. Lipoprotein (A) in clinical practice. J Pak Med Assoc. 2014;64:447–50.PubMed
56.
Stein EA, Giugliano RP, Koren MJ, Raal FJ, Roth EM, Weiss R, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J. 2014;35:2249–59.CrossRefPubMed
57.
Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, et al. Reduction in lipoprotein (a) with the PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of over 1300 patients in 4 phase 2 trials. J Am Coll Cardiol. 2014;63:1278–88.CrossRefPubMed
58.
Stein EA, Raal FJ. Insights Into PCSK9, low-density lipoprotein receptor, and low-density lipoprotein cholesterol metabolism: of mice and man. Circulation. 2013;127:2372–4.CrossRefPubMed
59.
Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB. 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.CrossRefPubMed
Metadata
Title
Update of Clinical Trials of Anti-PCSK9 Antibodies
Authors
Na-Qiong Wu
Sha Li
Jian-Jun Li
Publication date
01-04-2015
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 2/2015
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-015-6582-9

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