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| __NOTOC__
| | #REDIRECT [[PCSK9]] |
| [[File:PCSK9.png|200px|thumb|right|Structure of the PCSK9 protein]] | |
| {{SI}}
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| {{CMG}}; {{AE}} {{AO}}
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| ==Overview==
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| Increased low-density lipoprotein cholesterol (LDL-C) levels in the plasma is associated with the development and progression of [[atherosclerosis]] and associated diseases such as [[myocardial infarction]] and [[stroke]]. LDL receptors, which are responsible for clearing LDL-C from the circulation, get recycled back into the plasma membrane in order to bind more LDL-C. A novel approach to lipid management focuses on inhibiting a serine protease, [[PCSK9]], which is involved in the degradation of LDL receptors subsequently preventing the binding of new LDLs to be cleared from the circulation.
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| ==Historical Perspective==
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| ==Biochemistry==
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| ==Physiology==
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| ===Lipid Homeostasis===
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| ===Inflammation===
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| ===Apoptosis===
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| ===Blood Pressure Regulation===
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| ===Glucose Metabolism===
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| ===Adipose Tissue Metabolism===
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| ==PCSK9 Inhibition==
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| ==PCSK9 Inhibitors==
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| ===Natural===
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| * [[Annexin A2]] (AnxA2) - This is an endogenous compound that binds to the C-terminal domain of PCSK9 thereby preventing the interaction of PCSK9 and LDL receptors mostly in the extrahepatic tissues. It has been proven as a functional inhibitor of PCSK9.<ref name="Seidah-2012">{{Cite journal | last1 = Seidah | first1 = NG. | last2 = Poirier | first2 = S. | last3 = Denis | first3 = M. | last4 = Parker | first4 = R. | last5 = Miao | first5 = B. | last6 = Mapelli | first6 = C. | last7 = Prat | first7 = A. | last8 = Wassef | first8 = H. | last9 = Davignon | first9 = J. | title = Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. | journal = PLoS One | volume = 7 | issue = 7 | pages = e41865 | month = | year = 2012 | doi = 10.1371/journal.pone.0041865 | PMID = 22848640 }}</ref>
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| * [[Furin]] and PC5/6A - These two proprotein convertases act through the proteolytic cleavage of the PCSK9 protein between the R<sub>218</sub> and Q<sub>219</sub> residues resulting in a defective enzyme. Furin was shown to regulate PCSK9 mRNA levels in hepatocytes.<ref name="pmid21147780">{{cite journal| author=Essalmani R, Susan-Resiga D, Chamberland A, Abifadel M, Creemers JW, Boileau C et al.| title=In vivo evidence that furin from hepatocytes inactivates PCSK9. | journal=J Biol Chem | year= 2011 | volume= 286 | issue= 6 | pages= 4257-63 | pmid=21147780 | doi=10.1074/jbc.M110.192104 | pmc=PMC3039354 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21147780 }} </ref>
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| ===Pharmacologic===
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| Drugs can inhibit PCSK9, and lower cholesterol much more than the current available drugs. It is biologically plausible that this would also lower heart attacks and other diseases caused by raised cholesterol. Studies with humans, including phase III clinical trials are now underway to find out whether PCSK9 inhibition actually does lower disease, with acceptable side effects.<ref name=lopez>{{cite journal | author = Lopez D|title = Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia | journal = Drug News Perspect. | volume = 21|issue = 6 | pages = 323–30 | year = 2008 | pmid = 18836590 | doi = 10.1358/dnp.2008.21.6.1246795 }}</ref><ref name=steinberg>{{cite journal|author = Steinberg D, Witztum JL | title = Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 24 | pages = 9546–7 | year = 2009 | month = June | pmid = 19506257 | pmc = 2701045|doi = 10.1073/pnas.0904560106 }}</ref><ref name=mayer>{{cite journal | author = Mayer G, Poirier S, Seidah NG | title = Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels | journal = J. Biol. Chem. | volume = 283|issue = 46 | pages = 31791–801 | year = 2008 | month = November | pmid = 18799458 | doi = 10.1074/jbc.M805971200 }}</ref><ref name=bms>{{cite web | url = http://www.fiercebiotech.com/press-releases/bristol-myers-squibb-selects-isis-drug-targeting-pcsk9-development-candidate-preventi| title = Bristol-Myers Squibb selects Isis drug targeting PCSK9 as development candidate for prevention and treatment of cardiovascular disease | author = | authorlink = | coauthors = | date = 2008-04-08 | format = | work = Press Release | publisher = FierceBiotech | pages =| language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-18 }}</ref>
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| ====Monoclonal Antibodies====
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| A number of [[monoclonal antibodies]] that bind to PCSK9 near the catalytic domain that interact with the LDL receptors, and hence inhibit the function of PCSK9 are currently in clinical trials. These include:
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| '''AMG 145''' by [[Amgen]] pharmaceuticals- This is a human monoclonal IgG2 antibody against PCSK9.
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| * RUTHERFORD trial - This is a multicenter, double-blinded, randomized, placebo-controlled, dose-ranging study to determine the efficacy and safety of AMG 145in heterozygous familial hypercholesterolemia patients. 168 patients on statin with or without [[ezetimibe]] use were randomly assigned to subcutaneous AMG 145 350 mg, AMG 145 420 mg, or placebo administered every 4 weeks. At 12 weeks, LDL cholesterol was lowered by 43% and 55% with AMG 145 350 mg and 420 mg, respectively, compared with 1% increase with placebo. Serious adverse effects were observed in 2 patients taking the AMG 145.<ref name="Raal-2012">{{Cite journal | last1 = Raal | first1 = F. | last2 = Scott | first2 = R. | last3 = Somaratne | first3 = R. | last4 = Bridges | first4 = I. | last5 = Li | first5 = G. | last6 = Wasserman | first6 = SM. | last7 = Stein | first7 = EA. | title = 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. | journal = Circulation | volume = 126 | issue = 20 | pages = 2408-17 | month = Nov | year = 2012 | doi = 10.1161/CIRCULATIONAHA.112.144055 | PMID = 23129602 }}</ref>
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| * GAUSS trial - Based on the fact that an approximate of 10% to 20% of patients cannot tolerate statins, the GAUSS trial was designed to assess the efficacy and tolerability of AMG 145 in patients with statin intolerance due to muscle-related side effects. 160 patients with statin intolerance were randomized equally into 5 groups: AMG 145 alone at 280 mg, 350 mg, or 420 mg doses; AMG 145 at 420 mg plus 10 mg of ezetimibe and 10 mg of ezetimibe plus placebo - all given subcutaneously. At week 12, mean LDL-C levels was lowered by 41, 42, 51, 63 percent respectively as compared with 15 percent in the placebo/ezetimibe group. Four serious adverse events were reported with AMG 145 which were [[coronary artery disease]], [[acute pancreatitis]], [[hip fracture]], [[syncope]]. [[Myalgia]] was also the most common treatment-emergent adverse effect observed during the study.<ref name="Sullivan-2012">{{Cite journal | last1 = Sullivan | first1 = D. | last2 = Olsson | first2 = AG. | last3 = Scott | first3 = R. | last4 = Kim | first4 = JB. | last5 = Xue | first5 = A. | last6 = Gebski | first6 = V. | last7 = Wasserman | first7 = SM. | last8 = Stein | first8 = EA. | title = Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. | journal = JAMA | volume = 308 | issue = 23 | pages = 2497-506 | month = Dec | year = 2012 | doi = 10.1001/jama.2012.25790 | PMID = 23128163 }}</ref>
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| * LAPLACE-TIMI 57 study - This was also designed to assess the efficacy, safety and tolerability to a range of doses of AMG 145 in hypercholesterolemic patients. 631 patients on a stable dose of a statin (with or without ezetimibe) were randomly assigned to AMG 145 at 70, 105, or 140 mg or placebo every two weeks or AMG 145 at 280, 350, or 420 mg or placebo every four weeks. At week 12, mean LDL-C concentrations in the 2-week-dosing group was reduced from 42 to 66 % while in the 4-week-dosing group, it was reduced from 42 to 50%. No serious or life-threatening events was observed.
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| * MENDEL study - In this study, 406 untreated hypercholesterolemic patients were assigned to similar groups as in the LAPLACE-TIMI 57 study and after 12 weeks, similar results with the prior studies were obtained (39 to 51% reduction in LDL cholesterol).<ref name="pmid23141812">{{cite journal| author=Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L et al.| title=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. | journal=Lancet | year= 2012 | volume= 380 | issue= 9858 | pages= 1995-2006 | pmid=23141812 | doi=10.1016/S0140-6736(12)61771-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23141812 }} </ref>
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| '''SAR236553/REGN727''' by Sanofi-[[Aventis]]/[[Regeneron]] pharmaceuticals<ref name=lambert>{{cite journal | author = Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK | title = The PCSK9 decade | journal = J. Lipid Res. | volume = 53 | issue = 12 | pages = 2515–24 | year = 2012 | month = December | pmid = 22811413 | doi = 10.1194/jlr.R026658 | url = | pmc = 3494258 }}</ref>
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| * In a study to determine the safety and efficacy of SAR236553/REGN727, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy, 183 patients with LDL-C≥100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for≥6 weeks were assigned to subcutaneous injections of SAR236553 50, 100, or 150 mg every 2 weeks; SAR236553 200 or 300 mg every 4 weeks or placebo every 2 weeks. After 12 weeks, LDL-C levels were reduced by 40%, 64%, and 72% with 50, 100, and 150 mg in the 2-week-dosing group, and 43% and 48% with 200 and 300 mg in the 4-week-dosing groups as compared to a 5% reduction in the placebo group. SAR236553 was also found to reduce non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(A), and a case of leukocytoclastic vasculitis was also reported.<ref name="pmid22463922">{{cite journal| author=McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA| title=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. | journal=J Am Coll Cardiol | year= 2012 | volume= 59 | issue= 25 | pages= 2344-53 | pmid=22463922 | doi=10.1016/j.jacc.2012.03.007 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22463922 }} </ref>
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| * ODYSSEY OUTCOMES - A phase III trial designed to evaluate the cardiovascular outcomes after an acute coronary syndrome in patients who have experienced an acute coronary syndrome (ACS) event 4 to 16 weeks prior to enrollment in the study. This trial is currently enrolling and promises to enroll 18,000 participants by November, 2013.
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| '''RN316''' by [[Pfizer]] - In a study done by Pfizer to assess the safety and efficacy of RN316, intravenous doses of RN316 was shown to reduce the levels of LDL-C by 46% to 56% in patients already taking high-dose statins.
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| '''1D05-IgG2''' by [[Merck & Co.]] - This is a PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor thereby reducing LDL cholesterol.<ref name="pmid20959675">{{cite journal| author=Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W, Wang F et al.| title=A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. | journal=J Lipid Res | year= 2011 | volume= 52 | issue= 1 | pages= 78-86 | pmid=20959675 | doi=10.1194/jlr.M011445 | pmc=PMC2999929 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20959675 }} </ref>
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| * Other drugs being evaluated include RG7652 by Roche.
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| ====Gene Silencing====
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| Several agents work by shutting down the gene responsible for the synthesis of the PCSK9 protein.
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| * PCSK9 antisense oligonucleotide from Isis Pharmaceuticals has been shown to increase expression of the LDL receptors and decrease circulating total cholesterol levels in mice.<ref name=graham>{{cite journal | author = Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM | title = Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice| journal = J. Lipid Res. | volume = 48 | issue = 4 | pages = 763–7 | year = 2007 | month = April | pmid = 17242417 | doi = 10.1194/jlr.C600025-JLR200 }}</ref>
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| * A locked nucleic acid from Santaris Pharma reduced PCSK9 mRNA levels in mice.<ref name=gupta>{{cite journal | author = Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, Elmén J, Seidah NG, Straarup EM | title = A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo | journal = PLoS ONE | volume = 5 |issue = 5 | pages = e10682 | year = 2010 | pmid = 20498851 | pmc = 2871785 | doi = 10.1371/journal.pone.0010682 | url = | editor1-last = Deb| editor1-first = Sumitra }}</ref><ref name=lindholm>{{cite journal | author = Lindholm MW, Elmén J, Fisker N, Hansen HF, Persson R, Møller MR, Rosenbohm C, Ørum H, Straarup EM, Koch T | title = PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates | journal = Mol. Ther. | volume = 20 | issue = 2 | pages = 376–81 | year = 2012 | month = February | pmid = 22108858 | pmc = 3277239 | doi = 10.1038/mt.2011.260 }}</ref>
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| * The Medicines Company in conjunction with Alnylam Pharmaceuticals has shown in initial clinical trials positive results of ALN-PCS which acts by means of [[RNA interference]], which causes the gene to shut down production of the PCSK9 protein.<ref name=alnypharm>{{cite web | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148005&p=irol-newsArticle2&ID=1644329&highlight= | title = Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia | author = | authorlink = | coauthors = | date = 2011-01-04 | format = | work = Press Release | publisher = BusinessWire | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2011-01-04 }}</ref><ref name=frank>{{cite journal | author = Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y, Gamba-Vitalo C, Hadwiger P, Jayaraman M, John M, Jayaprakash KN, Maier M, Nechev L, Rajeev KG, Read T, Röhl I, Soutschek J, Tan P, Wong J, Wang G, Zimmermann T, de Fougerolles A, Vornlocher HP, Langer R, Anderson DG, Manoharan M, Koteliansky V, Horton JD, Fitzgerald K | title = Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates| journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 33 | pages = 11915–20 | year = 2008 | month = August | pmid = 18695239 |pmc = 2575310 | doi = 10.1073/pnas.0805434105 }}</ref> They currently have two drugs which are: ALN-PCS02 and ALN-PCSsc given intravenously and subcutaneously respectively.
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| ====Mimetic Peptides====
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| ====Adnectins====
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| ====Small-Molecule Inhibitors====
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| ==Clinical Significance of PCSK9 Inhibition==
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| With the discovery of the PCSK9, many convincing studies and trials have reported the clinical efficacy and safety of the novel approaches to PCSK9 inhibition in patients either intolerant to statins or in those who failed to reach target LDL-C levels even at high doses of statins. However, certain questions regarding the long-term safety are still left unanswered. First is the issue of immunogenicity. Monoclonal antibodies against PCSK9 may elicit immune-mediated responses. This may be reduced with the use of fully human monoclonal antibodies.<ref name="pmid23817198">{{cite journal| author=Petrides F, Shearston K, Chatelais M, Guilbaud F, Meilhac O, Lambert G| title=The promises of PCSK9 inhibition. | journal=Curr Opin Lipidol | year= 2013 | volume= 24 | issue= 4 | pages= 307-12 | pmid=23817198 | doi=10.1097/MOL.0b013e328361f62d | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23817198}}</ref> This also underscores the requirement for a long term surveillance for antidrug antibodies in these patients. Secondly, most PCSK9 inhibitors are administered subcutaneously (few given intravenously) and they require 2 to 4-weekly dosing. This raises concern with regards to compliance, and efforts in search of an orally administered drug has been productive. Anacetrapid, a cholesterol ester transfer protein inhibitor has been reported to effectively lower LDL-C and increase HDL-C.<ref name="Teramoto-2013">{{Cite journal | last1 = Teramoto | first1 = T. | last2 = Shirakawa | first2 = M. | last3 = Kikuchi | first3 = M. | last4 = Nakagomi | first4 = M. | last5 = Tamura | first5 = S. | last6 = Surks | first6 = HK. | last7 = McCrary Sisk | first7 = C. | last8 = Numaguchi | first8 = H. | title = Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidemia. | journal = Atherosclerosis | volume = 230 | issue = 1 | pages = 52-60 | month = Sep | year = 2013 | doi = 10.1016/j.atherosclerosis.2013.05.012 | PMID = 23958252 }}</ref> On the other hand, PCSK9 plays a role in triglyceride-rich lipoprotein metabolism. Statins have been shown to increase the serum levels of PCSK9, thus reducing their LDL-C lowering ability.<ref name="Dubuc-2004">{{Cite journal | last1 = Dubuc | first1 = G. | last2 = Chamberland | first2 = A. | last3 = Wassef | first3 = H. | last4 = Davignon | first4 = J. | last5 = Seidah | first5 = NG. | last6 = Bernier | first6 = L. | last7 = Prat | first7 = A. | title = Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. | journal = Arterioscler Thromb Vasc Biol | volume = 24 | issue = 8 | pages = 1454-9 | month = Aug | year = 2004 | doi = 10.1161/01.ATV.0000134621.14315.43 | PMID = 15178557 }}</ref> For this reason, a statin-PSCK9 inhibitor would have a synergistic effect in lowering the serum levels of LDL-C in the plasma. This has further shifted many effort towards this novel approach of PCSK9 inhibition as the next ultimate lipid modifier.
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| ==References==
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| {{Reflist|2}}
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