579
Views
22
CrossRef citations to date
0
Altmetric
Review

Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015)

, , , , , , & show all
Pages 1377-1392 | Received 20 Mar 2016, Accepted 22 Jun 2016, Published online: 12 Jul 2016

References

  • Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA. 2003;100:928–933.
  • Abifadel M, Varret M, Rabès J-P, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156.
  • Varret M, Rabès JP, Saint-Jore B, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet. 1999;64:1378–1387.
  • Hunt SC, Hopkins PN, Bulka K, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol. 2000;20:1089–1093.
  • Abifadel M, Elbitar S, El Khoury P, et al. 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. 2014;16:439.
  • Timms KM, Wagner S, Samuels ME, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet. 2004;114:349–353.
  • Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65:419–422.
  • Sun X-M, Eden ER, Tosi I, et al. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet. 2005;14:1161–1169.
  • Allard D, Amsellem S, Abifadel M, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005;26:497.
  • Abifadel M, Guerin M, Benjannet S, et al. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis. 2012;223:394–400.
  • Bourbon M, Alves AC, Medeiros AM, et al. Familial hypercholesterolaemia in Portugal. Atherosclerosis. 2008;196:633–642.
  • Cameron J, Holla OL, Laerdahl JK, et al. Characterization of novel mutations in the catalytic domain of the PCSK9 gene. J Intern Med. 2008;263:420–431.
  • 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;196:659–666.
  • Lin J, Wang L, Liu S, et al. A novel mutation in proprotein convertase subtilisin/kexin type 9 gene leads to familial hypercholesterolemia in a Chinese family. Chin Med J (Engl.). 2010;123:1133–1138.
  • Cameron J, Holla ØL, Ranheim T, et al. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet. 2006;15:1551–1558.
  • Cohen JC, Boerwinkle E, Mosley TH, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272.
  • 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;79:514–523.
  • 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;193:445–448.
  • Abifadel M, Pakradouni J, Collin M, et al. Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents. Expert Opin Ther Pat. 2010;20:1547–1571.
  • Maxwell KN, Soccio RE, Duncan EM, et al. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res. 2003;44:2109–2119.
  • Persson L, Gälman C, Angelin B, et al. Importance of proprotein convertase subtilisin/kexin type 9 in the hormonal and dietary regulation of rat liver low-density lipoprotein receptors. Endocrinol. 2009;150:1140–1146.
  • Langhi C, Le May C, Kourimate S, et al. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett. 2008;582:949–955.
  • Kamani CH, Gencer B, Montecucco F, et al. Stairs instead of elevators at the workplace decreases PCSK9 levels in a healthy population. Eur J Clin Invest. 2015;45:1017–1024.
  • Seidah NG, Awan Z, Chrétien M, et al. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114:1022–1036.
  • 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;24:1454–1459.
  • 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;102:5374–5379.
  • Careskey HE, Davis RA, Alborn WE, et al. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res. 2008;49:394–398.
  • Welder G, Zineh I, Pacanowski MA, et al. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res. 2010;51:2714–2721.
  • Chen F, Maridakis V, O’Neill EA, et al. The effects of simvastatin treatment on plasma lipid-related biomarkers in men with dyslipidaemia. Biomark Biochem Indic Expo Response Suscept Chem. 2011;16:321–333.
  • 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;58:183–189.
  • Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 2009;120:163–173.
  • Dubuc G, Tremblay M, Paré G, et al. A new method for measurement of total plasma PCSK9: clinical applications. J Lipid Res. 2010;51:140–149.
  • Berthold HK, Seidah NG, Benjannet S, et al. Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels. PloS One. 2013;8:e60095.
  • Miyoshi T, Nakamura K, Doi M, et al. Impact of Ezetimibe alone or in addition to a statin on plasma PCSK9 concentrations in patients with type 2 diabetes and hypercholesterolemia: a pilot study. Am J Cardiovasc Drugs Drugs Devices Interv. 2015;15:213–219.
  • Troutt JS, Alborn WE, Cao G, et al. Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels. J Lipid Res. 2010;51:345–351.
  • Noguchi T, Kobayashi J, Yagi K, et al. Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: results from a crossover study. Atherosclerosis. 2011;217:165–170.
  • Simonen P, Stenman U-H, Gylling H. Serum proprotein convertase subtilisin/kexin type 9 concentration is not increased by plant stanol ester consumption in normo- to moderately hypercholesterolaemic non-obese subjects. The BLOOD FLOW intervention study. Clin Sci Lond Engl. 1979;2015(129):439–446.
  • Pirillo A, Catapano AL. Berberine, a plant alkaloid with lipid- and glucose-lowering properties: from in vitro evidence to clinical studies. Atherosclerosis. 2015;243:449–461.
  • Cameron J, Ranheim T, Kulseth MA, et al. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 2008;201:266–273.
  • Li H, Dong B, Park SW, et al. Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem. 2009;284:28885–28895.
  • CVI Pharmaceuticals Limited. Berberine derivatives useful for modulating lipid levels and their methods of synthesis. WO2011006000 (US2010/041419). 2011.
  • Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10:1344–1351.
  • Dong H, Zhao Y, Zhao L, et al. The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials. Planta Med. 2013;79:437–446.
  • Derosa G, D’Angelo A, Bonaventura A, et al. Effects of berberine on lipid profile in subjects with low cardiovascular risk. Expert Opin Biol Ther. 2013;13:475–482.
  • Kong W-J, Wei J, Zuo Z-Y, et al. Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism. 2008;57:1029–1037.
  • Affuso F, Ruvolo A, Micillo F, et al. Effects of a nutraceutical combination (berberine, red yeast rice and policosanols) on lipid levels and endothelial function randomized, double-blind, placebo-controlled study. Nutr Metab Cardiovasc Dis NMCD. 2010;20:656–661.
  • Pisciotta L, Bellocchio A, Bertolini S. Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment. Lipids Health Dis. 2012;11:123.
  • FDA. FDA approves Praluent to treat certain patients with high cholesterol [Internet]. [Press Release]. 2015 [cited 2015 Jul 24]. Available from: http://www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm
  • FDA. FDA approves Repatha to treat certain patients with high cholesterol [Internet]. [Press Release]. 2015 [cited 2015 Aug 27]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm.
  • EMA. Praluent recommended for approval to lower cholesterol [Internet]. [Press Release]. 2015 [cited 2015July 24]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/07/news_detail_002377.jsp&mid=WC0b01ac058004d5c1.
  • EMA. First-in-class treatment to lower cholesterol. [Press Release]. [Internet]. 2015 [cited 2015 May 22]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/05/news_detail_002336.jsp&mid=WC0b01ac058004d5c1.
  • Ballantyne CM, Neutel J, Cropp A, et al. 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. 2015;115:1212–1221.
  • Kastelein JJP, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. Eur Heart J. 2016;37:1360–1369.
  • Regeneron Pharmaceuticals, INC. Anti-PCSK9 antibodies with PH-dependent binding characteristics. WO2014028354 (US2013/054456). 2014.
  • Regeneron Pharmaceuticals, INC. Stabilized formulations containing anti-PCSK9 antibodies. WO2013016648 (US2012/048574). 2013.
  • Sanofi. Human antibodies to PCSK9 for use in methods of treatment based on particular dosage regimens. WO2012101251 (EP2012/0511318). 2012.
  • Sanofi. Pharmaceutical compositions comprising human antibodies to PCSK9. WO2012101253 (EP2012/051321). 2012.
  • Sanofi. Human antibodies to PCSK9 for use in methods of treating particular groups of subjects. WO2012101252 (EP2012/051320). 2012.
  • Regeneron Pharmaceuticals, INC. Methods for reducing lipoprotein(a) levels by administering an inhibitor of proprotein convertase subtilisin Kexin-9 (PCSK9). WO2013039969 (US2012/054756). 2013.
  • Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014;114:711–715.
  • Regeneron Pharmaceuticals, INC. Methods for reducing remnant cholesterol and other lipoprotein fractions by administering an inhibitor of proprotein convertase subtilisin Kexin-9 (PCSK9). WO2014194168 (US2014/040163). 2014.
  • Koren MJ, Roth EM, McKenney JM, et al. Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: a Phase II pooled analysis. Postgrad Med. 2015;127:125–132.
  • Regeneron Pharmaceuticals, INC. Methods for treating autosomal dominant hypercholesterolemia associated with PCSK9 gain-of-function mutations. WO2014194111 (US2014/040050). 2014.
  • Hopkins PN, Defesche J, Fouchier SW, et al. 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. 2015;8:823–831.
  • Regeneron Pharmaceuticals, INC. Methods for inhibiting atherosclerosis by administering an inhibitor of PCSK9. WO2014197752 (US2014/041204). 2014.
  • Sanofi Biotechnology. Use of a PCSK9 inhibitor to treat hyperlipidemia. WO2015054619 (US2014/060109). 2015.
  • Sanofi. Methods for treating subjects with primary hypercholesterolemia that is not adequately controlled. WO2015140079 (EP2015/055369). 2015.
  • Regeneron Pharmaceuticals, INC. Methods for treating patients with hypercholesterolemia that is not adequately controlled by moderate-dose statin therapy. WO2015123423 (US2015/015633). 2015.
  • Sanofi Biotechnology. Dosing regimens for use with PCSK9 inhibitors. WO2015073494 (US2014/065149). 2015.
  • Bessac Laurence. Methods for reducing cardiovascular risk. WO2015142668 (US2015/020564). 2015.
  • Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–1118.
  • 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 Lond Engl. 2012;380:29–36.
  • 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;59:2344–2353.
  • McKenney JM. Understanding PCSK9 and anti-PCSK9 therapies. J Clin Lipidol. 2015;9:170–186.
  • Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–2853.
  • Romagnuolo R, Scipione CA, Boffa MB, et al. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem. 2015;290:11649–11662.
  • Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996–3003.
  • Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169:906–15.e13.
  • Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186–1194.
  • Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab. 2015;100:3140–3148.
  • Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: the ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138–146.
  • Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758–769.
  • Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–1499.
  • NCT01663402. ODYSSEY outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with Alirocumab. Clinical Trials. [[cited 2016 Feb]. Available from: https://clinicaltrials.gov/ct2/show/NCT01663402?term=NCT01663402&rank=1
  • Amgen INC. Stable formulations containing anti-PCSK9 antibodies. WO2013166448 (US2013/039561). 2013.
  • Amgen INC. Methods of treating or preventing cholesterol related disorders. WO2012154999 (US2012/037394). 2012.
  • Amgen INC. Human antigen binding proteins that bind to proprotein convertase subtilisin kexin type 9. WO2014144080 (US2014/028339). 2014.
  • Amgen INC. Human antigen binding proteins that bind to proprotein convertase subtilisin kexin type 9 (PCSK9). WO2014150983 (US2014/024702). 2014.
  • Amgen INC. Methods for treating homozygous familial hypercholesterolemia. WO2014209384 (US2013/048714). 2014.
  • Raal F, Honarpour N, Blom DJ, et al. Trial evaluating evolocumab, a pcsk9 antibody, in patients with homozygous FH (tesla): results of the randomized, double-blind, placebo-controlled trial. Atherosclerosis. 2014;235:e12.
  • Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2015;385:341–350.
  • Dias CS, Shaywitz AJ, Wasserman SM, 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;60:1888–1898.
  • Giugliano RP, Desai NR, Kohli P, 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 Lond Engl. 2012;380:2007–2017.
  • Raal F, Scott R, Somaratne R, 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;126:2408–2417.
  • Sullivan D, Olsson AG, Scott R, 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;308:2497–2506.
  • Koren MJ, Scott R, Kim JB, 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 Lond Engl. 2012;380:1995–2006.
  • Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278–1288.
  • Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2015;385:331–340.
  • Robinson JG, Nedergaard BS, Rogers WJ, 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;311:1870–1882.
  • Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–1819.
  • Stroes E, Colquhoun D, Sullivan D, et al. 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. 2014;63:2541–2548.
  • Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–1509.
  • NCT01764633. Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER). Clinical Trials. [[cited 2016 Jan]. Available from: https://clinicaltrials.gov/ct2/show/NCT01764633?term=NCT01764633&rank=1.
  • Pfizer INC. Treatment with anti-PCSK9 antibodies. WO2013008185 (IB2012/053534). 2013.
  • Tingley W, Luca D, Leabman M, et al. GW24-e2907 effects of RG7652, a fully human mAb against proprotein convertase subtilisin/kexin type 9, on LDL-c: a phase I, randomised, double-blind, placebo-controlled, single- and multiple-dose study. Heart. 2013;99:A153–A153.
  • Beyer TP, Eacho PI, Schroeder Krista M, et al. A PCSK9 Antibody that Blocks Binding to LDLR while Allowing Normal PCSK9 Inactivation by Furin is Afforded a Reduced Clearance Rate and a Longer Duration of Effect in Mice. Arterioscler Thromb Vasc Biol. 2015; 35:A538–A538;abstr 538.
  • Eli Lilly and Company. Antibodies to PCSK9 and uses thereof. WO2013039958 (US2012/054737). 2013.
  • Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. 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 Lond Engl. 2014;383:60–68.
  • Alnylam Pharmaceuticals, INC. PCSK9 iRNA compositions and methods of use thereof. WO2014089313 (US2013/073349). 2014.
  • Alnylam Pharmaceuticals, INC. Compositions and methods for inhibition of PCSK9 genes. WO2012058693 (US2011/058682). 2012.
  • Alnylam Pharmaceuticals, INC. Dual targeting siRNA agents. WO2011038031 (US2010/049868). 2011.
  • Alnylam Pharmaceuticals, INC. Methods for lowering serum cholesterol in a subject using inhibition of PCSK9. WO2011028938 (US2010/047726). 2011.
  • Roche Innovation Center Copenhagen A/S. Antisense oligomers and conjugates targeting PCSK9. WO2014207232 (EP2014/063757). 2014.
  • Santaris Pharma A/S. Antisense oligomers targeting PCSK9. WO2011009697 (EP2010/059257). 2011.
  • Van Poelgeest EP, Hodges MR, Moerland M, et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol. 2015;80:1350–1361.
  • Yamamoto T, Harada-Shiba M, Nakatani M, et al. Cholesterol-lowering action of BNA-based antisense oligonucleotides targeting PCSK9 in atherogenic diet-induced hypercholesterolemic Mice. Mol Ther Nucleic Acids. 2012;1:e22.
  • Osaka University. Oligonucleotide, and therapeutic agent for dyslipidemia which contains oligonucleotide as active ingredient. WO2014007305 (JP2013/068299). 2014.
  • Osaka University. Oligonucleotide, and therapeutic agent for dyslipidemia containing oligonucleotide as active ingredient. WO2012029870 (JP2011/069818). 2012.
  • Galabova G, Brunner S, Winsauer G, et al. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PloS One. 2014;9:e114469.
  • Affiris AG. PCSK9 vaccine. WO2015128287 (EP2015/053725). 2015.
  • Affiris AG. PCSK9 Peptide Vaccine. WO2014033158 (EP2013/067797). 2014.
  • Affiris AG. Vaccine. WO2013037889 (EP2012/067950). 2013.
  • Crossey E, Amar MJA, Sampson M, et al. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. 2015;33:5747–5755.
  • The USA, as represented by The Secretary, Dept. of Health and Human services. PCSK9 vaccine and methods of using the same. WO2015123291 (US2015/015408). 2015.
  • Carly Helfand. Pfizer developing cholesterol-fighting vaccine as part of PCSK9 “franchise” [Internet]. FierceVaccines. [cited 2015 Jan 15]. Available from: http://www.fiercevaccines.com/story/pfizer-developing-cholesterol-fighting-vaccine-part-pcsk9-franchise/2015-01-15
  • Kwon HJ, Lagace TA, McNutt MC, et al. Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci USA. 2008;105:1820–1825.
  • Mitchell T, Chao G, Sitkoff D, et al. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J Pharmacol Exp Ther. 2014;350:412–424.
  • Bristol-Myers Squibb Company. Fibronectin based scaffold domain proteins that bind PCSK9. WO2011130354 (US2011/032231). 2011.
  • Stein EA, Kasichayanula S, Turner T, et al. LDL cholesterol reduction with BMS-962476, an adnectin inhibitor of PCSK9: results of a single ascending dose study. J Am Coll Cardiol. 2014;63. doi:10.1016/S0735-1097(14)61372-3.
  • NCT01587365. single ascending dose safety study of BMS-962476 in healthy subjects and patients with elevated cholesterol on statins. Clinical Trials. [[cited 2013 Sep]. Availablefrom: https://clinicaltrials.gov/ct2/show/record/NCT01587365?term=NCT01587365&rank=1
  • Mbikay M, Sirois F, Simoes S, et al. Quercetin-3-glucoside increases low-density lipoprotein receptor (LDLR) expression, attenuates proprotein convertase subtilisin/kexin 9 (PCSK9) secretion, and stimulates LDL uptake by Huh7 human hepatocytes in culture. FEBS Open Bio. 2014;4:755–762.
  • Mbikay Majambu. Quercetin-3-glucoside and uses thereof. WO2014005224 (CA2013/050507). 2014.
  • Institut National de la Santé et de la Recherche Médicale. Mutations in the human PCSK9 gene associated to hypercholesterolemia. WO2004097047 (IB2004/001686). 2004.
  • Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:40–51.
  • Lipinski MJ, Benedetto U, Escarcega RO, et al. 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. 2016;37:536–545.
  • Seidah NG, Poirier S, Denis M, et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PloS One. 2012;7:e41865.
  • Melone M, Wilsie L, Palyha O, et al. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J Am Coll Cardiol. 2012;59:1697–1705.
  • Zaid A, Roubtsova A, Essalmani R, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatol Baltim Md. 2008;48:646–654.
  • Jonas MC, Costantini C, Puglielli L. PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 2008;9:916–922.
  • Postmus I, Trompet S, De Craen AJM, et al. PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population. J Lipid Res. 2013;54:561–566.
  • Folsom AR, Peacock JM, Boerwinkle E. Sequence variation in proprotein convertase subtilisin/kexin type 9 serine protease gene, low LDL cholesterol, and cancer incidence. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2007;16:2455–2458.
  • Labonté P, Begley S, Guévin C, et al. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatol Baltim Md. 2009;50:17–24.
  • Amgen’s PCSK9 patents upheld. Nat Biotechnol. 2016;34(5):452. doi:10.1038/nbt0516-452a.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.