PCSK9 Inhibition: Discovery, Current Evidence, and Potential Effects on LDL-C and Lp(a)

Cardiovascular Drugs and Therapy

Volumn 29, Issue 3, 2015, Pages 295-308

  Ferdinand, Keith C ^a   Nasser, Samar A ^b  

^a TULANE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES   (United States)

Author keywords

Alirocumab; Evolocumab; Hypercholesterolemia; Lipoprotein(a); Low density lipoprotein cholesterol; Proprotein convertase subtilisin kexin type 9

Indexed keywords

ALIROCUMAB; BOCOCIZUMAB; EVOLOCUMAB; LIPOPROTEIN A; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; SERINE PROTEINASE; UNCLASSIFIED DRUG; HYPOCHOLESTEROLEMIC AGENT; PCSK9 PROTEIN, HUMAN;

ARTICLE; CARDIOVASCULAR RISK; DRUG EFFICACY; DRUG SAFETY; ENZYME INHIBITION; HUMAN; LIPID METABOLISM; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRACTICE GUIDELINE; PRIORITY JOURNAL; PROTEIN LIPID INTERACTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; BLOOD; HYPERCHOLESTEROLEMIA;

ANTICHOLESTEREMIC AGENTS; CHOLESTEROL, LDL; HUMANS; HYPERCHOLESTEROLEMIA; LIPOPROTEIN(A); MODELS, BIOLOGICAL; PRACTICE GUIDELINES AS TOPIC; PROPROTEIN CONVERTASES; SERINE ENDOPEPTIDASES;

EID: 84938416567     PISSN: 09203206     EISSN: 15737241     Source Type: Journal    
DOI: 10.1007/s10557-015-6588-3     Document Type: Article

References (81)

1. Anderson KM, Castelli WP, Levy D. Cholesterol and mortality. 30 years of follow-up from the Framingham study. J Am Med Assoc. 1987;257:2176–80.
2. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012–8.
3. Kavey R-EW, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003;107:1562–6.
4. Pagidipati NJ, Gaziano TA. Estimating deaths from cardiovascular disease: a review of global methodologies of mortality measurement. Circulation. 2013;127:749–56.
5. LaRosa JC. Reduction of serum LDL-C levels: a relationship to clinical benefits. Am J Cardiovasc Drugs. 2003;3:271–81.
6. Forrester JS, Bairey-Merz CN, Kaul S. The aggressive low density lipoprotein lowering controversy. J Am Coll Cardiol. 2000;36:1419–25.
7. Cholesterol Treatment Trialists (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90.
8. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–8.
9. Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck study. J Am Coll Cardiol. 2014;64:851–60.
10. Nordestgaard BG, Chapman MJ, Ray K, for European Atherosclerosis Society Consensus Panel, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–53.
11. Rader DJ, Kastelein JJP. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129:1022–32.
12. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007;32:71–7.
13. 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 U S A. 2003;100:928–33.
14. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114:1022–36.
15. Catapano AL, Papadopoulos N. The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway. Atherosclerosis. 2013;228:18–28.
16. Abifadel M, Varret M, Rabès J-P, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.
17. Abifadel M, Rabès J-P, Devillers M, et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat. 2009;30:520–9.
18. Humphries SE, Whittall RA, Hubbart CS, for Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee, et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006;43:943–9.
19. 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.
20. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.
21. 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.
22. Cohen JC. Emerging LDL, therapies: using human genetics to discover new therapeutic targets for plasma lipids. J Clin Lipidol. 2013;7:S1–5.
23. 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.
24. European Association for Cardiovascular Prevention & Rehabilitation. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818.
25. O’Keefe Jr JH, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142–6.
26. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1–S45.
27. 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.
28. ATP III. Final report. VI: Drug therapy. Circulation. 2002;106:3303–25.
29. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64:485–94.
30. Ben-Yehuda O, DeMaria AN. LDL-cholesterol targets after the ACC/AHA 2013 guidelines: evidence that lower is better? J Am Coll Cardiol. 2014;64:495–7.
31. Dragan S, Serban M-C, Banach M. Proprotein convertase subtilisin/kexin 9 inhibitors: an emerging lipid-lowering therapy? J Cardiovasc Pharmacol Ther. 2015;20:157–68.
32. Blom DJ, Hala T, Bolognese M, for DESCARTES Investigators, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19.
33. Giugliano RP, Desai NR, Kohli P, for LAPLACE-TIMI 57 Investigators, 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.
34. Koren MJ, Giugliano RP, Raal FJ, for OSLER Investigators, 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.
35. Koren MJ, Lundqvist P, Bolognese M, for MENDEL-2 Investigators, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–40.
36. 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. 2012;380:1995–2006.
37. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand A-C, 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.
38. 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;126:2408–17.
39. Robinson JG, Nedergaard BS, Rogers WJ, for LAPLACE-2 Investigators, 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.
40. 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.
41. Stein EA, Bergeron J, Gaudet D, et al. One year open-label treatment with alirocumab 150 mg every two weeks in heterozygous familial hypercholesterolemic patients [abstract]. J Am Coll Cardiol. 2014;63:A1371.
42. 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.
43. 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.
44. Stroes E, Colquhoun D, Sullivan D, for GAUSS-2 Investigators, 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;63:2541–8.
45. 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;308:2497–506.
46. Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized Phase 3 trial. J Clin Lipidol. 2014;8:554–61.
47. Colhoun HM, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc Disord. 2014;14:121.
48. Robinson JG, Colhoun HM, Bays HE, et al. Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS studies. Clin Cardiol. 2014;37:597–604.
49. Sabatine MS, Giugliano RP, Wiviott SD, for Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.
50. Cannon CP, Cariou B, Blom D, for the ODYSSEY COMBO II Investigators, 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(19):1186–94.
51. Robinson JG, Farnier M, Krempf M, for ODYSSEY LONG TERM Investigators, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.
52. Roth EM, Taskinen M-R, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial. Int J Cardiol. 2014;176:55–61.
53. Farnier M. PCSK9: from discovery to therapeutic applications. Arch Cardiovasc Dis. 2014;107:58–66.
54. Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther. 2013;35:1082–98.
55. Robinson J, Farnier M, Chaudhari U, et al. Adverse events in patients with low-density lipoprotein cholesterol levels <25 or <15 mg/dL on at least two consecutive visits in fourteen randomized, controlled, clinical trials of alirocumab [abstract]. J Am Coll Cardiol. 2015;65:A1350.
56. 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(6):906–15.
57. Bays H, Farnier M, Gaudet D, et al. Efficacy and safety of combining alirocumab with atorvastatin or rosuvastatin versus statin intensification or adding ezetimibe in high cardiovascular risk patients: ODYSSEY OPTIONS I and II [abstract]. Circulation. 2014;130:2118–9.
58. Kastelein JJP, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014;28:281–9.
59. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia on maximally tolerated doses of statins: the ODYSSEY COMBO I study [abstract]. Circulation. 2014;130:2119–20.
60. Moriarty PM, Thompson PD, Cannon CP, et al. ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm [abstract]. Circulation. 2014;130:2108–9.
61. Schwartz GG, Bessac L, Berdan LG, et al. 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. 2014;168:682–9.
62. Ginsberg HN, Rader DJ, Raal FJ, et al. ODYSSEY HIGH FH: efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia [abstract]. Circulation. 2014;130:2119.
63. Jones PH, Bays H, Chaudhari U, et al. Pooled safety and adverse events in nine randomized, placebo-controlled, phase 2 and 3 clinical trials of alirocumab [abstract]. J Am Coll Cardiol. 2015;65:A1363.
64. Raal FJ, Honarpour N, Blom DJ, for TESLA Investigators, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341–50.
65. Raal FJ, Stein EA, Dufour R, for RUTHEFORD-2 Investigators, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331–40.
66. Desai NR, Giugliano RP, Zhou J, et al. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program–adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy–Thrombolysis In Myocardial infarction 57). J Am Coll Cardiol. 2014;63:430–3.
67. 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.
68. Koren M, Rosenson R, Khan B, et al. LDL cholesterol reduction in elderly patients with the pcsk9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of 1779 patients in phase 2, 3 and open label extension studies [abstract]. J Am Coll Cardiol. 2015;65:A1366.
69. Toth PP, Sattar N, Genest J, et al. A comprehensive safety analysis of 6026 patients from phase 2 and 3 short and long term clinical trials with evolocumab (AMG 145) [abstract]. J Am Coll Cardiol. 2015;65:A1351.
70. 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;115:1212–21.
71. Alonso R, Andres E, Mata N, for SAFEHEART Investigators, et al. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol. 2014;63:1982–9.
72. Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–23.
73. Kamstrup PR, Tybjærg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–9.
74. Deo RC, Wilson JG, Xing C, et al. Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. PLoS One. 2011;6:e14581.
75. Enkhmaa B, Anuurad E, Zhang W, Berglund L. Significant associations between lipoprotein(a) and corrected apolipoprotein B-100 levels in African-Americans. Atherosclerosis. 2014;235:223–9.
76. Virani SS, Brautbar A, Davis BC, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125:241–9.
77. 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;114:711–5.
78. 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;63:1278–88.
79. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12.
80. 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. 2014;383:60–8.
81. 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 [abstract]. J Am Coll Cardiol. 2014;63:A1372.