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Main groups of proprotein convertase subtilisin/kexin type 9 inhibitors: mechanisms of action and clinical efficacy. Part 1

DOI: https://doi.org/10.29296/25877305-2021-03-04
Issue: 
3
Year: 
2021

A. Chaulin(1, 2), N. Svechkov(1, 2), S. Volkova(1) (1)Samara Regional Cardiology Dispensary,
Samara (2)Samara State Medical University

Since establishing the important role of cholesterol and low-density lipoproteins (LDL) in the pathogenesis of atherosclerosis and cardiovascular diseases, many researchers have focused on developing drugs that lower the levels of atherogenic lipoproteins. Thanks to the work of Japanese researcher Akira Endo, the first effective anti-atherosclerotic drugs – statins-were created in the 1970s and 80s. The mechanism of hypocholesterolemic action of statins is based on competitive inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) – reductase, which is necessary for cholesterol biosynthesis. In 2003, a new enzyme, proprotein convertase subtilisin – Kexin type 9 (PCSK9), was discovered and a new mechanism for regulating LDL levels in blood serum. As a result of research, the PCSK9 enzyme has been considered as a target for therapeutic effects to reduce cholesterol and LDL levels. To date, several groups of drugs that inhibit PCSK9 have been developed. In this article, we will review the mechanisms of action and clinical efficacy of the main groups of PCSK9 inhibitors. The first part of the article is devoted to preparations of the group of monoclonal antibodies against PCSK9, antisense oligonucleotides, and small interfering ribonucleic acids.

Keywords: 
cardiology
proprotein convertase subtilisin-Kexin type 9
atherosclerosis
cholesterol
low-density lipoproteins
low-density lipoprotein receptors
cardiovascular diseases
PCSK9 inhibitors
monoclonal antibodies
antisense nucleotides
small interfering ribonucleic acids



References: 
  1. Cardiovascular diseases. URL: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (Available at: 10.11.2020).
  2. Chaulin A.M., Karsljan L.S., Grigor'eva E.V. i dr. Kliniko-diagnosticheskaja tsennost' kardiomarkerov v biologicheskih zhidkostjah cheloveka. Kardiologija. 2019; 59 (11): 66–75 [Chaulin A.M., Karslyan L.S., Grigoriyeva E.V. et al. Clinical and Diagnostic Value of Cardiac Markers in Human Biological Fluids. Kardiologiia. 2019; 59 (11): 66–75 (in Russ.)]. DOI: 10.18087/cardio.2019.11.n414
  3. Chaulin A.M., Grigor'eva Ju.V., Suvorova G.N. i dr. Cposoby modelirovanija ateroskleroza u krolikov. Sovremennye problemy nauki i obrazovanija. 2020; №5 [Chaulin A.M., Grigorieva Y.V., Suvorova G.N. et al. Methods of modeling of atherosclerosis in rabbits. Modern problems of science and education. 2020; №5 (in Russ.)]. URL: http://science-education.ru/ru/article/view?id=30101. DOI: 10.17513/spno.30101
  4. Chaulin A.M., Karsljan L.S., Aleksandrov A.G. i dr. Rol' proprotein konvertazy subtilizin/keksin tipa 9 v razvitii ateroskleroza. Bjulleten' nauki i praktiki. 2019; 5 (5): 112–20 [Chaulin A., Karslyan L., Aleksandrov A. et al. The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Atherosclerosis Development. Bulletin of Science and Practice. 2019; 5 (5): 112–20 (in Russ.)]. https://doi.org/10.33619/2414-2948/42/15
  5. Chaulin A.M., Dupljakov D.V. Biomarkery ostrogo infarkta miokarda: diagnosticheskaja i prognosticheskaja tsennost'. Chast' 1. Klinicheskaja praktika. 2020; 11 (3): 75–84 [Chaulin A.M., Duplyakov D.V. Biomarkers of acute myocardial infarction: diagnostic and prognostic value. Part 1. Journal of Clinical Practice. 2020; 11 (3): 75–84 (in Russ.)]. DOI: 10.17816/clinpract34284]
  6. Kuharchuk V.V. N.N. ANIChKOV (1885–1964). Ateroskleroz i dislipidemii. 2010; 1 (1): 58–60 [Kukharchuk V.V. N.N. ANICHKOV (1885–1964). The Journal of Atherosclerosis and Dyslipidemias = Ateroskleroz i Dislipidemii. 2010; 1 (1): 58–60 (in Russ.)].
  7. Gasanov M.Z., Batjushin M.M., Terent'ev V.P. Professor A.I. Ignatovskij kak osnovopolozhnik teorii ateroskleroza. Arhiv' vnutrennej meditsiny. 2017; 7 (6): 407–14 [Gasanov M.Z., Batiushin M.M., Terentev V.P. Professor Alexander I. Ignatowski a founder of the theory of atherosclerosis. The Russian Archives of Internal Medicine. 2017; 7 (6): 407–14 (in Russ.)]. https://doi.org/10.20514/2226-6704-2017-7-6-407-414
  8. Dreeva Z.V., Ageev F.T. Istorija rozhdenija statinov novye perspektivy. Meditsinskij sovet. 2017; 11: 202–7 [Dreeva Z.V., Ageev F.T. History of statins development. new prospect. Medical Council. 2017; 11: 202–7 (in Russ.)]. DOI: 10.21518/2079-701X-2017-11-202-207
  9. Scandinavian Simvastatin Surviavl Study Group (1994). Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–9. https://doi.org/10.1016/S0140-6736(94)90566-5
  10. Wilhelmsen L., Pyörälä K., Wedel H. et al. Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment. Eur Heart J. 2001; 22 (13): 1119–27. DOI: 10.1053/euhj.2000.2481
  11. Russo M.W., Scobey M., Bonkovsky H.L. Drug-induced liver injury associated with statins. Semin Liver Dis. 2009; 29 (4): 412–22. DOI: 10.1055/s-0029-1240010
  12. du Souich P., Roederer G., Dufour R. Myotoxicity of statins: Mechanism of action. Pharmacol Ther. 2017; 175: 1–16. DOI: 10.1016/j.pharmthera.2017.02.029
  13. Seidah N.G., 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 (3): 928–33. DOI: 10.1073/pnas.0335507100
  14. Abifadel M., Varret M., Rabes J.P. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34 (2): 154–6. DOI: 10.1038/ng1161
  15. Maxwell K.N., Fisher E.A., Breslow J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005; 102 (6): 2069–74. DOI: 10.1073/pnas.0409736102
  16. 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 (2): 394–400. DOI: 10.1016/j. atherosclerosis.2012.04.006
  17. Cohen J.C., Boerwinkle E., Mosley T.H. Jr. et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354 (12): 1264–72. DOI: 10.1056/NEJMoa054013
  18. Chaulin A.M., Dupljakov D.V. PCSK-9: sovremennye predstavlenija o biologicheskoj roli i vozmozhnosti ispol'zovanija v kachestve diagnosticheskogo markera serdechno-sosudistyh zabolevanij. Chast' 1. Kardiologija: novosti, mnenija, obuchenie. 2019; 7 (2): 45–57 [Chaulin A.M., Duplyakov D.V. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. Part 1. Kardiologiya: novosti, mneniya, obuchenie = Cardiology: News, Opinions, Training. 2019; 7 (2): 45–57 (in Russ.)]. DOI: 10.24411/2309-1908-2019-12005
  19. Chaulin A.M., Dupljakov D.V. PCSK-9: sovremennye predstavlenija o biologicheskoj roli i vozmozhnosti ispol'zovanija v kachestve diagnosticheskogo markera serdechno-sosudistyh zabolevanij. Chast' 2. Kardiologija: novosti, mnenija, obuchenie. 2019; 7 (4): 24–35 [Chaulin A.M., Duplyakov D.V. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. Part 2. Kardiologiya: novosti, mneniya, obuchenie = Cardiology: News, Opinions, Training. 2019; 7 (4): 24–35 (in Russ.)]. DOI: 10.24411/2309-1908-2019-14004
  20. Agafonova O.V., Bulgakova S.V., Bogdanova Ju.V. i dr. Poliklinicheskaja terapija. Uchebnik. 2-e izd., pererab. i dop. M., 2020 [Agafonova O.V., Bulgakova S.V., Bogdanova Yu.V. et al. Poliklinicheskaya terapiya. Uchebnik. 2-e izd., pererab. i dop. M., 2020 (in Russ.)]. DOI: 10.33029/9704-5545-6-PLT-2020-1-840
  21. Badimon L., Luquero A., Crespo J. et al. PCSK9 and LRP5 in macrophage lipid internalization and inflammation. Cardiovasc Res. 2020; cvaa254. (published online ahead of print, 2020 Sep 29). DOI: 10.1093/cvr/cvaa254
  22. Chan J.C., Piper D.E., Cao Q. et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci USA. 2009; 106 (24): 9820–5. DOI: 10.1073/pnas.0903849106
  23. Robinson J.G., Farnier M., Krempf M. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372 (16): 1489–99. DOI: 10.1056/NEJMoa1501031
  24. Sabatine M.S., Giugliano R.P., Wiviott S.D. et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372 (16): 1500–9. DOI: 10.1056/NEJMoa1500858
  25. Ray K.K., Ginsberg H.N., Davidson M.H. et al. Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control. Circulation. 2016; 134 (24): 1931–43. DOI: 10.1161/CIRCULATIONAHA.116.024604
  26. Schmidt A.F., Pearce L.S., Wilkins J.T. et al. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017; 4 (4): CD011748. DOI: 10.1002/14651858.CD011748.pub2
  27. Sabatine M.S., Giugliano R.P., Keech A.C. et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017; 376 (18): 1713–22. DOI: 10.1056/NEJMoa1615664
  28. Schwartz G.G., Steg P.G., Szarek M. et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018; 379 (22): 2097–107. DOI: 10.1056/NEJMoa1801174
  29. Farnier M., Colhoun H.M., Sasiela W.J. et al. Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years. J Clin Lipidol. 2017; 11 (4): 986–97. DOI: 10.1016/j.jacl.2017.05.016
  30. Arrieta A., Page T.F., Veledar E. et al. Economic Evaluation of PCSK9 Inhibitors in Reducing Cardiovascular Risk from Health System and Private Payer Perspectives. PLoS One. 2017; 12 (1): e0169761. DOI: 10.1371/journal.pone.0169761
  31. Bennett C.F., Swayze E.E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010; 50: 259–93. DOI: 10.1146/annurev.pharmtox.010909.105654
  32. Vickers T.A., Crooke S.T. The rates of the major steps in the molecular mechanism of RNase H1-dependent antisense oligonucleotide induced degradation of RNA. Nucleic Acids Res. 2015; 43 (18): 8955–63. DOI: 10.1093/nar/gkv920
  33. Liang X.H., Sun H., Nichols J.G. et al. RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus. Mol Ther. 2017; 25 (9): 2075–92. DOI: 10.1016/j.ymthe.2017.06.002
  34. Graham M.J., Lemonidis K.M., Whipple C.P. et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res. 2007; 48 (4): 763–7. DOI: 10.1194/jlr.C600025-JLR200
  35. Gupta N., Fisker N., Asselin M.C. et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One. 2010; 5 (5): e10682. DOI: 10.1371/journal.pone.0010682
  36. Lindholm M.W., Elmén J., Fisker N. et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther. 2012; 20 (2): 376–81. DOI: 10.1038/mt.2011.260
  37. van Poelgeest E.P., Hodges M.R., 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 (6): 1350–61. DOI: 10.1111/bcp.12738
  38. van Poelgeest E.P., Swart R.M., Betjes M.G. et al. Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9. Am J Kidney Dis. 2013; 62 (4): 796–800. DOI: 10.1053/j.ajkd.2013.02.359
  39. 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 (5): e22. DOI: 10.1038/mtna.2012.16
  40. Wierzbicki A.S., Viljoen A. Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia. Exp Opin Biol Ther. 2016; 16 (9): 1125–34. DOI: 10.1080/14712598.2016.1196182
  41. Nordestgaard B.G., Nicholls S.J., Langsted A. et al. Advances in lipid-lowering therapy through gene-silencing technologies. Nat Rev Cardiol. 2018; 15 (5): 261–72. DOI: 10.1038/nrcardio.2018.3
  42. Nobel Prizes 2006/ URL: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html (Available at: 10.11.2020)
  43. Fire A., Xu S., Montgomery M.K. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998; 391 (6669): 806–11. DOI: 10.1038/35888
  44. Carthew R.W., Sontheimer E.J. Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009; 136 (4): 642–55. DOI: 10.1016/j.cell.2009.01.035
  45. Bernards R. Exploring the uses of RNAi--gene knockdown and the Nobel Prize. N Engl J Med. 2006; 355 (23): 2391–3. DOI: 10.1056/NEJMp068242
  46. 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 (9911): 60–8. DOI: 10.1016/S0140-6736(13)61914-5
  47. Nair J.K., Willoughby J.L., Chan A. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014; 136 (49): 16958–61. DOI: 10.1021/ja505986a
  48. Khvorova A. Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering Drugs. N Engl J Med. 2017; 376 (1): 4–7. DOI: 10.1056/NEJMp1614154
  49. Ray K.K., Landmesser U., Leiter L.A. et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017; 376 (15): 1430–40. DOI: 10.1056/NEJMoa1615758
  50. Ray K.K., Stoekenbroek R.M., Kallend D. et al. Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Prespecified Secondary End Points in ORION 1. Circulation. 2018; 138 (13): 1304–16. DOI: 10.1161/CIRCULATIONAHA.118.034710