PCSK9: NEW VICTORY AND HORIZONS
https://doi.org/10.15372/ATER20180311
Abstract
The review presents the latest data from the world scientific literature of clinical studies of inhibitors protoprotein convertasesubtilisin/kexin 9 type (PCSK9). The results of the most important completed clinical trials and announcements of prospective clinical trials are presented, the completion of which is expected in the near future. The place of PCSK9 inhibitors in modern recommendations of the European and Russian Cardiological Society is highlighted.The results of studies on the efficacy and safety of PCSK9 inhibitors in selected patient groups (familial hypercholesterolemia, hypertriglyceridemia) are presented. A review of the research aimed at finding new inhibition mechanisms for PCSK9, opening new horizons in the treatment of patients with dyslipidemia.
About the Authors
M. O. Smolina
Institutе of Internal and Preventive Medicine - Вranch of Federal Research Institute of Cytology and Genetics of SB RAS
Russian Federation
Russian Federation
K. S. Benimetskaya
Institutе of Internal and Preventive Medicine - Вranch of Federal Research Institute of Cytology and Genetics of SB RAS
Russian Federation
Russian Federation
Yu. I. Ragino
Institutе of Internal and Preventive Medicine - Вranch of Federal Research Institute of Cytology and Genetics of SB RAS
Russian Federation
Russian Federation
M. I. Voevoda
Institutе of Internal and Preventive Medicine - Вranch of Federal Research Institute of Cytology and Genetics of SB RAS
Russian Federation
Russian Federation
References
1. Eerence B.A., Ginsberg H.N., Graham I. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel // Eur. Heart J. 2017. Vol. 38, N 32. P. 2459-2472.
2. Stoekenbroek R.M., Hartgers M.L., Rutte R. et al. PCSK9 inhibitors in clinical practice: Delivering on the promise // Atherosclerosis. 2018. Vol. 270. P. 205-210.
3. Abifadel M., Varret M., Rabes J.P. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia // Nat. Genet. 2003. Vol. 34. P. 154-156.
4. 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. Vol. 376, N 18. P. 1713- 1722.
5. Orringer C.E., Jacobson T.A., Saseen J.J. et al. Update on the use of PCSK9 inhibitors in adults: recommendations from an Expert Panel of the national lipid association // J. Clin. Lipidol. 2017. Vol. 11. P. 880-890.
6. Pirillo A., Catapano A.L. Proprotein Convertase SubtilisinKexin 9 Inhibitors // Cardiol. Clin. 2018. Vol. 36. P. 241-256.
7. Nicholls S.J., Puri R., Anderson T. et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial // JAMA. 2016. Vol. 316, N 22. P. 2373-2384.
8. Giugliano R.P., Mach F., Zavitz K.V. et al. Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial // Clin. Cardiol. 2017. Vol. 40, N 2. P. 59-65. DOI: 10.1002/clc.22678. Epub 2017 Feb 16.
9. McKenney J.M., Koren M.J., Kereiakes D.J. 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. Vol. 59, N 25. P. 2344-2353.
10. Moriarty P.M., Thompson P.D., Cannon C.P. 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. Vol. 9, N 6. P. 758-769.
11. Schwartz G.G., Szarek M., Bhatt D.L. et al. The ODYSSEY OUTCOMES Trial: Topline results. Alirocumab in patients after acute coronary syndrome. Clinical Latebreaker // 67th Scientific Sessions of the American College of Cardiology. Florida, 2018.
12. Navarese E.P., 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. Int. Med. 2015. Vol. 163, N 1. P. 40-51.
13. Kwakernaak A.J., Lambert G., Dullaart R.P. Plasma proprotein convertase subtilisin-kexin type 9 is predominantly related to intermediate density lipoproteins // Clin. Biochem. 2014. Vol. 47. P. 679-682.
14. Dijk W., Le May C., Cariou B., Beyond L.D.L. What Role for PCSK9 in Triglyceride-Rich Lipoprotein Metabolism? // Trends Endocrinol. Metab. 2018. Vol. 29, N 6. P. 420-434.
15. 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. Vol. 372. P. 1489-1499.
16. Austin M.A., Hutter C.M., Zimmern R.L., Humphries S.E. Genetic causes of monogenic heterozygous familial hypercholesterolaemia // A HuGE prevalence rev. Am. J. Epidemiol. 2004. Vol. 160. P. 402-407.
17. Титов В.Н., Алиджанова Х.Г., Малышев П.П. Семейная гиперхолестеринемия. М.: БИНОМ, 2011. С. 624.
18. Humphries S.E., Whittall R.A., Hubbart C.S. 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. Vol. 43, N 12. P. 943-949.
19. Marduel M., Carriй A., Sassolas A. et al. Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France // HUMAN MUTATION Mutation in Brief. 2010. Vol. 31. P. 1811-1824.
20. Poirier S., Mayer G., Poupon V. et al. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route // J. Biol. Chem. 2009. Vol. 284, N 42. P. 28856-28864.
21. 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. Vol. 126, N 20. P. 2408-2417.
22. Raal F., Stein E.A., Dufour R. et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial // Lancet. 2015. Vol. 385, N 9965. P. 331-340.
23. Stein E.A., Honarpour N., Wasserman S.M. et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia // Circulation. 2013. Vol. 128, N 19. P. 2113-2120.
24. Kastelein J.J., Ginsberg H.N., 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. Vol. 36, N 43. P. 2996-3003.
25. Moriarty P.M., Parhofer K.G., Babirak S.P. et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial // Eur. Heart. J. 2016. Vol. 37, N 48. P. 3588-3595.
26. Catapano A.L., Graham I., De Backer G. et al. ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) // Eur. Нeart J. 2016. Vol. 253. P. 281-344.
27. Ежов М.В., Сергиенко И.В., Кухарчук В.В. и др. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации (VI пересмотр). М., 2017.
28. Raal F.J., Hovingh G.K., Blom D. et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study // Lancet Diabetes Endocrinol. 2017. Vol. 5, N 4. P. 280-290.
29. Farnier M., Hovingh G.K., Langslet G. et al. Durability of alirocumab effect: data from an open-label extension to the ODYSSEY program for patients with heterozygous familial hypercholesterolemia // J. Clin. Lipidol. 2017. Vol. 11, N 3. P.840.
30. Mitchell T., Chao G., Sitkoffv D. Pharmacologic profile of the adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for LDL lowering // J. Pharmacol. Exp. Ther. 2014. Vol. 350, N 2. P. 412-424.
31. 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. Vol. 48. P. 763-767.
32. Fitzgerald K., White S., Borodovsky A. et al. A highly durable RNAi therapeutic inhibitor of PCSK9 // N. Engl. J. Med. 2017. Vol. 376. P. 41-51.
33. 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. Vol. 376. P. 1430-1440.
34. Raal D. New Approaches to PCSK9 inhibition. Режим доступа: https://www.pcsk9forum.org/new-approaches-pcsk9-inhibition/
Review
For citations:
Smolina M.O., Benimetskaya K.S., Ragino Yu.I., Voevoda M.I. PCSK9: NEW VICTORY AND HORIZONS. Ateroscleroz. 2018;14(3):70-77. (In Russ.) https://doi.org/10.15372/ATER20180311
Views:
287
Email this article 