АНТИСМЫСЛОВЫЕ ОЛИГОНУКЛЕОТИДЫ И ТЕРАПЕВТИЧЕСКИЕ МОНОКЛОНАЛЬНЫЕ АНТИТЕЛА - КАК ОСНОВА ДЛЯ СОЗДАНИЯ НОВЫХ ПОКОЛЕНИЙ БИОЛОГИЧЕСКИХ ЛИПИДСНИЖАЮЩИХ ПРЕПАРАТОВ

Разработка инновационных биотехнологических препаратов на основе гуманизированных или полностью человеческих моноклональных антител или антисмысловых олигонуклеодинов открыло новую эру в лечении нарушений липидного обмена. Высокая эффективность таких биологических лекарств, воздействующих на ключевые звенья липидного обмена: апобелок В100, апобелок(а), апобелок СIII, пропротеин-конвертаза субтилизин-кексинового типа 9, антиопоэтин подобный белок 3, открывает перспективу коррекции тяжелых или статин-резистентных форм дислипедимий, с возможностью достичь практически полной ремиссии заболевания. Однако, доказательство безопасности препаратов антисмысловых олигонуклеотидов, требует дополнительных обширных и продолжительных клинических исследований. Такие лекарства могут применяться у пациентов с орфанными заболеваниями или тяжелыми нарушениями липидного обмена не имеющими альтернативного лечения. Напротив, препараты на основе человеческих моноклональных антител благодаря доказанной в рамках  обширных программ клинических исследований безопасности начинают активно использоваться.

Внедрение новых поколений биологических препаратов в клиническую практику, дает врачам дополнительные возможности снижения сердечно-сосудистого риска у больных с тяжелыми и сложными нарушениями липидного обмена.

1. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466(7307):707-13. doi:10.1038/nature09270.

2. Bauer RC, Stylianou IM, Rader DJ. Functional validation of new pathways in lipoprotein metabolism identified by human genetics. Curr. Opin. Lipidol. 2011;22(2):123-8. doi:10.1097/MOL.0b013e32834469b3.

3. Rayner KJ, Fernandez-Hernando C, Moore KJ. MicroRNAs regulating lipid metabolism in atherogenesis. Thromb Haemost. 2012; 07(4):642-7. doi:10.1160/TH11-10-0694.

4. Афанасьева О. И., Покровский С. Н. Коррекция липидного обмена с использованием антисенстехнологий. Рациональная фармакотерапия в кардиологии. 2013;9(5):532-41. doi:10.20996/1819-6446-2013-9-5-532-541.

5. Visser ME, Witztum JL, Stroes ES, Kastelein JJ. Antisense oligonucleotide for the treatment of dyslipidaemia. Eur. Heart Jour. 2012;33:1451-8. doi:10.1093/eurheartj/ehs084.

6. Santos RD, Raal FJ, Catapano AL, et al. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler. Thromb. Vasc. Biol. 2015;35:689-99. doi:10.1161/ATVBAHA.114.304549.

7. Crooke RM, Graham MJ. Therapeutic potential of antisense oligonucleotides for the management of dyslipidemia. Clin. Lipidol. 2011;6(6):675-92. doi:10.2217/clp.11.59.

8. Raal FJ, Braamskamp MJ, Selvey SL, et al. Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia. J. Clin. Lipidol. 2016;10:860-69. doi:10.1016/j.jacl.2016.02.018.

9. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J. 2015;36(9):566-75. doi: 10.1093/eurheartj/eht549.

10. Santos RD, Raal FJ, Donovan JM, Cromwell WC. Mipomersen preferentially reduces small low-density lipoprotein particle number in patients with hypercholesterolemia. J Clin Lipidol. 2015;9(2):201-9. doi:10.1016/j.jacl.2014.12.008.

11. Duell PB, Santos RD, Kirwan BA, et al. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016;10(4):1011-21. doi:10.1016/j.jacl.2016.04.013.

12. Graham MJ, Lemonidis KM, Whipple CP, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid. Res. 2007;48:763-7.

13. Gupta N, Fisker N, Asselin MC, 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.

14. Lindholm MW, Elmén J, Fisker N, et al. PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Mol Ther. 2012; 20(2):37681. doi:10.1038/mt.2011.260.

15. 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(6):1350-61. doi:10.1111/bcp.12738.

16. Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA. 2008;105(33):11915-20. doi:10.1073/pnas.0805434105.

17. 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, singleblind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60-8. doi:10.1016/S01406736(13)61914-5.

18. Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136:16958-61. doi:10.1021/ja505986a.

19. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Eng J Med. 2017;376(1):41-51. doi:10.1056/NEJMoa1609243.

20. Ray KK, Landmesser U, Leiter LA, 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.

21. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Int Med 2013;273:630. doi:10.1111/j.1365-2796.2012.02592.x.

22. Thanassoulis G. Lipoprotein(a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis. J Lipid Res 2016; 57: 917-24. doi:10.1194/jlr.R051870.

23. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223(2):262-8. doi:10.1016/j.atherosclerosis.2012.02.019.

24. Merki E, Graham MJ, Mullick AE, et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation. 2008;118:743-53. doi:10.1161/CIRCULATIONAHA.108.786822.

25. Merki E, Graham MJ, Taleb A, et al. Antisens oligonucleotide lowers plasma levels of apolipoprotein(a) and lipoprotein(a) in transgenic mice. J Am Coll Cardiol. 2011;57(15):1611-21. doi:10.1016/j.jacc.2010.10.052.

26. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;10;386(10002):1472-83. doi:10.1016/S0140-6736(15)61252-1.

27. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388:2239-53. doi:10.1016/S01406736(16)31009-1.

28. Ooi EMM, Barrett HR, Chan DC, et al. Apolipoprotein CIII: understanding an emerging risk factor. Clin. Sci. 2008;114:611-24. doi:10.1042/CS20070308.

29. Olivieri O, Martinelli N, Girelli G, et al. Apolipoprotein CIII predicts cardiovascular mortality in severe coronary artery disease and is associated with an enhanced thrombin generation. J. Thromb. Haemost. 2010;8:463-71. doi:10.1111/j.1538-7836.2009.03720.x.

30. Holmberg R, Refai E, Hoog A, et al. Lowering apolipoprotein CIII delays onset of type 1 diabetes. Proc. Natl Acad. Sci. USA. 2011;108(26):10685-9. doi:10.1073/pnas.1019553108.

31. Graham MJ, Lee RG, Bell TA III, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ.Res. 2013;112:1479-90. doi:10.1161/CIRCRESAHA.111.300367.

32. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N. Engl. J. Med. 2014;371:2200-6. doi:10.1056/NEJMoa1400284.

33. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 2015;373:438-47. doi:10.1056/NEJMoa1400283.

34. Yamamoto T, Wada F, Harada-Shiba M. Development of Antisense Drugs for Dyslipidemia. J Atheroscler Thromb. 2016;23(9):1011-25. doi:10.5551/jat.RV16001.

35. Arca M, Hsieh A, Soran H, et al. The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS Study. Expert Rev Cardiovasc Ther. 2018. doi: 10.1080/14779072.2018.1487290.

36. Graham MJ, Lee RG, Brandt TA, et al Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377(3):222-32. doi:10.1056/ NEJMoa1701329.

37. Su X, Peng DQ. New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases. Lipids Health Dis. 2018;17(1):12. doi:10.1186/s12944-0180659.

38. Raal FJ, Santos RD Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, doubleblind, placebocontrolled trial. Lancet. 2010;375: 998-1006. doi:10.1016/S0140-6736(10)60284-X

39. Visser ME, Kastelein JJ, Stroes ES. Apolipoprotein B synthesis inhibition: results from clinical trials. Curr. Opin. Lipidol. 2010;21(4):319-23. doi:10.1097/MOL.0b013e32833af4c1.

40. Vickers TA, Lima WF, Nichols JG, et al. Reduced levels of Ago2 expression result in increased siRNA competition in mammalian cells. Nucleic Acids Res. 2007;35:6598-610.

41. Aagaard L, Rossi JJ. RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007;59(2-3):75-86.

42. Garber K. Alnylam terminates revusiran program, stock plunges. Nat Biotechnol. 2016;34(12):1213-4. doi:10.1038/nbt1216-1213.

43. Nordestgaard BG, Nicholls SJ, 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.

44. Ecker D., Jones S., Levine H. The therapeutic monoclonal antibody market. MAbs 2015;7:9-14. doi:10.4161/19420862.2015.989042.

45. Nicholls SJ, 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;316(22):2373-84. doi:10.1001/jama.2016.16951.

46. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study. JAMA Cardiol. 2017;2(6):598-607. doi:10.1001/jamacardio.2017.0747.

47. Sabatine MS, Giugliano RP, Keech AC, et al. FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-22. doi:10.1056/NEJMoa1615664.

48. Giugliano RP, Pedersen TR, Park JG, et al. FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):1962-71. doi:10.1016/S0140-6736(17)32290-0.

49. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941-50. doi:10.1016/S2213-8587(17)30313-3.

50. Bonaca MP, Nault P, Giugliano RP, et al. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation. 2018;137(4):338-50. doi:10.1161/CIRCULATIONAHA.117.032235.

51. Giugliano RP, Mach F, Zavitz K, et al. EBBINGHAUS Investigators. 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;40(2):59-65. doi:10.1002/clc.22678.

52. Robinson J, Rosenson RS, Farnier M, et al. Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab: Pooled Data From Randomized Trials. J. Am. Coll. Cardiol., 2017;69(5):471-82. doi:10.1016/j.jacc.2016.11.037.

53. 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(5):682-9. doi:10.1016/j.ahj.2014.07.028.

54. Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J. 2016;37(48):3588-95. doi:10.1093/eurheartj/ehw388.

55. Dewey FE, Gusarova V, Dunbar RL, et al Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017;377(3):211-21. doi:10.1056/ NEJMoa1612790.

56. Saonere J. Antisense therapy, a magic bullet for the treatment of various diseases: Present and future prospects. Journal of Medical Genetics and Genomics. 2011;3(5):77-83.