Inclisiran – a new era in lipid-lowering therapy

Inclisiran is a novel hypolipidemic drug that inhibits synthesis of the PCSK9 protein through the process called RNA interference. Inclisiran is a double-stranded, modified RNA bound to the N-acetylgalactosamine (GalNAc) carbohydrate molecule, a ligand of the acialoglycoprotein receptor, that is expressed by hepatocytes. After entering hepatocytes, inclisiran cleaves matrix RNA and, thereby, reduces the PCSK9 protein synthesis. This, in turn, enhances the uptake of circulating low-density lipoproteins (LDL) by specific receptors on hepatocytes, thereby lowering LDL levels in circulation. Efficacy and safety of inclisiran for lowering LDL cholesterol (C) in blood and its effect on the risk of clinical complications of atherosclerosis have been studied in the ORION program that includes multiple clinical trials. According to results of this program, inclisiran effectively reduces both LDL-C levels and the incidence of cardiovascular complications in the absence of clinically significant adverse reactions. An important advantage of inclisiran compared with other lipid-lowering drugs is the administration schedule (twice a year), which allows a considerable improvement of patients’ compliance with the treatment and also of the effectiveness of the hypolipidemic treatment.

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170000 participants in 26 randomised trials. The Lancet. 2010;376(9753):1670–81. DOI: 10.1016/S0140-6736(10)61350-5

2. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European Heart Journal. 2020;41(1):111–88. DOI: 10.1093/eurheartj/ehz455

3. Waters DD, Brotons C, Chiang C-W, Ferrières J, Foody J, Jukema JW et al. Lipid Treatment Assessment Project 2: A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals. Circulation. 2009;120(1):28–34. DOI: 10.1161/CIRCULATIONAHA.108.838466

4. Gitt AK, Lautsch D, Ferrieres J, Kastelein J, Drexel H, Horack M et al. Low-density lipoprotein cholesterol in a global cohort of 57,885 statintreated patients. Atherosclerosis. 2016;255:200–9. DOI: 10.1016/j.atherosclerosis.2016.09.004

5. Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M et al. Discontinuation of Statins in Routine Care Settings: A Cohort Study. Annals of Internal Medicine. 2013;158(7):526–34. DOI: 10.7326/0003-4819-158-7-201304020-00004

6. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease. New England Journal of Medicine. 2006;354(12):1264–72. DOI: 10.1056/NEJMoa054013

7. Banach M, Rizzo M, Obradovic M, Montalto G, Rysz J, Mikhailidis DP et al. PCSK9 Inhibition - A Novel Mechanism to Treat Lipid Disorders? Current Pharmaceutical Design. 2013;19(21):3869–77. DOI: 10.2174/13816128113199990303

8. Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid lowering therapy. World Journal of Cardiology. 2017;9(2):76–91. DOI: 10.4330/wjc.v9.i2.76

9. Watts GF, Chan DC, Dent R, Somaratne R, Wasserman SM, Scott R et al. Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism. Circulation. 2017;135(4):338–51. DOI: 10.1161/CIRCULATIONAHA.116.025080

10. Reyes-Soffer G, Pavlyha M, Ngai C, Thomas T, Holleran S, Ramakrishnan R et al. Effects of PCSK9 Inhibition with Alirocumab on Lipoprotein Metabolism in Healthy Humans. Circulation. 2017;135(4):352–62. DOI: 10.1161/CIRCULATIONAHA.116.025253

11. Karagiannis AD, Liu M, Toth PP, Zhao S, Agrawal DK, Libby P et al. Pleiotropic Anti-atherosclerotic Effects of PCSK9 Inhibitors From Molecular Biology to Clinical Translation. Current Atherosclerosis Reports. 2018;20(4):20. DOI: 10.1007/s11883-018-0718-x

12. Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K et al. Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Archives of Medical Science. 2015;11(1):1–23. DOI: 10.5114/aoms.2015.49807

13. Banach M, Patti AM, Giglio RV, Cicero AFG, Atanasov AG, Bajraktari G et al. The Role of Nutraceuticals in Statin Intolerant Patients. Journal of the American College of Cardiology. 2018;72(1):96–118. DOI: 10.1016/j.jacc.2018.04.040

14. Banerjee Y, Santos RD, Al-Rasadi K, Rizzo M. Targeting PCSK9 for therapeutic gains: Have we addressed all the concerns? Atherosclerosis. 2016;248:62–75. DOI: 10.1016/j.atherosclerosis.2016.02.018

15. Wittrup A, Lieberman J. Knocking down disease: a progress report on siRNA therapeutics. Nature Reviews Genetics. 2015;16(9):543–52. DOI: 10.1038/nrg3978

16. Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–55. DOI: 10.1016/j.cell.2009.01.035

17. Bernards R. Exploring the Uses of RNAi – Gene Knockdown and the Nobel Prize. New England Journal of Medicine. 2006;355(23):2391–3. DOI: 10.1056/NEJMp068242

18. Siomi H, Siomi MC. On the road to reading the RNA-interference code. Nature. 2009;457(7228):396–404. DOI: 10.1038/nature07754

19. Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song J-J et al. Argonaute2 Is the Catalytic Engine of Mammalian RNAi. Science. 2004;305(5689):1437–41. DOI: 10.1126/science.1102513

20. Meister G. Argonaute proteins: functional insights and emerging roles. Nature Reviews Genetics. 2013;14(7):447–59. DOI: 10.1038/nrg3462

21. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BRG. Activation of the interferon system by short-interfering RNAs. Nature Cell Biology. 2003;5(9):834–9. DOI: 10.1038/ncb1038

22. Ozcan G, Ozpolat B, Coleman RL, Sood AK, Lopez-Berestein G. Preclinical and clinical development of siRNA-based therapeutics. Advanced Drug Delivery Reviews. 2015;87: 108–19. DOI: 10.1016/j.addr.2015.01.007

23. Rand TA, Petersen S, Du F, Wang X. Argonaute2 Cleaves the Anti-Guide Strand of siRNA during RISC Activation. Cell. 2005;123(4):621–9. DOI: 10.1016/j.cell.2005.10.020

24. Huang X, Leroux J-C, Castagner B. Well-Defined Multivalent Ligands for Hepatocytes Targeting via Asialoglycoprotein Receptor. Bioconjugate Chemistry. 2017;28(2):283–95. DOI: 10.1021/acs.bioconjchem.6b00651

25. Wang N, Tall AR. A New Approach to PCSK9 Therapeutics. Circulation Research. 2017;120(7):1063–5. DOI: 10.1161/CIRCRESAHA.117.310610

26. Cupido AJ, Kastelein JP. Inclisiran for the treatment of hypercholesterolaemia: implications and unanswered questions from the ORION trials. Cardiovascular Research (2020) 116, e136–e139; doi:10.1093/cvr/cvaa212

27. Nishikido T, Ray KK. Inclisiran for the treatment of dyslipidemia. Expert Opinion on Investigational Drugs. 2018;27(3):287–94. DOI: 10.1080/13543784.2018.1442435

28. Springer AD, Dowdy SF. GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Therapeutics. 2018;28(3):109–18. DOI: 10.1089/nat.2018.0736

29. Nair JK, Willoughby JLS, Chan A, Charisse K, Alam MdR, Wang Q et al. Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing. Journal of the American Chemical Society. 2014;136(49):16958–61. DOI: 10.1021/ja505986a

30. Lamb YN. Inclisiran: First Approval. Drugs. 2021;81(3):389–95. DOI: 10.1007/s40265-021-01473-6

31. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proceedings of the National Academy of Sciences. 2008;105(33):11915–20. DOI: 10.1073/pnas.0805434105

32. Banerjee Y, Pantea Stoian A, Cicero AFG, Fogacci F, Nikolic D, Sachinidis A et al. Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia. Expert Opinion on Drug Safety. 2022;21(1):9–20. DOI: 10.1080/14740338.2022.1988568

33. Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. New England Journal of Medicine. 2020;382(16):1520–30. DOI: 10.1056/NEJMoa1913805

34. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. New England Journal of Medicine. 2020;382(16):1507–19. DOI: 10.1056/NEJMoa1912387

35. Khan SA, Naz A, Qamar Masood M, Shah R. Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia. The American Journal of Cardiology. 2020;134:69–73. DOI: 10.1016/j.amjcard.2020.08.018

36. Kallend D, Stoekenbroek R, He Y, Smith PF, Wijngaard P. Pharmacokinetics and pharmacodynamics of inclisiran, a small interfering RNA therapy, in patients with hepatic impairment. Journal of Clinical Lipidology. 2022;16(2):208–19. DOI: 10.1016/j.jacl.2022.01.001

37. Wright RS, Collins MG, Stoekenbroek RM, Robson R, Wijngaard PLJ, Landmesser U et al. Effects of Renal Impairment on the Pharmacokinetics, Efficacy, and Safety of Inclisiran: An Analysis of the ORION-7 and ORION-1 Studies. Mayo Clinic Proceedings. 2020;95(1):77–89. DOI: 10.1016/j.mayocp.2019.08.021

38. Leng G. Radical or not, NICE makes evidence based recommendations. BMJ. 2021;375:n2831. DOI: 10.1136/bmj.n2831