Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia

References

• World Health Organization. Top 10 causes of death. Geneva: WHO; 2018.
   Google Scholar
• Toth PP, Banach M. Statins: then and now. Methodist Debakey Cardiovasc J. 2019 Jan-Mar;15(1):23–31.
   PubMedGoogle Scholar
• Toth PP, Patti AM, Giglio RV, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018 Jun;18(3):157–173.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Khan I, Klimchak AC, et al. Simulation of lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017 Sep 1;2(9):959–966.
   PubMed Web of Science ®Google Scholar
• Ference BA, Ginsberg HN, 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 Aug 21;38(32):2459–2472.
   Web of Science ®Google Scholar
• Cohen JC, Boerwinkle E, Mosley TH Jr., et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006 Mar 23;354(12):1264–1272.
   PubMed Web of Science ®Google Scholar
• Banach M, Rizzo M, Obradović M, et al. PCSK9 inhibition - A novel mechanism to treat lipid disorders? Curr Pharm Des. 2013;19:3869–3877.
   Web of Science ®Google Scholar
• Chaudhary R, Garg J, Shah N, et al. PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol. 2017 Feb 26;9(2):76–91.
   PubMed Web of Science ®Google Scholar
• Watts GF, Chan DC, Dent R, et al. Factorial effects of evolocumab and atorvastatin on lipoprotein metabolism. Circulation. 2017 Jan 24;135(4):338–351.
   PubMed Web of Science ®Google Scholar
• Reyes-Soffer G, Pavlyha M, Ngai C, et al. Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans. Circulation. 2017 Jan 24;135(4):352–362.
   PubMed Web of Science ®Google Scholar
• Karagiannis AD, Liu M, Toth PP, et al. Pleiotropic anti-atherosclerotic effects of PCSK9 inhibitors from molecular biology to clinical translation. Curr Atheroscler Rep. 2018 Mar 10;20(4):20.
   PubMed Web of Science ®Google Scholar
• Wittrup A, Lieberman J. Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet. 2015 Sep;16(9):543–552.
   PubMed Web of Science ®Google Scholar
• Cohen JD, Cziraky MJ, Jacobson TA, et al. Barriers to PCSK9 inhibitor prescriptions for patients with high cardiovascular risk: results of a healthcare provider survey conducted by the National Lipid Association. J Clin Lipidol. 2017 Jul - Aug;11(4):891–900.
   PubMed Web of Science ®Google Scholar
• Baum SJ, Toth PP, Underberg JA, et al. PCSK9 inhibitor access barriers-issues and recommendations: improving the access process for patients, clinicians and payers. Clin Cardiol. 2017 Apr;40(4):243–254.
   PubMed Web of Science ®Google Scholar
• Banach M, Rizzo M, Toth PP, et al. Statin intolerance – an attempt at a unified definition. Position paper from an international lipid expert panel. Arch Med Sci. 2015;11:1–23.
   PubMed Web of Science ®Google Scholar
• Banach M, Patti AM, Giglio RV, et al. International lipid expert panel (ILEP). The role of nutraceuticals in statin intolerant patients. J Am Coll Cardiol. 2018;72:96–118.
   PubMed Web of Science ®Google Scholar
• Banerjee Y, Santos RD, Al-Rasadi K, et al. Targeting PCSK9 for therapeutic gains: have we addressed all the concerns? Atherosclerosis. 2016 May;248:62–75.
   PubMed Web of Science ®Google Scholar
• Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009 Feb 20;136(4):642–655.
   PubMed Web of Science ®Google Scholar
• Bernards R. Exploring the uses of RNAi–gene knockdown and the nobel prize. N Engl J Med. 2006 Dec 7;355(23):2391–2393.
   PubMed Web of Science ®Google Scholar
• Siomi H, Siomi MC. On the road to reading the RNA-interference code. Nature. 2009 Jan 22;457(7228):396–404.
   PubMed Web of Science ®Google Scholar
• Liu J, Carmell MA, Rivas FV, et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004 Sep 3;305(5689):1437–1441.
   PubMed Web of Science ®Google Scholar
• Meister G. Argonaute proteins: functional insights and emerging roles. Nat Rev Genet. 2013 Jul;14(7):447–459.
   PubMed Web of Science ®Google Scholar
• Sledz CA, Holko M, De Veer MJ, et al. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol. 2003 Sep;5(9):834–839.
   PubMed Web of Science ®Google Scholar
• Ozcan G, Ozpolat B, Coleman RL, et al. Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev. 2015 Jun;29(87):108–119.
   Google Scholar
• Rand TA, Petersen S, Du F, et al. Argonaute2 cleaves the anti-guide strand of siRNA during RISC activation. Cell. 2005 Nov 18;123(4):621–629.
   PubMed Web of Science ®Google Scholar
• Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov. 2010 Jan;9(1):57–67.
   PubMed Web of Science ®Google Scholar
• Behlke MA. Chemical modification of siRNAs for in vivo use. Oligonucleotides. 2008 Dec;18(4):305–319.
   PubMed Web of Science ®Google Scholar
• Shen X, Corey DR. Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 2018 Feb 28;46(4):1584–1600.
   PubMed Web of Science ®Google Scholar
• Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009 Feb;8(2):129–138.
   PubMed Web of Science ®Google Scholar
• Alexis F, Pridgen E, Molnar LK, et al. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008 Jul-Aug;5(4):505–515.
   PubMed Web of Science ®Google Scholar
• Huang X, Leroux JC, Castagner B. Well-defined multivalent ligands for hepatocytes targeting via asialoglycoprotein receptor. Bioconjug Chem. 2017 Feb 15;28(2):283–295.
   PubMed Web of Science ®Google Scholar
• Wang N, Tall AR, New A. Approach to PCSK9 Therapeutics. Circ Res. 2017;120(7):1063–1065.
   PubMed Web of Science ®Google Scholar
• Nishikido T, Ray KK. Inclisiran for the treatment of dyslipidemia. Expert Opin Investig Drugs. 2018 Mar;27(3):287–294.
   PubMed Web of Science ®Google Scholar
• Akinc A, Zumbuehl A, Goldberg M, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol. 2008 May;26(5):561–569.
   PubMed Web of Science ®Google Scholar
• 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 U S A. 2008 Aug 19;105(33):11915–11920.
   PubMed Web of Science ®Google Scholar
• 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 Jan 4;383(9911):60–68.
   PubMed Web of Science ®Google Scholar
• Springer AD, Dowdy SF. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 2018;28(3):109–118.
   PubMed Web of Science ®Google Scholar
• 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(49):16958–16961.
   PubMed Web of Science ®Google Scholar
• Lamb YN. Inclisiran: first Approval. Drugs. 2021;81(3):389–395.
   PubMed Web of Science ®Google Scholar
• 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 Dec 10;136(49):16958–16961.
   PubMed Web of Science ®Google Scholar
• Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017 Apr 13;376(15):1430–1440.
   PubMed Web of Science ®Google Scholar
• Fitzgerald K, White S, Borodovsky A, et al. RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2017Jan5;376(1):41–51.
   PubMed Web of Science ®Google Scholar
• German CA, Shapiro MD. Small interfering RNA therapeutic inclisiran: a new approach to targeting PCSK9. BioDrugs. 2020 Feb;34(1):1–9.
   PubMed Web of Science ®Google Scholar
• Wright RS, Collins MG, Stoekenbroek RM, 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 Clin Proc. 2020Jan;95(1):77–89. Epub 2019 Oct 17.
   PubMed Web of Science ®Google Scholar
• Ray K, Landmesser U, Leiter L, et al. Impact of a 1-or 2-dose starting regimen of Inclisiran, a novel siRNA inhibitor to PCSK9 on time averaged LDL-C reductions over 1 year. 2018.
   Google Scholar
• 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 Aug 5;64(5):485–494.
   PubMed Web of Science ®Google Scholar
• Hovingh GK, Lepor NE, Kallend D, et al. Inclisiran durably lowers low-density lipoprotein cholesterol and proprotein convertase subtilisin/Kexin type 9 expression in homozygous familial hypercholesterolemia: the ORION-2 pilot study. Circulation. 2020 Jun 2;141(22):1829–1831.
   PubMed Web of Science ®Google Scholar
• Kastelein JJ Interim Results of The Medicines Company’s ORION-3 Study of Inclisiran Presented at National Lipid Association Scientific Sessions. National Lipid Association Scientific Sessions; Miami 2019.
   Google Scholar
• Brandts J, Ray KK. Clinical implications and outcomes of the ORION Phase III trials. Future Cardiol. 2020 Dec 21. doi:https://doi.org/10.2217/fca-2020-0150. Online ahead of print.
   Google Scholar
• Raal FJ, Kallend D, Ray KK, et al. ORION-9 investigators. inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020 Apr 16;382(16):1520–1530.
   PubMed Web of Science ®Google Scholar
• KK R, Wright RS, Kallend D, et al. ORION-10 and ORION-11 Investigators. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020Apr16;382(16):1507–1519.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Leqvio 284 mg solution for injection in pre-filled syringe: summary of product characteristics. 2021. http://www.ema.europa.eu/. cited 2021 Jul 6
   Google Scholar
• Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–742.
   PubMed Web of Science ®Google Scholar
• Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–1929.
   PubMed Web of Science ®Google Scholar
• Thakker D, Nair S, Pagada A, et al. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf. 2016;25(10):1131–1149.
   PubMed Web of Science ®Google Scholar
• Thakker D, Nair SR, Shukla H, et al. Statin use and risk of developing diabetes in cardiovascular disease: systematic literature review and meta-analysis. Value Health. 2014;17(7):A478.
   PubMed Web of Science ®Google Scholar
• Peng J, Zhu CG, Li JJ. The predictive utility of circulating PCSK9 levels on diabetes mellitus. Cardiovasc Diabetol. 2021;20(1):45.
   PubMed Web of Science ®Google Scholar
• Leiter LA, Teoh H, Kallend D, et al. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: the ORION-1 randomized clinical trial. Diabetes Care. 2019;42(1):173–176.
   PubMed Web of Science ®Google Scholar
• Dijk W, Le May C, Cariou B, et al. what role for PCSK9 in triglyceride-rich lipoprotein metabolism? Trends Endocrinol Metab. 2018;29(6):420–434.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Kei A, Rizos CV, et al. Effects of PCSK9 inhibitors on other than low-density lipoprotein cholesterol lipid variables. J Cardiovasc Pharmacol Ther. 2018;23(1):3–12.
   PubMed Web of Science ®Google Scholar
• Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol. 2015;9:129–169.
   PubMed Web of Science ®Google Scholar
• U.S. National Libraries of Medicine. An extension trial of inclisiran compared to evolocumab in participants with cardiovascular disease and high cholesterol (2018) https://clinicaltrials.gov/ct2/show/NCT03060577. cited 2021 Jul 6
   Google Scholar
• Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res. 2002;43(9):1363–1379.
   PubMed Web of Science ®Google Scholar
• Rizzo M, Nikolic D, Patti AM, et al. GLP-1 receptor agonists and reduction of cardiometabolic risk: potential underlying mechanisms. Biochim Biophys Acta Mol Basis Dis. 2018;1864(9):2814–2821.
   PubMed Web of Science ®Google Scholar
• Corrado E, Rizzo M, Coppola G, et al. Endothelial dysfunction and carotid lesions are strong predictors of clinical events in patients with early stages of atherosclerosis: a 24-month follow-up study. Coron Artery Dis. 2008;19(3):139–144.
   PubMed Web of Science ®Google Scholar
• Rizzo M, and Berneis K. Who needs to care about small, dense low-density lipoproteins? Int J Clin Pract. 2007;61(11):1949–1956. DOI: https://doi.org/10.1111/j.1742-1241.2007.01596.x.
   PubMed Web of Science ®Google Scholar
• Rizzo M, Berneis K, Altinova AE, et al. Atherogenic lipoprotein phenotype and LDL size and subclasses in women with gestational diabetes. Diabet Med. 2008;25(12):1406–1411.
   PubMed Web of Science ®Google Scholar
• Rizzo M, Spinas Ga, Cesur M, et al. Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naïve patients with early rheumatoid arthritis. Atherosclerosis. 2009;207(2):502–506.
   PubMed Web of Science ®Google Scholar
• Goedecke JH, Utzschneider K, Faulenbach MV, et al. Ethnic differences in serum lipoproteins and their determinants in South African women. Metabolism. 2010;59:1341–1350.
   PubMed Web of Science ®Google Scholar
• Rizzo M, Pernice V, Frasheri A, et al. Atherogenic lipoprotein phenotype and LDL size and subclasses in patients with peripheral arterial disease. Atherosclerosis. 2008;197:237–241.
   PubMed Web of Science ®Google Scholar
• Shapiro MD, Miles J, Tavori H, et al. Diagnosing resistance to a proprotein convertase subtilisin/Kexin type 9 inhibitor. Ann Intern Med. 2018;168(5):376–379.
   PubMed Web of Science ®Google Scholar
• Qamar A, Giugliano RP, Keech AC, et al. Interindividual variation in low-density lipoprotein cholesterol level reduction with evolocumab: an analysis of Fourier trial data. JAMA Cardiol. 2019;4:59–63.
   PubMed Web of Science ®Google Scholar
• Bays HE, Rosenson RS, Baccara-Dinet MT, et al. Assessment of the 1% of patients with consistent < 15% reduction in low-density lipoprotein cholesterol: pooled analysis of 10 phase 3 ODYSSEY alirocumab trials. Cardiovasc Drugs Ther. 2018;32:175–180.
   PubMed Web of Science ®Google Scholar
• Toth PP, Hamon Sc, Jones SR, et al. Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo. Lipids Health Dis. 2016;15:28–28.
   PubMed Web of Science ®Google Scholar
• Toth PP, Sattar N, Blom DJ, et al. Effect of evolocumab on lipoprotein particles. Am J Cardiol. 2018 Feb 1;121(3):308–314.
   PubMed Web of Science ®Google Scholar
• Rizzo M, Barylski M, Rizvi AA, et al. Combined Dyslipidemia: should the focus be LDL cholesterol or atherogenic dyslipidemia? Curr Pharm Des. 2013;19:3858–3868.
   Web of Science ®Google Scholar
• Barylski M, Toth PP, Nikolic D, et al. Emerging therapies for raising high-density lipoprotein cholesterol (HDL-C) and augmenting HDL particle functionality. Best Pract Res Clin Endocrinol Metab. 2014 Jun;28(3):453–461.
   PubMed Web of Science ®Google Scholar
• Bayram F, Kocer D, Gundogan K, et al. Prevalence of dyslipidemia and associated risk factors in Turkish adults. J Clin Lipidol. 2014;8:206–216.
   PubMed Web of Science ®Google Scholar
• Toth PP, Barylski M, Nikolic D, et al. Should low high-density lipoprotein cholesterol (HDL-C) be treated? Best Pract Res Clin Endocrinol Metab. 2014;28:353–368.
   PubMed Web of Science ®Google Scholar
• Tomari Y, Matranga C, Haley B, et al. A protein sensor for siRNA asymmetry. Science. 2004;306:1377–1380.
   PubMed Web of Science ®Google Scholar