Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia
Abstract
:1. Introduction
2. siRNAs: Mechanism of Action
3. Inclisiran
4. Clinical Trials with Inclisiran
5. Conclusions and Future Directions
Funding
Conflicts of Interest
References
- World Health Organization. Cardiovascular Diseases (CVDs). Available online: http://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (accessed on 17 May 2017).
- O’Keefe, J.H., Jr.; Cordain, L.; Harris, W.H.; Moe, R.M.; Vogel, R. Optimal low-density lipoprotein is 50 to 70 mg/dL: Lower is better and physiologically normal. J. Am. Coll. Cardiol. 2004, 43, 2142–2146. [Google Scholar] [CrossRef] [PubMed]
- LaRosa, J.C.; Grundy, S.M.; Waters, D.D.; Shear, C.; Barter, P.; Fruchart, J.C.; Gotto, A.M.; Greten, H.; Kastelein, J.J.; Shepherd, J.; et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 2005, 352, 1425–1435. [Google Scholar] [CrossRef] [PubMed]
- Waters, D.D. What the statin trials have taught us. Am. J. Cardiol. 2006, 98, 129–134. [Google Scholar] [CrossRef] [PubMed]
- Grundy, S.M.; Cleeman, J.I.; Merz, C.N.; Brewer, H.B., Jr.; Clark, L.T.; Hunninghake, D.B.; Pasternak, R.C.; Smith, S.C., Jr.; Stone, N.J.; National Heart, Lung, and Blood Institute; et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004, 110, 227–239. [Google Scholar] [CrossRef] [PubMed]
- Ridker, P.M.; Mora, S.; Rose, L.; JUPITER Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: Potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur. Heart J. 2016, 7, 1373–1379. [Google Scholar] [CrossRef] [PubMed]
- Martin, S.S.; Gosch, K.; Kulkarni, K.R.; Spertus, J.A.; Mathews, R.; Ho, P.M.; Maddox, T.M.; Newby, L.K.; Alexander, K.P.; Wang, T.Y. Modifiable factors associated with failure to attain low-density lipoprotein cholesterol goal at 6 months after acute myocardial infarction. Am. Heart J. 2013, 165, 26–33. [Google Scholar] [CrossRef] [PubMed]
- Virani, S.S.; Woodard, L.D.; Chitwood, S.S.; Landrum, C.R.; Urech, T.H.; Wang, D.; Murawsky, J.; Ballantyne, C.M.; Petersen, L.A. Frequency and correlates of treatment intensification for elevated cholesterol levels in patients with cardiovascular disease. Am. Heart J. 2011, 162, 725–732. [Google Scholar] [CrossRef] [PubMed]
- Cohen, J.D.; Brinton, E.A.; Ito, M.K.; Jacobson, T.A. Understanding Statin Use in America and Gaps in Patient Education (USAGE): An internet-based survey of 10,138 current and former statin users. J. Clin. Lipidol. 2012, 6, 208–215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kosmas, C.E.; Frishman, W.H. New and emerging LDL cholesterol-lowering drugs. Am. J. Ther. 2015, 22, 234–241. [Google Scholar] [CrossRef] [PubMed]
- Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S.B.; Stifani, S.; Basak, A.; Prat, A.; Chretien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA 2003, 100, 928–933. [Google Scholar] [CrossRef] [PubMed]
- Leren, T.P. Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis 2014, 237, 76–81. [Google Scholar] [CrossRef] [PubMed]
- Cohen, J.C.; Boerwinkle, E.; Mosley, T.H., Jr.; Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 2006, 354, 1264–1272. [Google Scholar] [CrossRef] [PubMed]
- Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med. 2017, 376, 1713–1722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Steg, P.G. Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome during Treatment with Alirocumab—ODYSSEY OUTCOMES. In Proceedings of the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, USA, 10–12 March 2018. [Google Scholar]
- Carthew, R.W.; Sontheimer, E.J. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009, 136, 642–655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bernards, R. Exploring the uses of RNAi-gene knockdown and the Nobel Prize. N. Engl. J. Med. 2006, 355, 2391–2393. [Google Scholar] [CrossRef] [PubMed]
- Agrawal, N.; Dasaradhi, P.V.; Mohmmed, A.; Malhotra, P.; Bhatnagar, R.K.; Mukherjee, S.K. RNA interference: Biology, mechanism, and applications. Microbiol. Mol. Biol. Rev. 2003, 67, 657–685. [Google Scholar] [CrossRef] [PubMed]
- Ciccarelli, G.; D’Elia, S.; De Paulis, M.; Golino, P.; Cimmino, G. Lipid Target in Very High-Risk Cardiovascular Patients: Lesson from PCSK9 Monoclonal Antibodies. Diseases 2018, 6, 22. [Google Scholar] [CrossRef] [PubMed]
- Kosmas, C.E.; DeJesus, E.; Morcelo, R.; Garcia, F.; Montan, P.D.; Guzman, E. Lipid-lowering interventions targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): An emerging chapter in lipid-lowering therapy. Drugs Context 2017, 6, 212511. [Google Scholar] [CrossRef] [PubMed]
- Nair, J.K.; Willoughby, J.L.; Chan, A.; Charisse, K.; Alam, M.R.; Wang, Q.; Hoekstra, M.; Kandasamy, P.; Kel’in, A.V.; Milstein, S.; et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 2014, 136, 16958–16961. [Google Scholar] [CrossRef] [PubMed]
- Fitzgerald, K.; Frank-Kamenetsky, M.; Shulga-Morskaya, S.; Liebow, A.; Bettencourt, B.R.; Sutherland, J.E.; Hutabarat, R.M.; Clausen, V.A.; Karsten, V.; Cehelsky, J.; et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: A randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014, 383, 60–68. [Google Scholar] [CrossRef]
- Fitzgerald, K.; White, S.; Borodovsky, A.; Bettencourt, B.R.; Strahs, A.; Clausen, V.; Wijngaard, P.; Horton, J.D.; Taubel, J.; Brooks, A.; et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N. Engl. J. Med. 2017, 376, 41–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ray, K.K.; Landmesser, U.; Leiter, L.A.; Kallend, D.; Dufour, R.; Karakas, M.; Hall, T.; Troquay, R.P.; Turner, T.; Visseren, F.L.; et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 2017, 376, 1430–1440. [Google Scholar] [CrossRef] [PubMed]
- Inclisiran for Subjects with ACSVD or ACSVD-Risk Equivalents and Elevated Low-Density Lipoprotein Cholesterol (ORION-11). ClinicalTrials.gov Identifier: NCT03400800. Available online: http://clinicaltrials.gov/ct2/show/NCT03400800 (accessed on 26 April 2018).
- The Medicines Company. The Medicines Company and Alnylam Pharmaceuticals Announce Initiation of Phase III Clinical Trials of Inclisiran. Available online: http://www.themedicinescompany.com/investors/news/medicines-company-and-alnylam-pharmaceuticals-announce-initiation-phase-iii-clinical (accessed on 6 November 2017).
- Bandyopadhyay, D.; Hajra, A.; Ashish, K.; Qureshi, A.; Ball, S. New hope for hyperlipidemia management: Inclisiran. J. Cardiol. 2018, 71, 523–524. [Google Scholar] [CrossRef] [PubMed]
- Chi, X.; Gatti, P.; Papoian, T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov. Today 2017, 22, 823–833. [Google Scholar] [CrossRef] [PubMed]
- Giugliano, R.P.; Sabatine, M.S. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field? J. Am. Coll. Cardiol. 2015, 65, 2638–2651. [Google Scholar] [CrossRef] [PubMed]
- Landlinger, C.; Pouwer, M.G.; Juno, C.; van der Hoorn, J.W.A.; Pieterman, E.J.; Jukema, J.W.; Staffler, G.; Princen, H.M.G.; Galabova, G. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur. Heart J. 2017, 38, 2499–2507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kosmas, C.E.; Muñoz Estrella, A.; Sourlas, A.; Silverio, D.; Hilario, E.; Montan, P.D.; Guzman, E. Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases 2018, 6, 63. https://doi.org/10.3390/diseases6030063
Kosmas CE, Muñoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E. Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia. Diseases. 2018; 6(3):63. https://doi.org/10.3390/diseases6030063
Chicago/Turabian StyleKosmas, Constantine E., Alba Muñoz Estrella, Andreas Sourlas, Delia Silverio, Elizabeth Hilario, Peter D. Montan, and Eliscer Guzman. 2018. "Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia" Diseases 6, no. 3: 63. https://doi.org/10.3390/diseases6030063