Inclisiran: A Small Interfering RNA for Treating Hypercholesterolemia
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Abstract
Hyperlipidemia is one of important risk factors for cardiovascular diseases (CVDs), which are among main causes of death. Lipid-lowering drugs play a crucial role in reducing cholesterol levels and the risk of CVDs. However, there are some patients who received lipid-lowering drugs but did not achieve their target cholesterol levels or may not tolerate the side effects of current lipid-lowering drugs. Recently, efforts in drug discovery and development have focused on developing new drugs to improve the effectiveness of treatment and provide alternative regimens for patients who cannot tolerate existing drugs.
Inclisiran is a novel lipid-lowering drug that inhibits the production of proprotein convertase subtilisin/kexin type 9 (PCSK9) at the genetic level by using small interfering RNA (siRNA). It is effective in reducing low-density lipoprotein cholesterol (LDL-C) levels in patients who have CVDs or familial hypercholesterolemia and have reached the maximum dose of statins but are still unable to achieve their LDL-C target levels or cannot tolerate statins side effect. Inclisiran can be administered as a subcutaneous injection every six months, and no serious side effects have been observed. However, injection site pain, redness, or swelling are the most commonly reported local adverse reactions.
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References
American Heart Association. What is Atherosclerosis? [Internet]. 2020. [cited 2023 Dec 6]. Available from: https://www.heart.org/en/health-topics/cholesterol/about-cholesterol/atherosclerosis
Suwannabupha S, Kamsa-ard S. Incident and Associated Factors of Dyslipidemia in Personnel of Faculty of Medicine, Khon Kaen University. Srinagarind Med J. 2021;36(3):317-27.
Davidson MH, Pradeep P. Overview of Lipid Metabolism [Internet]. 2023. [cited 2023 Dec 7]. Available from: https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/lipid-disorders/overview-of-lipid-metabolism
Michaeli DT, Michaeli JC, Albers S, Boch T, Michaeli T. Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention. Am J Cardiovasc Drugs. 2023;23(5):477-95.
Natesan V, Kim S-J. Lipid Metabolism, Disorders and Therapeutic Drugs - Review. Biomol Ther (Seoul). 2021;29(6):596-604.
Hajar R. PCSK 9 Inhibitors: A Short History and a New Era of Lipid-lowering Therapy. Heart Views. 2019;20(2):74-5.
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161-5.
Riam-Amatakun W, Nuntharatanapong N. Development of PCSK9 inhibitor to lower LDL-cholesterol. Thai Bull Pharm Sci. 2018;13(1):105-23. Thai.
Wołowiec Ł, Osiak J, Wołowiec A, Wijata A, Grześk E, Kozakiewicz M, et al. Inclisiran- Safety and Effectiveness of Small interfering RNA in inhibition of PCSK-9. Pharmaceutics. 2023;15(2):323.
Lamb YN. Inclisiran: First Approval. Drugs. 2021;81(3):389-95.
Ebenezer O, Comoglio P, Wong GK, Tuszynski JA. Development of Novel siRNA Therapeutics: A Review with a Focus on Inclisiran for the Treatment of Hypercholesterolemia. Int J Mol Sci. 2023;24(4)4019.
Novartis Pharmaceuticals Corporation. LEQVIO® (inclisiran) injection, for subcutaneous use. In: Drugs@ FDA: FDA-Approved Drugs [Internet]. n.p.: U.S. Food and Drug Administration; 2021 [cited 2023 Dec 7]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214012lbl.pdf
Novartis. Professional Information-Sybrava Injection [Internet]. 2022 [cited 2023 Dec 7]. Available from: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2023/01/Final_PI_SYBRAVA_Applicant.pdf
Nishikido T, Ray KK. Targeting the peptidase PCSK9 to reduce cardiovascular risk: Implications for basic science and upcoming challenges. Br J Pharmacol. 2021;178(11):2168-85.
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430-40.
Ray KK, Troquay RPT, Visseren FLJ, Leiter LA, Scott Wright R, Vikarunnessa S, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023;11(2):109-19.
Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520-30.
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. N Engl J Med. 2020;382(16):1507-19.
Huo Y, Lesogor A, Lee CW, Chiang CE, Mena-Madrazo J, Poh KK, et al. Efficacy and Safety of Inclisiran in Asian Patients: Results From ORION-18. JACC Asia. 2024;4(2):123-34.
Bowman L, Mafham M, Preiss D, Landray M. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4). ClinicalTrials.gov [Preprint]. 2023 [cited 2023 Dec 10]. Available from: https://clinicaltrials.gov/study/NCT03705234.
Novartis Pharmaceuticals. Study of Inclisiran to Prevent Cardiovascular (CV) Events in Participants with Established Cardiovascular Disease (VICTORION-2P). ClinicalTrials.gov [Preprint]. 2023 [cited 2023 Dec 10]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05030428
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350.
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. Eur Heart J. 2020;41(1):111-88.
Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-418.