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inclisiran (Leqvio, ALN-PCS)

Indications: - experimental siRNA to lower LDL cholesterol (FDA-approved December 2021) - cardiovascular disease - lowers LDL cholesterol in maximally-treated statin recipients [2] Dosage: - initial injection 284 mg SC, then at 3 months, thereafter - 300-500 mg injection every 6 months (Leqvio) - 300 mg SC QD safe for up to 6 years [5] - 0.40 mg/kg IV infusion (ALN-PCS) Mechanism of action: - siRNA that prevents hepatic PCSK9 synthesis [6]

Interactions

drug adverse effects of anti-hyperlipidemic agents

General

PCSK9 inhibitor (ALN-PCS) short interfering double-stranded RNA; antisense oligonucleotide (siRNA, microRNA, miRNA)

References

  1. Fitzgerald K 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. The Lancet, Early Online Publication, 3 October 2013 PMID: 24094767 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61914-5/abstract - Fitzgerald K, White S, Borodovsky A et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2016 Nov 13 PMID: 27959715 http://www.nejm.org/doi/10.1056/NEJMoa1609243
  2. Ray KK, Landmesser U, Leiter LA et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017 Mar 17; PMID: 28306389
  3. Stiles S FDA Approves First-in-Class Inclisiran to Lower LDL-C. Medscape. December 22, 2021 https://www.medscape.com/viewarticle/965464 - Larkin HD News From the Food and Drug Administration Injectable siRNA Approved for Lowering Cholesterol. JAMA. 2022;327(9):805. PMID: 35230412 https://jamanetwork.com/journals/jama/fullarticle/2789563
  4. Ray KK, Wright RS, Kallend D et al Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519 PMID: 32187462 https://www.nejm.org/doi/10.1056/NEJMoa1912387
  5. Wright RS, Koenig W, Landmesser U et al Safety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials. J Am Coll Cardiol. 2023 Dec 12;82(24):2251-2261. PMID: 38057066 Free article. https://www.sciencedirect.com/science/article/pii/S0735109723077392
  6. Wright RS, Ray KK, Landmesser U et al Effects of Inclisiran in Patients With Atherosclerotic Cardiovascular Disease. A Pooled Analysis of the ORION-10 and ORION-11 Randomized Trials. Mayo Clinic Proceedings. 2024. August PMID: 39093262 https://www.mayoclinicproceedings.org/article/S0025-6196(24)00167-8/fulltext