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A Highly Durable RNAi Therapeutic Inhibitor of PCSK9
Open accessAbstract
BACKGROUND: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS: The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS: In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442 .).
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“Inclisiran is the first siRNA approved by both US FDA and EMA for the treatment of hypercholesterolemia; the subcutaneous injection of a lipid nanoparticle formulation of the drug, which specifically binds hepatocyte asialoglycoprotein receptors, displays high potency in lowering liver PCSK9 and plasma LDL-C levels [161,162].”
From The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer’s Disease: A Possible Target for the Disease Treatment (2024) · cites this paper as [161]
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“A single subcutaneous injection of trivalent GalNAc-conjugated siRNA can achieve efficacy for >12 months22, 2324.”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [22]
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“However, a fibrate-induced increase in homocysteine may blunt elevation of both HDL-C and ApoA1 levels, and this effect may contribute to the smaller than estimated benefits of fenofibrate in CV outcome parameters [322].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [322]
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Metadata
- Authors
- Fitzgerald, K., White, S., Borodovsky, A., Bettencourt, B. R., Strahs, A., Clausen, V., Wijngaard, P., Horton, J. D., Taubel, J., Brooks, A., Fernando, C., Kauffman, R. S., Kallend, D., Vaishnaw, A., & Simon, A.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- St George's, University of London (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-01-05
- Volume
- 376
- Issue
- 1
- Pages
- 41-51
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5778873
- OpenAlex
- W2555483953
- Cited by
- 768
- References
- 29
- Citations by year
- 2026: 43 · 2025: 61 · 2024: 84 · 2023: 89 · 2022: 85 · 2021: 68 · 2020: 88 · 2019: 76 · 2018: 95 · 2017: 74
- FWCI
- 91.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL020948)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- inclisiran, PCSK9 inhibition, RNA interference therapy, LDL cholesterol lowering, hypercholesterolemia, statin therapy, pharmacokinetics, pharmacodynamics, safety, multiple-dose regimen, single ascending dose, healthy volunteers, lipid-lowering drugs, hypertriglyceridemia, hyperuricemia
- MeSH terms
- RNAi Therapeutics, Proprotein Convertase 9, PCSK9 Inhibitors, Acetylgalactosamine, Adolescent, Adult, Aged, Anticholesteremic Agents, Female, Humans, Injections, Subcutaneous, Cholesterol, LDL, Male, Middle Aged, Single-Blind Method, RNA, Small Interfering, RNA-Induced Silencing Complex, Young Adult, Healthy Volunteers
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