Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol
Open accessAbstract
BACKGROUND: In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS: We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS: A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS: In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127 .).
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A single subcutaneous injection of trivalent GalNAc-conjugated siRNA can achieve efficacy for >12 months.
“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 [23]
The Methods describe a single subcutaneous dose of inclisiran, an siRNA, and the LDL Cholesterol Levels and Other Laboratory Measures section reports LDL-cholesterol reductions after a single dose through day 240. That is less than 12 months; our copy does not establish efficacy beyond 12 months or identify inclisiran as trivalent GalNAc-conjugated. (LLM, conf=0.89)
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- Authors
- Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., Hall, T., Troquay, R. P. T., Turner, T., Visseren, F. L. J., Wijngaard, P., Wright, R. S., & Kastelein, J. J. P.
- Affiliations
- St. Michael's Hospital (CA)
- Medpace (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-04-13
- Volume
- 376
- Issue
- 15
- Pages
- 1430-1440
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2595169180
- Cited by
- 992
- References
- 5
- Citations by year
- 2026: 56 · 2025: 91 · 2024: 100 · 2023: 102 · 2022: 114 · 2021: 107 · 2020: 129 · 2019: 123 · 2018: 108 · 2017: 60
- FWCI
- 117.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- inclisiran, PCSK9 inhibition, siRNA, LDL cholesterol lowering, hypercholesterolemia, high cardiovascular risk, dose-dependent effects, subcutaneous injection, lipid-lowering therapy, injection site reactions, serious adverse events
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Aged, Transaminases, Anticholesteremic Agents, Cardiovascular Diseases, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hypercholesterolemia, Injections, Subcutaneous, Cholesterol, LDL, Male, Middle Aged, Risk Factors, RNA, Small Interfering
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