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Cited by 329Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

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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

Open access
Ray, Kausik K, Troquay, Roel P T, Visseren, Frank L J, Leiter, Lawrence A, Scott Wright, R, Vikarunnessa, Sheikh, Talloczy, Zsolt, Zang, Xiao, Maheux, Pierre, Lesogor, Anastasia, Landmesser, Ulf·2023·The Lancet Diabetes & Endocrinology
DOI 10.1016/s2213-8587(22)00353-9
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Abstract

INTRODUCTION: Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol. METHODS: ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577. FINDINGS: Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm. INTERPRETATION: Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran. FUNDING: Novartis Pharma.

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  • Inclisiran is a safe and effective treatment for lipid reduction among diverse patient groups.

    “The research findings demonstrate that Inclisiran functions as a safe and effective treatment for lipid reduction among diverse patient groups [70].”

    From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [70]

    The paper’s conclusion (Table 4 section; page not provided) says inclisiran was well tolerated and produced sustained LDL-cholesterol reductions over four years. The eligibility criteria and Results describe patients with ASCVD or at high risk of cardiovascular disease, but the copy does not establish safety and efficacy across diverse patient groups broadly; 94% of participants were White. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The studies presented demonstrated sustained maximum LDL-C reduction levels that persisted throughout six months following the last administered dose.

    “The studies presented demonstrated sustained maximum LDL-C reduction levels that persisted throughout six months following the last administered dose [25, 42, 70].”

    From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [70]

    The Results report sustained LDL-C reductions with twice-yearly inclisiran over four years. But reductions varied from 34.3% to 53.8% across time points, so the paper does not show that the maximum reduction persisted throughout six months after the last dose. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Of the ORION-3 participants, 23% had diabetes and 33% were not taking statin therapy.

    “It is important to note that of the ORION-3 participants, 23% had diabetes and 33% were not taking statin therapy.”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [133]

  • In ORION-3, an LDL cholesterol reduction of ∼45% was maintained through the end of year 4.

    “Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol [ORION-3]), where an LDL cholesterol reduction of ∼45% was maintained through the end of year 4 (133).”

    From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [133]

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Metadata

Authors
Ray, K. K., Troquay, R. P. T., Visseren, F. L. J., Leiter, L. A., Scott Wright, R., Vikarunnessa, S., Talloczy, Z., Zang, X., Maheux, P., Lesogor, A., & Landmesser, U.
Affiliations
  • Imperial College London (GB)
  • VieCuri Medisch Centrum (NL)
  • University Medical Center Utrecht (NL)
  • St. Michael's Hospital (CA)
  • Novartis (Switzerland) (CH)
  • German Centre for Cardiovascular Research (DE)
Corresponding author
Ray, Kausik K
ORCID
Venue
The Lancet Diabetes & Endocrinology
Publisher
Elsevier BV
Published
2023-02
Volume
11
Issue
2
Pages
109-119
ISSN
2213-8587 (ISSN-L)
DOI
10.1016/s2213-8587(22)00353-9
OpenAlex
W4313554841
Cited by
328
References
28
Citations by year
2026: 55 · 2025: 102 · 2024: 103 · 2023: 67
FWCI
87.61
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Diabetes & Endocrinology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, cc-by)
Funders
  • Novartis
  • NIHR Imperial Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
inclisiran, PCSK9 inhibition, siRNA therapeutics, LDL cholesterol lowering, high cardiovascular risk, atherosclerotic cardiovascular disease, statin intolerance, long-term efficacy, safety
MeSH terms
Proprotein Convertase 9, Heart Disease Risk Factors, Anticholesteremic Agents, Cardiovascular Diseases, Humans, Cholesterol, LDL, Prospective Studies, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering

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