American heart journal · 2026
HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease: Trial design, recruitment, and baseline characteristics.
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Mafham Marion M, Zayed Mohammed G, Collins Rory, Sabatine Marc S, Armitage Jane, Brittain Dominic, da Costa Bruno R, Chen Fang, Goonasekera Michelle A, Hill Michael, Hopewell Jemma C, Landray Martin J, Lay Michael D, Lesogor Anastasia, Maggioni Aldo P, Morrow David A, Nunn Michelle, O'Donoghue Michelle L, Ray Kausik K, Rizkala Adel, Schwartz Gregory G, Stevens Will, Wallendszus Karl, Wright R Scott, Wijesurendra Rohan, Wincott Elizabeth, Preiss David, Bowman Louise, ORION-4 Collaborative Group
Аннотация
BACKGROUND: Despite widespread statin use, atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality worldwide. Monoclonal antibodies targeting circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. However, the requirement for self-administration every 2 to 4 weeks may limit adherence to treatment. Inclisiran, a first-in-class small interfering ribonucleic acid (siRNA) therapy targeting hepatic PCSK9 production, has several potential advantages over the anti-PCSK9 monoclonal antibodies, principally longer duration of action. To date, however, the efficacy and safety of inclisiran have not been proven in a cardiovascular outcomes trial.
METHODS: The ORION-4 study is the first large-scale clinical outcomes trial of an siRNA therapy, aiming to assess the efficacy and safety of inclisiran among participants with pre-existing atherosclerotic cardiovascular disease. The primary assessment is an intention-to-treat comparison of the effect of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran), given by subcutaneous injection at randomization, at approximately 3 months and then approximately every 6 months thereafter, on major adverse cardiovascular events (MACE), defined as the composite of coronary death, myocardial infarction, fatal or nonfatal ischemic stroke, or urgent coronary revascularization. Participants will be followed until the median time since randomization is at least 5 years and at least 1,700 participants have a recorded adjudicated MACE. With a planned sample size of ∼15,000 participants, ORION-4 was designed to have >99% power to detect a relative reduction in the primary outcome of about 1 quarter, while also providing an opportunity to assess efficacy in different subgroups as well as on secondary outcomes of interest.
RESULTS: Between 2019 and 2023 a total of 16,124 participants were randomized in the UK and the US. The mean (SD) age was 70 (8) years and 30% were female. At baseline, 78% had a history of coronary heart disease, 22% of ischemic stroke, 15% of revascularization for peripheral arterial disease, and 23% had diabetes mellitus. 85% were on statin therapy (53% high intensity statin, 29% moderate and 3% low intensity statins). Overall, baseline mean (SD) LDL-C was 96 (32) mg/dL, and was similar among participants on high- and moderate/low-intensity statin regimens (87 [27] mg/dL and 93 [26] mg/dL respectively), with higher levels in those receiving no statin therapy (133 [33] mg/dL). Follow-up will complete during 2026 and results will be available in early 2027.
INTERPRETATION: Inclisiran potentially offers a scalable lipid-lowering treatment, either alone or in combination with other agents. ORION-4 will evaluate the clinical efficacy of inclisiran, and provide a robust assessment of the safety of prolonged use of an siRNA therapeutic.
TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT03705234) and the EU Clinical Trials Register (EudraCT Number: 2017-005066-22).
METHODS: The ORION-4 study is the first large-scale clinical outcomes trial of an siRNA therapy, aiming to assess the efficacy and safety of inclisiran among participants with pre-existing atherosclerotic cardiovascular disease. The primary assessment is an intention-to-treat comparison of the effect of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran), given by subcutaneous injection at randomization, at approximately 3 months and then approximately every 6 months thereafter, on major adverse cardiovascular events (MACE), defined as the composite of coronary death, myocardial infarction, fatal or nonfatal ischemic stroke, or urgent coronary revascularization. Participants will be followed until the median time since randomization is at least 5 years and at least 1,700 participants have a recorded adjudicated MACE. With a planned sample size of ∼15,000 participants, ORION-4 was designed to have >99% power to detect a relative reduction in the primary outcome of about 1 quarter, while also providing an opportunity to assess efficacy in different subgroups as well as on secondary outcomes of interest.
RESULTS: Between 2019 and 2023 a total of 16,124 participants were randomized in the UK and the US. The mean (SD) age was 70 (8) years and 30% were female. At baseline, 78% had a history of coronary heart disease, 22% of ischemic stroke, 15% of revascularization for peripheral arterial disease, and 23% had diabetes mellitus. 85% were on statin therapy (53% high intensity statin, 29% moderate and 3% low intensity statins). Overall, baseline mean (SD) LDL-C was 96 (32) mg/dL, and was similar among participants on high- and moderate/low-intensity statin regimens (87 [27] mg/dL and 93 [26] mg/dL respectively), with higher levels in those receiving no statin therapy (133 [33] mg/dL). Follow-up will complete during 2026 and results will be available in early 2027.
INTERPRETATION: Inclisiran potentially offers a scalable lipid-lowering treatment, either alone or in combination with other agents. ORION-4 will evaluate the clinical efficacy of inclisiran, and provide a robust assessment of the safety of prolonged use of an siRNA therapeutic.
TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT03705234) and the EU Clinical Trials Register (EudraCT Number: 2017-005066-22).