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.

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 2-4 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 non-fatal ischaemic stroke, or urgent coronary revascularization. Participants will be followed until the median time since randomization is at least 5 years and at least 1700 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 one 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 (8.1) years and 30% were female. At baseline, 78% had a history of coronary heart disease, 22% of ischaemic 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.