In-silico trial emulation to predict the cardiovascular protection of new lipid-lowering drugs: an illustration through the design of the SIRIUS programme

Abstract

Abstract Introduction Inclisiran, an siRNA targeting hepatic PCSK9 mRNA, administered twice-yearly (after initial and 3-month doses), substantially and sustainably reduced LDL-cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) is not yet established. In-silico trials applying a disease computational model to virtual patients receiving new treatments allow to emulate large scale long-term clinical trials. The SIRIUS in-silico trial programme aims to predict the efficacy of inclisiran on CV events in individuals with established atherosclerotic cardiovascular disease (ASCVD). Methods and results A knowledge-based mechanistic model of ASCVD was built, calibrated, and validated to conduct the SIRIUS programme (NCT05974345) aiming to predict the effect of inclisiran on CV outcomes. The SIRIUS Virtual Population included patients with established ASCVD (previous myocardial infarction (MI), previous ischemic stroke (IS), previous symptomatic lower limb peripheral arterial disease (PAD) defined as either intermittent claudication with ankle-brachial index <0.85, prior peripheral arterial revascularization procedure, or vascular amputation) and fasting LDL-C ≥ 70 mg/dL, despite stable (≥4 weeks) well-tolerated lipid-lowering therapies. SIRIUS is an in-silico multi-arm trial programme. It follows an idealized crossover design where each virtual patient is its own control, comparing inclisiran to (i) placebo as adjunct to high-intensity statin therapy with or without ezetimibe, (ii) ezetimibe as adjunct to high-intensity statin therapy, (iii) evolocumab as adjunct to high-intensity statin therapy and ezetimibe. The co-primary efficacy outcomes are based on the time to the first occurrence of any component of 3P-MACE (composite of CV death, nonfatal MI, or nonfatal IS) and time to occurrence of CV death over 5 years. Perspectives/conclusion The SIRIUS in-silico trial programme will provide early insights regarding potential effect of inclisiran on MACE in ASCVD patients, several years before the availability of the results from ongoing CV outcomes trials (ORION-4 and VICTORION-2-P). Clinical trial registration Clinicaltrials.gov identifier: NCT05974345