Prediction of inclisiran efficacy in patients with established atherosclerotic cardiovascular disease: the SIRIUS In-Silico modelling of cardiovascular outcomes

Abstract Aims Inclisiran, an siRNA-targeting hepatic PCSK9 mRNA, reduces low-density lipoprotein cholesterol (LDL-C), but its effect on major adverse cardiovascular event (MACE) remains unconfirmed. The SIRIUS in-silico modelling program aimed to predict the efficacy of inclisiran on MACE in virtual patients with atherosclerotic cardiovascular disease (ASCVD). Methods The SIRIUS simulation (NCT05974345) used a validated mechanistic model of ASCVD and lipid-lowering therapy (LLT) effects in a virtual population with established ASCVD and LDL-C ≥70 mg/dL. Each virtual patient served as their own control to compare inclisiran versus placebo as an adjunct to high-intensity statin therapy, alone or with ezetimibe over 5 years. The model did not account for non-adherence, recurrent events, or adverse effects. Results Among 204 691 virtual patients, inclisiran was predicted to reduce LDL-C by 49.7% versus placebo (from 91.1 to 48.3 mg/dL). Relative to placebo, inclisiran was predicted to lower 5 years risk of 3-point MACE by 25.2% (11.3% vs. 14.9%), myocardial infarction by 34.8% (5.7% vs. 8.6%; HR 0.65), ischaemic stroke by 26% (2.6% vs. 3.4%; HR 0.74), and major adverse limb event by 34.1% (0.5% vs. 0.8%; HR 0.66). A 7.1% relative reduction of cardiovascular death was predicted (4.2% vs. 4.5%; HR 0.93). Conclusions SIRIUS is the first in-silico simulation using a knowledge-based mechanistic model to predict the efficacy of LLT on cardiovascular outcomes in ASCVD. These findings offer early model-based prediction of inclisiran’s potential cardiovascular benefit ahead of phase 3 outcome trials.