Abstract

Background: Inclisiran, an siRNA targeting PCSK9 mRNA, administered twice-yearly, substantially and sustainably reduced LDL-C. Data quantifying how lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) and comparison to available lipid-lowering therapies are lacking. In silico trials applying a disease computational model to virtual patients receiving various treatments allow such predictions in large scale clinical trials. Purpose: The aim of the in silico SIRIUS trial (NCT05974345) was to predict the effect of inclisiran compared to ezetimibe or evolocumab on MACE in participants with atherosclerotic cardiovascular disease (ASCVD). Methods: Two distinct in silico trials were conducted using knowledge-based mechanistic computational model of ASCVD applied to virtual populations (Vpop) with ASCVD and LDL-C ≥ 70 mg/dL, each virtual patient being its own control. This model was previously calibrated to reproduce the results of FOURIER and ORION-10 trials and validated based on the results of other trials results including ODYSSEY-OUTCOMES. The first trial compared inclisiran efficacy to ezetimibe as an adjunct to high-intensity (HI) statins, while the second one compared inclisiran efficacy to evolocumab as adjunct to HI statin and ezetimibe. In both trials, the main outcome was a 3-Point-MACE defined as a composite of time to first occurrence of cardiovascular (CV) death, nonfatal myocardial infarction or nonfatal ischemic stroke over 5 years. Results: In a Vpop of 162,453 ASCVD patients under HI statin, the difference in mean percentage reduction in LDL-C with inclisiran as compared to ezetimibe was 32.7% from a median baseline value of 91.1 mg/dL to 48.3 mg/dL and 77.2 mg/dL at 5 years. Inclisiran was more effective than ezetimibe to lower the risk of 3P-MACE (11.3 vs. 13.3%; HR 0.82, low degree of prediction uncertainty). In a Vpop of 42,238 ASCVD patients under HI statin and ezetimibe, similar mean percentage reduction in LDL-C with inclisiran as compared to evolocumab was achieved at 5 years. Inclisiran and evolocumab had similar efficacy on lowering the risk of 3P-MACE (12.5 vs. 12.4%; HR 1.01, medium degree of prediction uncertainty). Conclusions: These in silico trials provide early insights into the potential effect of inclisiran on ASCVD events compared to alternative treatments suggesting a higher 3P-MACE reduction compared to ezetimibe and a similar effect compared to evolocumab.