Abstract 4134364: Predicted Low-Density Lipoprotein Cholesterol and Cardiovascular Outcomes Lowering With Inclisiran in Patients With or Without stroke: Insights from SIRIUS in silico trial.

Introduction: Inclisiran, an siRNA, targeting PCSK9 mRNA, reduces LDL-c levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower cardiovascular (CV) events in virtual patients with atherosclerotic cardiovascular disease (ASCVD). Research question: This analysis predicted the potential efficacy of inclisiran on CV outcomes in virtual patients with or without prior ischemic stroke (IS). Methods: The SIRIUS trial was conducted using a calibrated and validated knowledge-based mechanistic computational model of ASCVD applied to a virtual population with LDL-C ≥ 70 mg/dL. Each virtual patient was its own control. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statin with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal IS over 5 years in patients with or without prior IS. Occurrence of fatal and non-fatal (IS) was also individually assessed in time-to-first-event analyses. Results: Among 204,691 virtual SIRIUS ASCVD patients, 39 371 (19%) had prior IS. At 5 years, the predicted mean percentage reduction in LDL-C with inclisiran as compared to placebo was –49.17% and –49.88% in patients with or without prior IS respectively. Patients with prior IS were at higher risk of 3P-MACE than patients without IS both with placebo and inclisiran (17.01% vs 14.41% with placebo and 13.44% vs 10.83% with inclisiran). However, the predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm for both prior IS and no prior IS (HR 0.78 medium uncertainty and 0.74 low uncertainty respectively). Compared to placebo, inclisiran was also predicted to consistently reduce fatal and non-fatal IS in patients with or without prior IS (5.45% vs 7.22%; HR: 0.75 medium uncertainty and 1.87% vs 2.54%; HR: 0.73 medium uncertainty respectively). Conclusion: SIRIUS provides insights into the potential efficacy of inclisiran on CV events suggesting a substantial 3P-MACE and fatal and non-fatal IS reduction in ASCVD patients including those with prior IS, several years before the availability of results from ongoing outcomes trials (ORION-4, VICTORION-2P).