Prospective prediction of cardiovascular outcomes for HORIZON-Lp(a) trial using a mechanistic QSP model of ASCVD

Background: Long, expensive outcomes trials are typically required to quantify cardiovascular (CV) benefit under lipid-lowering therapy (LLT). Mechanistic in-silico trials built on Quantitative Systems Pharmacology (QSP) offer a complementary pathway to anticipate efficacy and inform trial design. Objective: Using an ASCVD QSP framework, we prospectively predicted impact of Pelacarsen on cardiovascular composite outcomes (3P-MACE and 4P-MACE) before the completion of the Phase 3 HORIZON-Lp(a). Methods: We used a previously published and validated QSP model that was improved for this context of use. Calibration/Validation was performed on FOURIER and ODYSSEY-OUTCOMES trial and CGPS cohort data. Simulation based on HORIZON-Lp(a) protocol was then performed.Results: The model predicted a set of relative risk reduction in the Pelacarsen effect depending on the time of median follow-up and the expected placebo effect in the comparator arm.Conclusions: Within a credibility framework inspired by recent work on ASCVD mechanistic modeling, this prospective validation delivered consistant results about the clinical benefit in lowering Lp(a).