Atherosclerosis · 2026
In silico prediction of the lipid-lowering efficacy of the oral PCSK9 inhibitor enlicitide using a mechanistic computational model.
СтатьяВалидационное исследованиеНазвание и аннотация: Перевод в очереди
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Cariou Bertrand, Wang Yishu, Angoulvant Denis, Boccara Franck, Mahé Guillaume, Steg Philippe Gabriel, Bechet Emmanuelle
Аннотация
BACKGROUND AND AIMS: Regulatory agencies increasingly support model-informed drug development, including quantitative systems pharmacology (QSP) models, but confidence in model-based predictions for decision making remains limited. We previously developed a mechanistic QSP model of atherosclerosis to simulate LDL-C responses to lipid-lowering therapies, which was extensively calibrated and retrospectively validated using published data from prior clinical trials. The recent completion of two phase 3 trials of the oral PCSK9 inhibitor enlicitide decanoate, CORALreef Lipids (NCT05952856) and CORALreef AddOn (NCT06450366), provided an opportunity for prospective validation, the highest standard for establishing predictive credibility.
METHODS: The model was recalibrated using phase 1 PK/PD data and phase 2b LDL-C response data to incorporate enlicitide's effect. Predictions for both trials were generated and publicly posted, independently of the sponsor and prior to any data release.
RESULTS: For CORALreef Lipids, the predicted week-24 LDL-C reduction was -54.5% (95% PPI: -56.1%, -53.0%), closely matching the subsequently reported -55.8% (95% CI: -60.9%, -50.7%). For CORALreef AddOn, predicted week-8 LDL-C reductions were -59.4% (95% PPI: -65.7, -53.4) with enlicitide, -18.0% (-20.1, -15.8) with bempedoic acid, -24.6% (-26.6, -22.7) with ezetimibe, and -39.8% (-42.8, -36.9) with their combination; comparison with actual trial outcomes is pending trial readout.
CONCLUSIONS: This first successful prospective validation of our mechanistic QSP model against a large cardiovascular phase 3 trial, confirms the model's credibility. It supports the contribution of in silico trials to accelerate the development and evaluation of innovative lipid-lowering therapies to improve cardiovascular outcomes.
METHODS: The model was recalibrated using phase 1 PK/PD data and phase 2b LDL-C response data to incorporate enlicitide's effect. Predictions for both trials were generated and publicly posted, independently of the sponsor and prior to any data release.
RESULTS: For CORALreef Lipids, the predicted week-24 LDL-C reduction was -54.5% (95% PPI: -56.1%, -53.0%), closely matching the subsequently reported -55.8% (95% CI: -60.9%, -50.7%). For CORALreef AddOn, predicted week-8 LDL-C reductions were -59.4% (95% PPI: -65.7, -53.4) with enlicitide, -18.0% (-20.1, -15.8) with bempedoic acid, -24.6% (-26.6, -22.7) with ezetimibe, and -39.8% (-42.8, -36.9) with their combination; comparison with actual trial outcomes is pending trial readout.
CONCLUSIONS: This first successful prospective validation of our mechanistic QSP model against a large cardiovascular phase 3 trial, confirms the model's credibility. It supports the contribution of in silico trials to accelerate the development and evaluation of innovative lipid-lowering therapies to improve cardiovascular outcomes.