Abstract 4359604: Model-Based Evaluation of LDL-C Lowering for Laroprovstat (AZD0780), An Oral Small Molecule PCSK9 Inhibitor, and Rosuvastatin

Introduction: Approximately 70% of patients who are at high or very high risk for an atherosclerotic CV event fail to achieve their treatment targets. Laroprovstat (AZD0780), an oral small-molecule PCSK9 inhibitor, demonstrated robust LDL-C reduction in the Ph2b PURSUIT study (NCT06173570). Laroprovstat’s clinical pharmacology profile supports co-formulation with a statin, potentially providing the convenience of a once daily oral therapy. This model-based analysis quantified the superiority of laroprovstat and rosuvastatin combination over statin monotherapy. Methods: A kinetic-pharmacodynamic (K-PD) model was established using partial data from the PURSUIT study in patients receiving only rosuvastatin as standard of care to characterize LDL-C changes for laroprovstat on top of rosuvastatin. The impact of rosuvastatin dose on LDL-C lowering was evaluated within the laroprovstat K-PD model. Separately, a rosuvastatin dose–response K-PD model was developed using published data to quantify its LDL-C lowering effect. The two models were integrated to simulate LDL-C changes over 12 weeks in patients transitioning from 6 weeks of rosuvastatin monotherapy to 6 weeks of combination treatment of laroprovstat 30 mg with rosuvastatin. Results: Both models adequately described observed LDL-C responses and enabled dose-specific predictions. Laroprovstat produced a consistent LDL-C reduction regardless of the background rosuvastatin dose. The simulations from the integrated model demonstrated that laroprovstat 30 mg, when added on top of rosuvastatin, produced an additional clinically meaningful LDL-C reduction of approximately 50%, with the effect being rapid and reaching maximal levels within 2 weeks (Figure 1). The combination of rosuvastatin 20 mg and laroprovstat 30 mg resulted in a predicted mean LDL-C reduction of –76% (95% CI: –86% to –62%) at Week 12, aligning with the 80% total LDL-C reduction from pre-treatment baseline observed in the Phase 1 multiple ascending dose study. Conclusions: The modeling analyses demonstrate superior efficacy of combination therapy with laroprovstat and rosuvastatin across the therapeutic range of rosuvastatin. There is no need for dose adjustment of laroprovstat. The findings support a co-formulation with a statin to achieve guideline-directed LDL-C goals in patients not reaching target LDL-C levels with statins alone, providing a convenient, a once daily oral option.