Abstract
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional ∼20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.
Highlights
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development
We developed a quantitative systems pharmacology (QSP) model to include key elements of lipoprotein homeostasis, PCSK9 dynamics, as well as features of dose-exposure-target modulation to reproduce experimental data of plasma cholesterol response upon administration of anti-PCSK9 monoclonal antibody (mAb) or small interfering RNA (siRNA) compounds (Fig. 1A, supplemental Table S1)
To describe endogenous and reverse cholesterol metabolism pathways within the model, we incorporated essential features such as the cholesterol fraction in LDL particles and their VLDL precursors, LDL-R-mediated clearances of LDL-C and Lp(a), HDL-C turnover, PCSK9 expression influenced by siRNA, and plasma PCSK9 binding by mAbs
Summary
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA) To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDLC), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). The discovery of the proprotein convertase subtilisin/ kexin type 9 (PCSK9) and the protein’s ability to regulate LDL-receptor (LDL-R) numbers expressed on hepatocytes made PCSK9 a potent target against hypercholesterolemia and resulted in a drug-development surge of various antiPCSK9 pharmacological modalities [6].
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