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Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia S

Journal article
Authors V. Sokolov
G. Helmlinger
C. Nilsson
K. Zhudenkov
Stanko Skrtic
B. Hamren
K. Peskov
E. Hurt-Camejo
R. Jansson-Lofmark
Published in Journal of Lipid Research
Volume 60
Issue 9
Pages 1610-1621
ISSN 0022-2275
Publication year 2019
Published at Institute of Medicine
Pages 1610-1621
Language en
Keywords atherosclerosis, lipoproteins, cholesterol metabolism, plasma proprotein convertase subtilisin, kexin, subtilisin/kexin type 9, density-lipoprotein cholesterol, heterozygous, familial hypercholesterolemia, human monoclonal-antibody, high, cardiovascular risk, ldl cholesterol, healthy-volunteers, pcsk9, inhibition, serine-protease, clinical-trial, Biochemistry & Molecular Biology
Subject categories Clinical Medicine


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 similar to 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.

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