Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9

Abstract

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple subcutaneous doses. Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to explain the antibody PK and LDLc time course data. The PK and PD models based on data from healthy subjects were used to simulate the effects of RG7652 on LDLc levels for a range of potential dose regimens in patients with coronary heart disease. A one-compartment PK model combined with an indirect PD response model was able to adequately describe the PK and LDLc data. Simulations of 400 mg every 4 weeks or 800 mg every 8 weeks regimens show significant LDLc reduction and suggest that dosing RG7652 once every month or once every 2 months is predicted to be optimal for the treatment of hypercholesterolemia. The PK and PD model successfully described the PK and LDLc data from healthy subjects in a Phase 1 study, and the model-based simulations provided useful insights and quantitative understanding for the selection of Phase 2 study doses in patients with coronary heart disease. The approach used in the case study demonstrates the utility of modeling and simulation in designing dose-ranging studies.

Fig. 1

Mean (+/− standard deviation) serum RG7652 concentration versus time (left panels) and LDLc (direct method) change from baseline versus time (right panels) after single dose (top panels) and multiple doses (bottom panels) of RG7652 in the Phase 1 study. The points and the error bars represent the mean and standard deviation (RG7652 serum concentration) or standard error (LDLc change from baseline). The lines represent the mean of model predicted concentrations. SD single dose, QWx4 once weekly for 4 weeks, QWx4 + A once weekly for 4 weeks on atorvastatin treatment

Fig. 2

Schematic representation of the PK and PD models used to describe serum RG7652 pharmacokinetic and pharmacodynamic (LDLc) data. SC subcutaneous space

Fig. 3

Effect of baseline LDLc on E _max parameter in the population PD model. Circles and triangles represent individual Phase 1 subjects in the nonstatin and statin cohorts, respectively. Solid gray line indicates loess smoother

Fig. 4

Predicted mean LDLc change from baseline at 24 weeks versus milligrams of RG7652 dose per 4 weeks (left panel) and predicted % subjects with nadir LDLc < 15 mg/dL (right panel) at three regimens

Fig. 5

Predicted serum LDLc profiles for simulated Phase 2 trials using the population PD model. The solid black line indicates the mean of 100 simulated trials and the gray band indicates the 90% prediction intervals. The dotted gray line indicates 50 mg/dL reduction in LDLc from baseline. Upper: predicted profiles for Q4W regimens. Middle: predicted profiles for the Q8W regimens. Lower: predicted profiles for Q12W regimens