A Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for Bococizumab, a Humanized Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, and Its Application in Early Clinical Development

Abstract

Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies. First, simulations performed with this model demonstrated that the conventional method of the area-under-the-curve ratio for bioavailability determination underestimated the subcutaneous bioavailability of bococizumab due to its target-mediated disposition. Second, a covariate model component for statin effects on bococizumab PK/PD was characterized, including a description of the decreased baseline LDL-C, increased baseline PCSK9, and increased LDL-C lowering with concomitant use of statins. Last, the impact of the dosing regimens with and without a dose holiday on bococizumab's LDL-C-lowering effectiveness was shown to be predictable due to the well-characterized PK-PD relationship.

The effects of single‐ and multiple‐dose administration of bococizumab (RN316/PF‐04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies

“…Indeed, mean baseline concentrations of PCSK9 were higher in Study 2 (61 ng/mL) compared with Study 1 (40 ng/mL). A recent PK/PD analysis using bococizumab phase I and IIA trial data to construct a mechanism‐based drug–target binding model indicated that coadministration of bococizumab with a statin predicted an increase in LDL‐C clearance in the presence of background statin therapy . Combined with the enhanced bococizumab clearance reported here, these observations are consistent with the proposed effect of statins in stimulating both LDLR and PCSK9 production and the target‐mediated disposition of bococizumab …”

A Phase I Randomized Study of a Specifically Engineered, pH‐Sensitive PCSK9 Inhibitor RN317 (PF‐05335810) in Hypercholesterolemic Subjects on Statin Therapy

“…More specifically, single‐dose bococizumab produced maximum LDL‐C reductions of up to 70%, and 100% of subjects receiving bococizumab s.c. 3 mg/kg achieved a ≥ 50% reduction from baseline at day 8. These reductions are in line with data and modeled predictions from other clinical studies of bococizumab, using a similar assay technique …”

Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018

“…A mechanism-based drug–target binding model using bococizumab Phase I and IIA trial data was developed to account for bococizumab, PCSK9, and LDL-C concentrations, and the effects of co-administration of statins. The model indicated that statins could predict an increase in LDL-C clearance of bococizumab by co-administration, which was consistent with the proposed effect of statins in stimulating both LDLR and PCSK9 production and the target-mediated disposition of bococizumab [83,90]. In July 2016, a Phase I trial for hypercholesterolemia in combination with recombinant human hyaluronidase (rHuPH20) was terminated due to business priorities regarding study execution [91,92].…”

“…PCSK9 is a serine protease, which bonding to LDL receptor (LDL-R) results in the aggregation of LDL cholesterol (LDL-C), an important factor causing atherosclerotic heart disease. Working as a humanized monoclonal antibody (mAb), bococizumab extracellularly influences circulating PCSK9 either by secluding it or blocking the bonding [83,84].…”