Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor

Sreeneeranj Kasichayanula, Anita Grover, Maurice G Emery, Megan A Gibbs, Ransi Somaratne, Scott M Wasserman, John P Gibbs, Sreeneeranj Kasichayanula, Anita Grover, Maurice G Emery, Megan A Gibbs, Ransi Somaratne, Scott M Wasserman, John P Gibbs

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11-17 days. The pharmacodynamic effects of evolocumab on PCSK9 are rapid, with maximum suppression within 4 h. At steady state, peak reduction of LDL-C occurs approximately 1 week after a subcutaneous dose of 140 mg every 2 weeks (Q2W) and 2 weeks after a subcutaneous dose 420 mg once monthly (QM), and returns towards baseline over the dosing interval. In several clinical studies, these doses of evolocumab reduced LDL-C by approximately 55-75% compared with placebo. Evolocumab also reduced lipoprotein(a) [Lp(a)] levels and improved those of other lipids in clinical studies. No clinically meaningful differences in pharmacodynamic effects on LDL-C were observed in adult subjects regardless of mild/moderate hepatic impairment, renal impairment or renal failure, body weight, race, sex, or age. No clinically meaningful differences were observed for the pharmacodynamic effects of evolocumab on LDL-C between patients who received evolocumab alone or in combination with a statin, resulting in additional lowering of LDL-C when evolocumab was combined with a statin. No dose adjustment is necessary based on patient-specific factors or concomitant medication use.

Conflict of interest statement

Funding

This work was supported by Amgen Inc.

Conflict of interest

Drs. Somaratne and Wasserman are employees of and stockholders in Amgen, Inc. Drs. Somaratne and J.P. Gibbs are identified as inventors on at least one pending patent application owned by Amgen, Inc. relating to evolocumab. Dr. Wasserman appears on a number of pending patents owned by Amgen Inc. relating to evolocumab and PCSK9 inhibition. Drs. Kasichayanula, Grover, Emery, M. Gibbs, and J.P. Gibbs were employees of and stockholders in Amgen at the time this work was completed. Drs. Kasichayanula, M. Gibbs, and J.P. Gibbs are currently employed by AbbVie, Inc. Dr. Grover is currently employed by BioMarin Pharmaceutical Inc. Dr. Emery is currently employed by Seattle Genetics.

Figures

Fig. 1
Fig. 1
Mechanism of action: PCSK9 inhibition with evolocumab increases LDL-R and decreases serum concentrations of LDL-C [, , , , –55]. a The liver is responsible for catabolism of plasma LDL. Hepatocytes express LDL-R that bind LDL and remove it from the plasma. Upon internalization, vesicles containing the LDL–LDL-R complex fuse with endosomes. LDL-R cycles back to the hepatocyte surface to bind additional LDL. Free LDL in endosomes is degraded into lipids, free fatty acids, and amino acids. b PCSK9 is a protein that regulates the expression of LDL-R in the liver. Hepatocytes produce a precursor of PCSK9 that undergoes self-cleavage in the endoplasmic reticulum and ultimately is secreted into plasma as functional PCSK9. Extracellular PCSK9 binds to LDL-Rs on the surface of the hepatocyte and is internalized with the LDL–LDL-R complex. The LDL-R–PCSK9 complex is routed to the lysosome for degradation, thereby preventing the cycling of LDL-R back to the hepatocyte surface. The reduced concentration of LDL-R on the surface of hepatocytes results in a lower rate of plasma LDL elimination. c A monoclonal antibody directed against PCSK9 could lower LDL if binding to circulating PCSK9 blocks the interaction of PCSK9 with cell surface LDL-R. Internalized LDL-R could cycle back to the cell surface instead of being degraded in lysosomes, leading to increased concentrations of LDL-R on the cell surface. This could result in a higher LDL elimination rate by hepatocytes and an overall reduction in plasma LDL. LDL-C low-density lipoprotein cholesterol, LDL-R low-density lipoprotein receptor, PCSK9 proprotein convertase subtilisin/kexin type 9
Fig. 2
Fig. 2
Mean unbound evolocumab serum concentrations and geometric mean percent change from baseline in ultracentrifugation LDL-C and unbound PCSK9 in healthy subjects. a Single-dose SC evolocumab 140 mg. b Single-dose SC evolocumab 420 mg. LDL-C low-density lipoprotein cholesterol, PCSK9 proprotein convertase subtilisin/kexin type 9, SC subcutaneous. Amgen data on file
Fig. 3
Fig. 3
Percent change (mean and 95% confidence interval) from baseline for lipid parameters: time-averaged effect, mean of weeks 10 and 12, and week 12. ApoA1 apolipoprotein A1, ApoB apolipoprotein B, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, Q2W once every 2 weeks

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