Pharmacodynamic relationship between PCSK9, alirocumab, and LDL-C lowering in the ODYSSEY CHOICE I trial.

Abstract

BACKGROUND:

The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin.

OBJECTIVE:

The objective of the study was to assess the relationship between alirocumab, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein cholesterol (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen.

METHODS:

This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W), or placebo. 300 mg Q4W and 75 mg Q2W doses were adjusted to 150 mg Q2W at Week 12 if Week 8 LDL-C was >70 or >100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline.

RESULTS:

Most patients remained on 300 mg Q4W without dose adjustment as they achieved study-defined LDL-C goals at Week 8 (statin-treated: 80.7%; no statin: 85.3%). LDL-C was reduced by 60.5%-71.9% over Weeks 20-24 in patients on 300 mg Q4W and 57.2%-63.0% in patients with dose adjustment from 300 mg Q4W to 150 mg Q2W. Statin-treated patients had higher cardiovascular risk as well as higher free PCSK9 and lower alirocumab concentrations (vs no statin), suggesting increased target-mediated clearance. Regardless of statin status, the most common adverse events in alirocumab-treated patients were injection-site reaction and headache.

CONCLUSIONS:

Data provide further insight on alirocumab's mode of action in terms of relationship between alirocumab, PCSK9, and LDL-C, and disease severity, and support the use of alirocumab 300 mg Q4W as an efficacious dosing regimen for clinically meaningful LDL-C reductions.

• Authors: Eli M Roth, John J P Kastelein, Christopher P Cannon, Michel Farnier, James M McKenney, A Thomas DiCioccio, Aurélie Brunet, Garen Manvelian, William J Sasiela, Marie T Baccara-Dinet, Jian Zhao, Jennifer G Robinson
• Journal: Journal of clinical lipidology (J Clin Lipidol) 2020 Sep - Oct Vol. 14 Issue 5 Pg. 707-719 ISSN: 1933-2874 [Print] United States
• PMID: 32928709 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Cholesterol, LDL
• PCSK9 protein, human
• Proprotein Convertase 9
• alirocumab

Topics

• Antibodies, Monoclonal, Humanized (therapeutic use)
• Cholesterol, LDL (metabolism)
• Female
• Humans
• Hypercholesterolemia (drug therapy, metabolism, pathology)
• Male
• Middle Aged
• Prognosis
• Proprotein Convertase 9 (metabolism)