Clinical Research
Cardiometabolic Risk
Reduction in Lipoprotein(a) With PCSK9 Monoclonal Antibody Evolocumab (AMG 145): A Pooled Analysis of More Than 1,300 Patients in 4 Phase II Trials

https://doi.org/10.1016/j.jacc.2014.01.006Get rights and content
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Objectives

The purpose of this study was assess the effect of evolocumab (AMG 145) on lipoprotein (Lp)(a) from a pooled analysis of 4 phase II trials.

Background

Lp(a), a low-density lipoprotein (LDL) particle linked to the plasminogen-like glycoprotein apolipoprotein(a), shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies. Current therapeutic options to reduce Lp(a) are limited.

Methods

A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9, on Lp(a), the relationship between Lp(a) and lowering of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin therapy. Lp(a) was measured using a standardized isoform-independent method.

Results

Evolocumab treatment for 12 weeks resulted in significant (p < 0.001) mean (95% confidence interval) dose-related reductions in Lp(a) compared to control: 29.5% (23.3% to 35.7%) and 24.5% (20.4% to 28.7%) with 140 mg and 420 mg, dosed every 2 and 4 weeks, respectively, with no plateau of effect. Lp(a) reductions were significantly correlated with percentages of reductions in LDL-C (Spearman correlation coefficient, 0.5134; p < 0.001) and apolipoprotein B (Spearman correlation coefficient, 0.5203; p < 0. 001). Mean percentage reductions did not differ based on age or sex but the trend was greater in those patients taking statins.

Conclusions

Inhibition of PCSK9 with evolocumab resulted in significant dose-related reductions in Lp(a). While the mean percentage of reduction was significantly greater in those patients with baseline Lp(a) of ≤125 nmol/l, the absolute reduction was substantially larger in those with levels >125 nmol/l.

Key Words

dyslipidemia
evolocumab
lipoprotein(a)
PCSK9 inhibition

Abbreviations and Acronyms

CVD
cardiovascular disease
LDL
low-density lipoprotein
PCSK9
proprotein convertase subtilisin/kexin type 9
Q2W
every 2 weeks
Q4W
every 4 weeks
SC
subcutaneous
UC LDL-C
low-density lipoprotein cholesterol measured by ultracentrifugation

Cited by (0)

This study was funded by Amgen, Inc. Dr. Raal has received consulting fees from Amgen, Inc., and Sanofi related to PCSK9 inhibitors; and his institution has received research funding related to PCSK9 inhibitor clinical trials from Amgen, Inc., and Sanofi. Dr. Giugliano has received honoraria for consulting and CME lectures from Amgen, Daiichi Sankyo, Bristol-Myers Squibb, Merck, Regeneron, and Sanofi; and participates in lipid research as a member of the TIMI Study Group, which has received research grant support for clinical trials from Amgen, Daiichi-Sankyo, and Merck. Dr. Sabatine has received grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi Joint Venture, Daiichi Sankyo, Eisai, Genzyme, GlaxoSmithKline, Merck, Sanofi, Takeda, Abbott Laboratories, Accumetrics, Critical Diagnostics, Nanosphere, and Roche Diagnostics; and has consulted for Aegerion, Amgen, Diasorin, GlaxoSmithKline, Merck, Pfizer, Sanofi, AstraZeneca, and Vertex. Dr. Koren is an employee of Jacksonville Center for Clinical Research, which has received grants from Amgen Inc. Dr. Langslet is a consultant for and advisory board member of Janssen Pharmaceutical. Dr. Bays has consulted for and received speaker fees from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Catabasis, Daiichi Sankyo, Eisai Merck, VIVUS, and WBL Biotech Co.; and his research site has received grants from Alere, Amarin, Amgen, Ardea, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, California Raisin Board, Catabasis, Eisai, Elcelyx, Eli Lilly, Esperion, Essentialis, Forest, Gilead, Given, GlaxoSmithKline, High Point Pharmaceuticals LLC, Hoffman LaRoche, Home Access, Janssen, Merck, Micropharma Limited, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Stratum Nutrition, Takeda, TIMI, Transtech Pharma, Trygg, VIVUS, WBL Biotech Co., and Xoma. Dr. Blom has received consulting fees from Amgen Inc. and Sanofi related to PCSK9 inhibitors; has served on advisory boards of Amgen, Sanofi, Aegerion, and Merck, Sharpe, Dohme; has received speaker honoraria from Amgen, Aegerion, Merck, Sharpe, Dohme, Unilever, Pfizer, AstraZeneca, Ranbaxy, PharmaDynamics, and Sanofi; and his institution has received research funding related to PCSK9 inhibitor clinical trials from Amgen, Inc., and Sanofi. Dr. Eriksson has received lecture fees from Merck, Sharpe, Dohme and AstraZeneca and consulting fees from Amgen, Sanofi, and Novo Nordisk. Drs. Dent, Wasserman, Huang, Xue, Albizem, and Scott are employees of Amgen, Inc., and have received Amgen stock/stock options. Dr. Stein has received consulting fees from Amgen Inc., Adnexus Therapeutics/Bristol-Myers Squibb, Genentech/Roche, and Regeneron/Sanofi related to PCSK9 inhibitors.