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

J Am Coll Cardiol. 2014 Apr 8;63(13):1278-1288. doi: 10.1016/j.jacc.2014.01.006. Epub 2014 Feb 5.

Abstract

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.

Keywords: PCSK9 inhibition; dyslipidemia; evolocumab; lipoprotein(a).

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal, Humanized
  • Apolipoproteins B / blood
  • Apoptosis
  • Cholesterol, LDL / blood
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Female
  • Humans
  • Lipoprotein(a) / blood*
  • Lipoprotein(a) / drug effects
  • Male
  • Middle Aged
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors*
  • Proprotein Convertases / blood
  • Serine Endopeptidases / blood
  • Treatment Outcome
  • Ultracentrifugation

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Apolipoproteins B
  • Cholesterol, LDL
  • Lipoprotein(a)
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • evolocumab