Elsevier

The Lancet

Volume 380, Issue 9858, 8–14 December 2012, Pages 2007-2017
The Lancet

Articles
Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study

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Summary

Background

LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin.

Methods

In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18–80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730.

Findings

631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening.

Interpretation

The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials.

Funding

Amgen.

Introduction

Reduction in LDL-cholesterol (LDL-C) concentrations has been shown to reduce subsequent cardiovascular events, both in primary and secondary prevention populations;1 the most compelling data were from trials of statins.2 However, many patients do not achieve their goal LDL-C concentration due to an insufficient response, intolerance to the drugs, or both,3 and thus are at risk of subsequent events.4

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key part in aiding the intracellular degradation of the LDL receptor (LDL-R) within the hepatocyte lysosome.5 Loss-of-function mutations in PCSK9 increase the number of LDL-Rs available to recycle to the hepatocyte cell surface, resulting in a reduction in LDL-C concentrations and fewer cardiovascular events.6

AMG 145 is a human monoclonal antibody that binds human PCSK9 with high affinity. In phase 1 studies, it reduced LDL-C concentrations up to 64% versus placebo 1 week after a single dose, and up to 81% with repeated weekly doses.7 We therefore tested the hypothesis that, compared with placebo, 12 weeks of AMG 145 would reduce LDL-C concentrations when used in addition to a statin with or without ezetimibe in patients with hypercholesterolaemia.

Section snippets

Patients and study design

The design and rationale of LAPLACE-TIMI 57 has been described previously.8 Briefly, the study was a multinational, double-blind, placebo-controlled, dose-ranging trial done in 78 centres in five countries (USA, Canada, Denmark, Hungary, and Czech Republic; appendix pp 3–5).

Eligible patients (aged 18–80 years) had a history of hypercholesterolaemia and fasting LDL-C concentration greater than 2·2 mmol/L while on a stable dose of statin (with or without ezetimibe) for at least 4 weeks. Patients

Results

Of 934 patients screened, we randomly assigned 631 (67·6%) between July 18, and Dec 22, 2011 (figure 1). The most common reasons cited by patients for not wanting to be randomly assigned despite meeting entry criteria were related to family concerns or travel. None of the patients stated that intolerance to placebo injections during the run-in phase was the reason for not proceeding with randomisation. Baseline characteristics of the patients were similar between the eight groups (table 1).

Two

Discussion

AMG 145 significantly reduced the LDL-C concentration from baseline compared with placebo by up to 66% at the end of the dosing interval in stable patients with hypercholesterolaemia already treated with a statin. The addition of AMG 145 to background treatment with statin, with or without ezetimibe, helped most patients achieve an LDL-C concentration of 1·8 mmol/L; 94% achieved this concentration with AMG 140 mg every 2 weeks (panel). Additionally, all regimens of AMG 145 significantly reduced

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