ArticlesEfficacy, 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
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.
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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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Members listed in appendix pp 3–5