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Evolocumab Reduces LDL Cholesterol in Phase III Studies

Treatment is significantly more effective than ezetimibe

In data from two phase III pivotal studies, treatment with the investigational cholesterol-lowering medication evolocumab (formerly AMG 145, Amgen) resulted in statistically significant reductions in low-density lipoprotein cholesterol (LDL-C) of 37% to 39% compared with ezetimibe in patients with high cholesterol who could not tolerate statins (the GAUSS-2 trial), and significant reductions of 55% to 76% compared with placebo when used in combination with statin therapy in patients with high cholesterol (the LAPLACE-2 trial).

Results from the two studies were presented at the American College of Cardiology's 63rd Annual Scientific Session. Data from the GAUSS-2 study were simultaneously published in the Journal of the American College of Cardiology.

Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation, thereby reducing the liver’s ability to remove LDL-C, or “bad” cholesterol, from the blood. Evolocumab is designed to bind to PCSK9 and to inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.

GAUSS-2 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) was a phase III randomized, double-blind, placebo- and ezetimibe-controlled trial designed to evaluate the safety, tolerability, and efficacy of evolocumab in 307 hyperlipidemic patients who could not tolerate effective doses of at least two different statins because of muscle-related adverse effects. The patients were randomly assigned to one of four treatment groups: subcutaneous evolocumab 140 mg every two weeks and oral placebo daily; subcutaneous evolocumab 420 mg monthly and oral placebo daily; subcutaneous placebo every two weeks and oral ezetimibe 10 mg daily; or subcutaneous placebo monthly and oral ezetimibe 10 mg daily. The co-primary endpoints were the percent reduction from baseline in LDL-C at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12.

Mean percent reductions from baseline in LDL-C at weeks 10 and 12 were 37% for evolocumab 140 mg every 2 weeks and 39% for evolocumab 420 mg monthly compared with ezetimibe (P < 0.001).

The LAPLACE-2 (LDL-C Assessment With PCSK9 MonoclonaL Antibody Inhibition Combined With Statin ThErapy-2) trial was a phase III, randomized, double-blind, placebo- and ezetimibe-controlled study designed to evaluate the safety, tolerability, and efficacy of evolocumab when added to statin therapy in 1,896 patients with primary hypercholesterolemia and mixed dyslipidemia. The patients were randomly assigned to one of 24 treatment groups in a two-step randomization.

Eligible patients were initially treated with one of five open-label background statin therapies: atorvastatin 10 mg, atorvastatin 80 mg, rosuvastatin 5 mg, rosuvastatin 40 mg, or simvastatin 40 mg daily. The patients were then randomly assigned to one of six treatment groups: evolocumab every 2 weeks and oral placebo; evolocumab every month and oral placebo; subcutaneous (SC) placebo every 2 weeks and oral placebo; SC placebo every month and oral placebo; SC placebo every 2 weeks and ezetimibe 10 mg; or SC placebo every month and ezetimibe 10 mg. Patients treated with rosuvastatin or simvastatin were randomly assigned to one of four treatment groups: evolocumab every 2 weeks; evolocumab every month; SC placebo every 2 weeks; or SC placebo every month.

The co-primary endpoints were the mean percent change from baseline in LDL-C at weeks 10 and 12 and the percent change in LDL-C reduction at week 12.

Results from the study showed that the mean reduction in LDL-C from baseline at weeks 10 and 12 was between 66% and 75% for evolocumab 140 mg every 2 weeks versus placebo and between 38% and 45% percent versus ezetimibe for all statin cohorts.

Source: Amgen; March 29, 2014.

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