Amgen announced that the phase III LAPLACE-2 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin ThErapy-2) trial evaluating evolocumab in combination with statin therapy in patients with high cholesterol has met its co-primary endpoints: the percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12.

The mean percent reductions in LDL-C, or "bad" cholesterol, were consistent with the published results observed for the same doses in the phase II LAPLACE-TIMI 57 (LAPLACE-Thrombolysis In Myocardial Infarction-57) trial for evolocumab compared to placebo; and in the phase II MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy For Easing Lipid Levels) study for evolocumab compared to ezetimibe.

Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver's ability to remove LDL-C from the blood.

The LAPLACE-2 trial evaluated safety, tolerability and efficacy of evolocumab in combination with statin therapy compared to placebo and ezetimibe in 1,896 patients with high cholesterol. Patients were randomized to one of 24 treatment groups to compare subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) with subcutaneous placebo (every two weeks or monthly) or ezetimibe (10 mg daily) when added to different daily doses of statin therapies.

Safety was balanced across treatment groups. No adverse events (AEs) occurred in = two per cent of the evolocumab combined group. The most common AEs in the evolocumab combined group were back pain, arthralgia, headache, muscle spasms and pain in extremity.

"As statins continue to be an important treatment option in patients with high cholesterol, we are very encouraged by the phase III data from the LAPLACE-2 study," said Sean E Harper, MD, executive vice president of Research and Development at Amgen. "Adding evolocumab to statin therapy may help patients control their LDL cholesterol levels when high doses of statins are not sufficient."

Details of the phase III LAPLACE-2 study results will be submitted to a future medical conference and for publication.

LAPLACE-2 is a phase III randomized, multicentre, double-blind, placebo- and ezetimibe-controlled study designed to evaluate safety, tolerability and efficacy of evolocumab in 1,896 patients with primary hypercholesterolemia and mixed dyslipidemia (LDL-C > 80 mg/dL) when added to statin therapy. Patients were randomized to one of 24 treatment groups in a two-step randomization. Eligible patients were initially randomized to one of five open label background statin treatments: atorvastatin 10 mg, atorvastatin 80 mg, rosuvastatin 5 mg, rosuvastatin 40 mg or simvastatin 40 mg daily. Patients randomized to atorvastatin were then randomized to one of six treatment groups: evolocumab every two weeks and oral placebo, evolocumab every month and oral placebo, subcutaneous placebo every two weeks and oral placebo, subcutaneous placebo every month and oral placebo, subcutaneous placebo every two weeks and ezetimibe 10 mg, or subcutaneous placebo every month and ezetimibe 10 mg. Patients randomized to rosuvastatin or simvastatin were then randomized to one of four treatment groups: evolocumab every two weeks, evolocumab every month, subcutaneous placebo every two weeks, or subcutaneous 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. Co-secondary efficacy endpoints included means at weeks 10 and 12 and at week 12 for the following: LDL-C < 70 mg/dL; absolute change from baseline in LDL-C; and the percentage change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC)/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol (VLDL-C).

Reference above to the published phase II MENDEL study results for evolocumab compared to ezetimibe is made because the phase II MENDEL study included a randomized comparison to ezetimibe and the phase II LAPLACE-TIMI 57 study did not.

PROFICIO, which stands for the Programme to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulations, is a large and comprehensive clinical trial program evaluating evolocumab. Phase III clinical trials for evolocumab are currently underway and build upon the phase II studies.

The phase III programme includes 13 trials, with a combined planned enrollment of more than 28,000 patients. The phase III studies will evaluate evolocumab administered every two weeks and monthly in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2), in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2), as a stand-alone treatment in patients with hyperlipidemia (MENDEL-2), and in patients whose elevated cholesterol is caused by genetic disorders called heterozygous (RUTHERFORD-2) and homozygous (TESLA and TAUSSIG) familial hypercholesterolemia.

Five studies of evolocumab will provide long-term safety and efficacy data. These include FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), which will assess whether treatment with evolocumab in combination with statin therapy compared to placebo and statin therapy reduces recurrent cardiovascular events in approximately 22,500 patients with cardiovascular disease, DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) in patients with hyperlipidemia at risk for cardiovascular disease, and GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound), which will determine the effect of evolocumab on coronary atherosclerosis in approximately 950 patients undergoing cardiac catheterization.

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