The European Commission (EC) has granted marketing authorization for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be approved in the world, for the treatment of patients with uncontrolled cholesterol who require additional intensive low-density lipoprotein cholesterol (LDL-C) reduction. Evolocumab is a human monoclonal antibody that inhibits PCSK9, a protein that targets LDL receptors for degradation and thereby reduces the liver's ability to remove LDL-C from the blood.

The EC approved evolocumab for:

• The treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial [HeFH]) or mixed dyslipidemia, as an adjunct to diet:
  - in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or
  - alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.
• The treatment of adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia (HoFH) in combination with other lipid-lowering therapies.

The effect of evolocumab on cardiovascular morbidity and mortality has not yet been determined.

More than 60 percent of high-risk patients in Europe are still unable to adequately lower their LDL-C levels with statins or other currently approved lipid-lowering agents. Among very high-risk patients, the percentage is increased to more than 80 percent.

One high-risk patient group includes those with familial hypercholesterolemia (FH), an inherited condition caused by genetic mutations which lead to high levels of LDL-C at an early age. It is estimated that less than one percent of people with FH (heterozygous and homozygous forms) in most countries are diagnosed.

"Many patients who are taking cholesterol-lowering therapies, including those with familial hypercholesterolemia, still struggle to control their LDL cholesterol levels," said John J.P. Kastelein, professor of medicine and chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam. "As the first in a new class of drugs in the European Union, evolocumab will offer physicians an important and innovative treatment option for patients with uncontrolled cholesterol who require additional LDL cholesterol reduction."

Approval from the EC grants a centralized marketing authorization with unified labeling in the 28 countries that are members of the EU. Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions on the basis of the decision of the EC.

Data show evolocumab has demonstrated substantial and consistent reductions in LDL-C levels with supporting beneficial changes in other lipid parameters in approximately 6,000 patients with primary hyperlipidemia and mixed dyslipidemia, including more than 4,500 patients with high cholesterol in 10 Phase 3 trials. In these studies, evolocumab significantly reduced LDL-C by approximately 55 percent to 75 percent compared with placebo, and by approximately 35 percent to 45 percent compared with ezetimibe. In patients with homozygous FH, evolocumab significantly reduced LDL-C by approximately 15 percent to 30 percent compared with placebo. Reduction of LDL-C was maintained with long-term treatment.

The adverse event profile for evolocumab was comparable overall to that of the control groups.The most common adverse reactions that occurred in greater than or equal to 2 percent of the evolocumab group, and more frequently than in the control group, were nasopharyngitis, upper respiratory tract infection, back pain, arthralgia, influenza and nausea.

Evolocumab is for subcutaneous injection into the abdomen, thigh or upper arm region. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard. Evolocumab must not be administered intravenously or intramuscularly. Before starting treatment with evolocumab, secondary causes (non-genetic) of excess cholesterol and abnormal fat levels in blood should be excluded. The medicine can only be obtained with a prescription.

Press release Amgen July 21 2015