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FDA Accepts Application for LDL Cholesterol-Lowering Drug Evolocumab

Approval decision expected in August 2015

The FDA has accepted for review a biologics license application (BLA) for evolocumab (Amgen) for the treatment of high cholesterol.

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 low-density lipoprotein cholesterol (LDL-C) –– or “bad” cholesterol –– from the blood. Evolocumab is designed to bind to PCSK9, thereby inhibiting that protein’s ability to bind to LDL receptors on the surface of the liver. In the absence of PCSK9, more LDL receptors are present on the liver to remove LDL-C from the blood.

The BLA, submitted in August 2014, is based on data from approximately 6,800 patients, including more than 4,500 patients with high cholesterol in 10 phase III trials. These studies evaluated the safety and efficacy of evolocumab in 1) patients with elevated cholesterol receiving statins with or without other lipid-lowering therapies; 2) patients who could not tolerate statins; 3) patients with heterozygous familial hypercholesterolemia (HeFH); and 4) patients with homozygous familial hypercholesterolemia (HoFH).

The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of August 27, 2015, for the evolocumab application.

High cholesterol, particularly elevated LDL-C, is the most common form of dyslipidemia. Elevated LDL-C is recognized as a major risk factor for cardiovascular disease. Familial hypercholesterolemia (FH) is an inherited condition caused by genetic mutations that lead to high levels of LDL-C at an early age. It is estimated that less than 1% of people with FH (both HeFH and HoFH) in the U.S. are diagnosed.

HeFH is the more common type of FH and occurs globally in approximately one in 200 to 500 people. It can cause LDL-C levels that are twice as high as normal (e.g., > 190 mg/dL). Individuals with HeFH have one altered copy of a cholesterol-regulating gene.

HoFH is the rare, more severe form, occurring in approximately one in 1 million individuals. It can cause LDL-C levels that are more than six times higher than normal (e.g., 650–1,000 mg/dL). An individual with HoFH has two altered copies of cholesterol-regulating genes (one from each parent). In 2013, the FDA granted evolocumab an orphan drug designation for HoFH.

The PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulations) clinical trial program is evaluating evolocumab in 22 studies, with a combined planned total enrollment of approximately 35,000 patients.

The phase III program includes 16 trials evaluating evolocumab administered every 2 weeks or monthly in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2 and YUKAWA-2); in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2 and GAUSS-3); as a stand-alone treatment in patients with hyperlipidemia (MENDEL-2); in patients whose elevated cholesterol is caused by HeFH (RUTHERFORD-2 and TAUSSIG) or HoFH (TESLA and TAUSSIG); the effects of evolocumab on lipoprotein metabolism (FLOREY); and the administration of evolocumab in statin-treated patients with hyperlipedmia (THOMAS-1 and THOMAS-2).

Source: Amgen; November 10, 2014.

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