Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol

• Published in: The New England journal of medicine Vol. 366; no. 12; pp. 1108 - 1118
• Main Authors: Stein, Evan A, Mellis, Scott, Yancopoulos, George D, Stahl, Neil, Logan, Douglas, Smith, William B, Lisbon, Eleanor, Gutierrez, Maria, Webb, Cheryle, Wu, Richard, Du, Yunling, Kranz, Therese, Gasparino, Evelyn, Swergold, Gary D
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 22.03.2012
• Subjects: Adult; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - adverse effects; Anticholesteremic Agents - therapeutic use; Atorvastatin; Atorvastatin Calcium; Biological and medical sciences; Cardiovascular disease; Cholesterol; Cholesterol, LDL - blood; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; General aspects; Heptanoic Acids - therapeutic use; Humans; Hypercholesterolemia; Hypercholesterolemia - drug therapy; Hypercholesterolemia - metabolism; Hyperlipoproteinemia Type II - drug therapy; Hyperlipoproteinemia Type II - metabolism; Injections, Intravenous; Injections, Subcutaneous; Kexin; Least-Squares Analysis; Lipoproteins - blood; Low density lipoprotein; Male; Medical sciences; Middle Aged; Monoclonal antibodies; Proprotein Convertase 9; Proprotein convertases; Proprotein Convertases - antagonists & inhibitors; Proprotein Convertases - immunology; Proprotein Convertases - metabolism; Pyrroles - therapeutic use; Receptors, LDL - drug effects; Receptors, LDL - metabolism; Serine; Serine Endopeptidases - immunology; Serine Endopeptidases - metabolism; Subtilisin; Medicine; Cholesterol LDL; Monoclonal antibody
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa1105803

A monoclonal antibody to PCSK9 was studied in two single-dose trials in healthy volunteers and one multiple-dose trial in patients with familial or nonfamilial hypercholesterolemia. In all three groups, the antibody reduced levels of LDL cholesterol. In 2003, Abifadel and colleagues 1 described two families with autosomal dominant hypercholesterolemia that was associated with gain-of-function mutations in proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases. These patients had high plasma levels of low-density lipoprotein (LDL) cholesterol, which was associated with an increased incidence of coronary heart disease. Shortly thereafter, studies of animal models identified a role for PCSK9 in the post-translational regulation of LDL-receptor activity. 2 , 3 PCSK9, which is synthesized primarily in the liver, enters the circulation, where it binds to hepatic LDL receptors and targets them for degradation. This process reduces the capacity of the . . .