title: PCSK9: From discovery to therapeutic applications.
abstract: The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol metabolism mainly by targeting the low-density lipoprotein receptor (LDLR) for degradation in the liver. Gain-of-function mutations in PCSK9 are one of the genetic causes of autosomal dominant hypercholesterolaemia. Conversely, loss-of-function mutations are associated with lower concentrations of LDL cholesterol (LDL-C) and reduced coronary heart disease. As these loss-of-function mutations are not associated with apparent deleterious effects, PCSK9 inhibition is an attractive new strategy for lowering LDL-C concentration. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. A dramatic decrease in LDL-C up to 70% can be obtained with the most efficacious doses. Efficacy has been evaluated so far in addition to statins in hypercholesterolaemic patients with or without familial hypercholesterolaemia, in patients with intolerance to statin therapy and in monotherapy. Large phase III programmes are ongoing to evaluate the long-term efficacy and safety of these very promising new agents.
authors.affiliation: Point médical, rond point de la nation, 21000 Dijon, France. Electronic address: michelfarnier@nerim.net.
authors.forename: Michel
authors.initials: M
authors.lastname: Farnier
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015195:Drug Design; D020022:Genetic Predisposition to Disease; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D047428:Protein Kinase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C577155:evolocumab
keywords: Anticorps monoclonaux; Familial hypercholesterolaemia; Hypercholestérolémie familiale; LDL cholesterol; LDL-cholestérol; LDL-receptor; Monoclonal antibodies; Proprotein convertase subtilisin/kexin type 9 (PCSK9); Récepteur des LDL