title: Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.
abstract: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported.
  
  
  
  We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001).
  
  
  
  PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.forename: Joep
authors.initials: J
authors.lastname: Defesche
authors.forename: Sigrid W
authors.initials: SW
authors.lastname: Fouchier
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.forename: Gérald
authors.initials: G
authors.lastname: Luc
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.forename: Barbara
authors.initials: B
authors.lastname: Sjouke
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
authors.forename: Alain
authors.initials: A
authors.lastname: Carrié
authors.forename: Charles
authors.initials: C
authors.lastname: van Heyningen
authors.forename: Valérie
authors.initials: V
authors.lastname: Carreau
authors.forename: Michel
authors.initials: M
authors.lastname: Farnier
authors.forename: Yee P
authors.initials: YP
authors.lastname: Teoh
authors.forename: Mafalda
authors.initials: M
authors.lastname: Bourbon
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Bernard
authors.initials: B
authors.lastname: Chanu
authors.forename: Shoji
authors.initials: S
authors.lastname: Katsuda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.forename: Hisashi
authors.initials: H
authors.lastname: Makino
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Matthieu
authors.initials: M
authors.lastname: Pichelin
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Yagi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Yassine
authors.initials: Y
authors.lastname: Zair
authors.forename: Scott
authors.initials: S
authors.lastname: Mellis
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.forename: Johanna
authors.initials: J
authors.lastname: Mendoza
authors.forename: Yunling
authors.initials: Y
authors.lastname: Du
authors.forename: Sara
authors.initials: S
authors.lastname: Hamon
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Gary D
authors.initials: GD
authors.lastname: Swergold
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C571059:alirocumab
keywords: PCSK9 protein; alirocumab; cardiovascular diseases; clinical trial; genetics; human; hypercholesterolemia