Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Circulation: Genomic and Precision Medecine Année : 2015

Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

Joep Defesche
  • Fonction : Auteur
Sigrid W. Fouchier
  • Fonction : Auteur
Trond P. Leren
  • Fonction : Auteur
Hiroshi Mabuchi
  • Fonction : Auteur
Charles Van Heyningen
  • Fonction : Auteur
Yee P. Teoh
  • Fonction : Auteur
Mafalda Bourbon
  • Fonction : Auteur
Masa-Aki Kawashiri
  • Fonction : Auteur
Atsushi Nohara
  • Fonction : Auteur
Handrean Soran
  • Fonction : Auteur
A. David Marais
  • Fonction : Auteur
Hayato Tada
  • Fonction : Auteur
Catherine Boileau
Shoji Katsuda
  • Fonction : Auteur
Ichiro Kishimoto
  • Fonction : Auteur
Hisashi Makino
  • Fonction : Auteur
Yoshihiro Miyamoto
  • Fonction : Auteur
Kunimasa Yagi
  • Fonction : Auteur
Masakazu Yamagishi
  • Fonction : Auteur
Scott Mellis
  • Fonction : Auteur
George D. Yancopoulos
  • Fonction : Auteur
Neil Stahl
  • Fonction : Auteur
Johanna Mendoza
  • Fonction : Auteur
Yunling Du
  • Fonction : Auteur
Sara Hamon
  • Fonction : Auteur
Gary D. Swergold
  • Fonction : Auteur

Résumé

BACKGROUND: 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. METHODS AND RESULTS: 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\textless0.0001) 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\textless0.0001). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
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hal-01830975 , version 1 (13-07-2018)

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Paul N. Hopkins, Joep Defesche, Sigrid W. Fouchier, Eric Bruckert, Gérald Luc, et al.. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circulation: Genomic and Precision Medecine, 2015, Equipe 5, 8 (6), pp.823--831. ⟨10.1161/CIRCGENETICS.115.001129⟩. ⟨hal-01830975⟩
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