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

Medientyp: E-Artikel
Titel: Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody
Beteiligte: Hopkins, Paul N.; Defesche, Joep; Fouchier, Sigrid W.; Bruckert, Eric; Luc, Gérald; Cariou, Bertrand; Sjouke, Barbara; Leren, Trond P.; Harada-Shiba, Mariko; Mabuchi, Hiroshi; Rabès, Jean-Pierre; Carrié, Alain; van Heyningen, Charles; Carreau, Valérie; Farnier, Michel; Teoh, Yee P.; Bourbon, Mafalda; Kawashiri, Masa-aki; Nohara, Atsushi; Soran, Handrean; Marais, A. David; Tada, Hayato; Abifadel, Marianne; Boileau, Catherine; [...]
Erschienen: Ovid Technologies (Wolters Kluwer Health), 2015
Erschienen in: Circulation: Cardiovascular Genetics
Sprache: Englisch
DOI: 10.1161/circgenetics.115.001129
ISSN: 1942-325X; 1942-3268
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Beschreibung: <jats:sec> <jats:title>Background—</jats:title> <jats:p> Patients with <jats:italic>PCSK9</jats:italic> 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> We compiled clinical characteristics of <jats:italic>PCSK9</jats:italic> 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 <jats:italic>PCSK9</jats:italic> 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 <jats:italic>PCSK9</jats:italic> 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 <jats:italic>LDLR</jats:italic> (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in <jats:italic>PCSK9</jats:italic> GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% ( <jats:italic>P</jats:italic> <0.0001) from baseline, 53.7% compared with placebo-treated <jats:italic>PCSK9</jats:italic> GOF mutation patients ( <jats:italic>P</jats:italic> =0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline ( <jats:italic>P</jats:italic> <0.0001). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> <jats:italic>PCSK9</jats:italic> 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trial Registration—</jats:title> <jats:p> URL: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</jats:ext-link> . Unique Identifier: NCT01604824. </jats:p> </jats:sec>
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