Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody
Year: 2015
Type: article
Abstract: 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<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). 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.
Authors: Paul N. Hopkins, Joep Defesche, Sigrid W. Fouchier, Eric Bruckert, Gérald Luc, Bertrand Cariou, Barbara Sjouke, Trond P. Leren, Mariko Harada-Shiba, Hiroshi Mabuchi, Jean-Pierre Rabès, Alain Carrié, Charles van Heyningen, Valérie Carreau, Michel Farnier, Yee P. Teoh, Mafalda Bourbon, Masa-aki Kawashiri, Atsushi Nohara, Handrean Soran, A. David Marais, Hayato Tada, Marianne Abifadel, Catherine Boileau, Bernard Chanu, Shoji Katsuda, Ichiro Kishimoto, Gilles Lambert, Hisashi Makino, Yoshihiro Miyamoto, Matthieu Pichelin, Kunimasa Yagi, Masakazu Yamagishi, Yassine Zair, Scott Mellis, George D. Yancopoulos, Neil Stahl, Johanna Mendoza, Yunling Du, Sara Hamon, Michel Krempf, Gary D. Swergold
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Danone, Johns Hopkins University, Central Manchester University Hospitals NHS Foundation Trust, Regeneron Pharmaceuticals, Université de Lille, Kowa Company, National Cerebral and Cardiovascular Center, Kanazawa University, Institut National de la Santé et de la Recherche Médicale, Novo Nordisk, Saint Joseph University, Astellas Pharma, Université Pierre et Marie Curie, Universidade de Lisboa, University of Cape Town, Astellas Foundation for Research on Metabolic Disorders, Université de Nantes, Assistance publique-Hôpitaux de Paris, Université de Versailles Saint-Quentin-en-Yvelines, Medical Research Council, Japan Society for the Promotion of Science, Fundação para a Ciência e a Tecnologia
OpenAlex ID: W2153159453