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

• Autor(a) principal: Hopkins, P.N.
• Data de Publicação: 2015
• Outros Autores: Defesche, J., Fouchier, S.W., Bruckert, E., Luc, G., Cariou, B., Sjouke, B., Leren, T.P., Harada-Shiba, M., Mabuchi, H., Rabès, J.P., Carrié, A., van Heyningen, C., Carreau, V., Farnier, M., Teoh, Y.P., Bourbon, M., Kawashiri, M.A., Nohara, A., Soran, H., Marais, A.D., Tada, H., Abifadel, M., Boileau, C., Chanu, B., Katsuda, S., Kishimoto, I., Lambert, G., Makino, H., Miyamoto, Y., Pichelin, M., Yagi, K., Yamagishi, M., Zair, Y., Mellis, S., Yancopoulos, G.D., Stahl, N., Mendoza, J., Du, Y., Hamon, S., Krempf, M., Swergold, G.D.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.18/3173
• topic: PCSK9; Alirocumab; Cardiovascular Disease; Clinical Trial; Genetics; Hypercapnia; Hypercholesterolemia; PCSK9; Doenças Cardio e Cérebro-vasculares

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 four 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 to placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary endpoint). 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 for premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and appears to be well tolerated in these patients. Clinical Trial Registration-www.clinicaltrials.gov; Unique Identifier: NCT01604824