TY - JOUR
T1 - Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody
AU - Hopkins, Paul N.
AU - Defesche, Joep
AU - Fouchier, Sigrid W.
AU - Bruckert, Eric
AU - Luc, Gérald
AU - Cariou, Bertrand
AU - Sjouke, Barbara
AU - Leren, Trond P.
AU - Harada-Shiba, Mariko
AU - Mabuchi, Hiroshi
AU - Rabès, Jean-Pierre
AU - Carrié, Alain
AU - van Heyningen, Charles
AU - Carreau, Valérie
AU - Farnier, Michel
AU - Teoh, Yee P.
AU - Bourbon, Mafalda
AU - Kawashiri, Masa-Aki
AU - Nohara, Atsushi
AU - Soran, Handrean
AU - Marais, A. David
AU - Tada, Hayato
AU - Abifadel, Marianne
AU - Boileau, Catherine
AU - Chanu, Bernard
AU - Katsuda, Shoji
AU - Kishimoto, Ichiro
AU - Lambert, Gilles
AU - Makino, Hisashi
AU - Miyamoto, Yoshihiro
AU - Pichelin, Matthieu
AU - Yagi, Kunimasa
AU - Yamagishi, Masakazu
AU - Zair, Yassine
AU - Mellis, Scott
AU - Yancopoulos, George D.
AU - Stahl, Neil
AU - Mendoza, Johanna
AU - Du, Yunling
AU - Hamon, Sara
AU - Krempf, Michel
AU - Swergold, Gary D.
PY - 2015
Y1 - 2015
N2 - 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). ConclusionsPCSK9 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
AB - 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). ConclusionsPCSK9 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
U2 - https://doi.org/10.1161/CIRCGENETICS.115.001129
DO - https://doi.org/10.1161/CIRCGENETICS.115.001129
M3 - Article
C2 - 26374825
SN - 1942-325X
VL - 8
SP - 823
EP - 831
JO - Circulation. Cardiovascular genetics
JF - Circulation. Cardiovascular genetics
IS - 6
ER -