title: Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies.
abstract: BACKGROUND
  Evolocumab, a fully human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), markedly reduces low-density lipoprotein cholesterol across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group.
  
  
  METHODS
  This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and, of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in 2 OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs, laboratory assessments, and AEs of interest were evaluated.
  
  
  RESULTS
  Overall AE rates were similar between evolocumab and control in the parent trials (51.1% versus 49.6%) and in year 1 of OLE trials (70.0% versus 66.0%), as were those for serious AEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups versus 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing antievolocumab antibodies were detected.
  
  
  CONCLUSIONS
  Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in OLE trials for 1 year supports a favorable benefit-risk profile for evolocumab.
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.). peter.toth@cghmc.com.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Toth
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Descamps
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: David
authors.initials: D
authors.lastname: Preiss
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Ricardo
authors.initials: R
authors.lastname: Dent
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Constantine
authors.initials: C
authors.lastname: Djedjos
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Yuna
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Geller
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Magdalena
authors.initials: M
authors.lastname: Uhart
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.affiliation: From CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD (P.P.T.); Lipid Clinic, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium (O.D.); The McGill University Health Centre, Montreal, Canada (J.G.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK (N.S.); Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK (D.P.); and Amgen Inc, Thousand Oaks, CA (R.D., C.D., Y.W., M.G., M.U., R.S., S.M.W.).
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D004311:Double-Blind Method; D006801:Humans; D009135:Muscular Diseases / Q000139:chemically induced* / Q000453:epidemiology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C577155:evolocumab
keywords: antibodies monoclonal; cholesterol, LDL; long-term adverse events; myalgia; proprotein convertase 9