title: Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials.
abstract: OBJECTIVE
  Prior trials with monoclonal antibodies to proprotein convertase subtilizin/kexin type 9 (PCSK9) reported robust low density lipoprotein cholesterol (LDL-C) reductions. However, the ability to detect potentially beneficial changes in other lipoproteins such as lipoprotein (a), triglycerides, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (Apo) A1, and adverse events (AEs) was limited by sample sizes of individual trials. We report a pooled analysis from four phase 2 studies of evolocumab (AMG 145), a monoclonal antibody to PCSK9.
  
  
  RESULTS
  The trials randomized 1359 patients to various doses of subcutaneous evolocumab every 2 weeks (Q2W) or 4 weeks (Q4W), placebo, or ezetimibe for 12 weeks; 1252 patients contributed to efficacy and 1314, to safety analyses. Mean percentage (95% CI) reductions in LDL-C vs. placebo ranged from 40.2% (44.6%, 35.8%) to 59.3% (63.7%, 54.8%) among the evolocumab groups (all P < 0.001). Statistically significant reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides and lipoprotein (a) [Lp(a)], and increases in HDL-C were also observed. Adverse events (AEs) and serious AEs with evolocumab were reported in 56.8 and 2.0% of patients, compared with 49.2% and 1.2% with placebo. Adjudicated cardiac and cerebrovascular events were reported in 0.3 and 0% in the placebo and 0.9 and 0.3% in the evolocumab arms, respectively.
  
  
  CONCLUSIONS
  In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W, demonstrated significant and favourable changes in other atherogenic and anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment period.
authors.affiliation: Metabolic and Atherosclerosis Research Centre, Cincinnati, OH, USA esteinmrl@aol.com.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: Jacksonville Centre for Clinical Research, Jacksonville, FL, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Koren
authors.affiliation: Carbohydrate & Lipid Metabolism Research Unit, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
authors.affiliation: Sterling Research Group, Cincinnati, OH, USA.
authors.forename: Eli M
authors.initials: EM
authors.lastname: Roth
authors.affiliation: Maine Research Associates, Auburn, ME, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Weiss
authors.affiliation: Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Sullivan
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Jae B
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liu
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Moetaz
authors.initials: M
authors.lastname: Albizem
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001384:Azetidines / Q000008:administration & dosage*; D017322:Clinical Trials, Phase II as Topic; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000276:immunology*; D016032:Randomized Controlled Trials as Topic; D012697:Serine Endopeptidases / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D001384:Azetidines; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe; C577155:evolocumab
keywords: Low-density lipoprotein cholesterol; Proprotein convertase subtilizin/kexin type 9; Randomized controlled trials