title: Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial.
abstract: BACKGROUND
  An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels.
  
  
  OBJECTIVE
  To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects.
  
  
  METHODS
  A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites.
  
  
  METHODS
  Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks.
  
  
  METHODS
  The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe.
  
  
  RESULTS
  Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.
  
  
  CONCLUSIONS
  In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764.
authors.affiliation: Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Sullivan
authors.forename: Anders G
authors.initials: AG
authors.lastname: Olsson
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.forename: Jae B
authors.initials: JB
authors.lastname: Kim
authors.forename: Allen
authors.initials: A
authors.lastname: Xue
authors.forename: Val
authors.initials: V
authors.lastname: Gebski
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
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; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects*; D000075202:Contraindications; D003327:Coronary Disease / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006620:Hip Fractures / Q000139:chemically induced; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced; D059352:Musculoskeletal Pain / Q000139:chemically induced; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000276:immunology*; D012306:Risk; D012697:Serine Endopeptidases / Q000276:immunology*; D013575:Syncope / Q000139:chemically induced
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C577155:evolocumab