title: Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia.
abstract: BACKGROUND
  Homozygous familial hypercholesterolemia is a rare, serious disorder with a substantial reduction in low-density lipoprotein (LDL) receptor function, severely elevated LDL cholesterol, cardiovascular disease, and often death in childhood. Response to conventional drug therapies is modest. Monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK9) reduce LDL cholesterol in heterozygous familial hypercholesterolemia. The effect in homozygous familial hypercholesterolemia is unknown and uncertain. We evaluated the efficacy and safety of AMG 145 in an open-label, single-arm, multicenter, dose-scheduling pilot study in patients with homozygous familial hypercholesterolemia.
  
  
  RESULTS
  Eight patients with LDL receptor-negative or -defective homozygous familial hypercholesterolemia on stable drug therapy were treated with subcutaneous 420 mg AMG 145 every 4 weeks for ≥12 weeks, followed by 420 mg AMG 145 every 2 weeks for an additional 12 weeks. All patients completed both treatment periods. Mean change from baseline in LDL cholesterol at week 12 was -16.5% (range, 5.2% to -43.6%; P=0.0781) and -13.9% (range, 39.9% to -43.3%; P=0.1484) with 4- and 2-week dosing, respectively. No reduction was seen in the 2 receptor-negative patients. Over the treatment periods, mean±SD LDL cholesterol reductions in the 6 LDL receptor-defective patients were 19.3±16% and 26.3±20% with 4- and 2-week dosing, respectively (P=0.0313 for both values), ranging from 4% to 48% with 2-week dosing. No serious side effects were reported.
  
  
  CONCLUSIONS
  This study demonstrates significant and dose-related LDL cholesterol lowering with a PCSK9 monoclonal antibody in homozygous familial hypercholesterolemia patients with defective LDL receptor activity but no reduction in those who were receptor negative.
authors.affiliation: Metabolic and Atherosclerosis Research Center, Cincinnati, OH (E.A.S.); Global Development (N.H., S.M.W., R.S.) and Biostatistics (F.X.), Amgen Inc, Thousand Oaks, CA; and Carbohydrate & Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.J.R.).
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
authors.forename: Narimon
authors.initials: N
authors.lastname: Honarpour
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000276:immunology*; D011973:Receptors, LDL / Q000235:genetics / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: AMG 145; antibodies, monoclonal; cholesterol, LDL; hypercholesterolemia