title: Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial.
abstract: BACKGROUND
  Despite statin treatment, many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol (LDL-C) targets. AMG 145, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease, demonstrated significant reductions in LDL-C in phase 1 studies. This phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients.
  
  
  RESULTS
  Patients with heterozygous familial hypercholesterolemia diagnosed by Simon Broome criteria with LDL-C ≥2.6 mmol/L (100 mg/dL) despite statin therapy with or without ezetimibe were randomized 1:1:1 to AMG 145 350 mg, AMG 145 420 mg, or placebo-administered subcutaneously every 4 weeks. The primary end point was percentage change from baseline in LDL-C at week 12. Of 168 patients randomized, 167 received investigational product and were included in the full analysis set (mean [SD] age, 50 [13] years; 47% female; 89% white; mean [SD] baseline LDL-C, 4.0 [1.1] mmol/L (156 [42] mg/dL)). At week 12, LDL-C reduction measured by preparative ultracentrifugation (least squares mean [standard error (SE)]) was 43 (3)% and 55 (3)% with AMG 145 350 mg and 420 mg, respectively, compared with 1 (3)% increase with placebo (P<0.001 for both dose groups). Serious adverse events (not considered treatment-related) occurred in 2 patients on AMG 145.
  
  
  CONCLUSIONS
  AMG 145 administered every 4 weeks yielded rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients despite intensive statin use, with or without ezetimibe, with minimal adverse events and good tolerability.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01375751.
authors.affiliation: Carbohydrate & Lipid Metabolism Research Unit, Division of Endocrinology & Metabolism, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Frederick
authors.initials: F
authors.lastname: Raal
authors.forename: Rob
authors.initials: R
authors.lastname: Scott
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.forename: Ian
authors.initials: I
authors.lastname: Bridges
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe; C577155:evolocumab