Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia

Circulation. 2013 Nov 5;128(19):2113-20. doi: 10.1161/CIRCULATIONAHA.113.004678. Epub 2013 Sep 6.


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.

Methods and 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT01588496 NCT01624142.

Keywords: AMG 145; antibodies, monoclonal; cholesterol, LDL; hypercholesterolemia.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Child
  • Cholesterol, LDL / blood*
  • Female
  • Homozygote
  • Humans
  • Hyperlipoproteinemia Type II* / blood
  • Hyperlipoproteinemia Type II* / drug therapy
  • Hyperlipoproteinemia Type II* / genetics
  • Male
  • Middle Aged
  • Pilot Projects
  • Proprotein Convertase 9
  • Proprotein Convertases / immunology*
  • Receptors, LDL / genetics
  • Receptors, LDL / immunology
  • Serine Endopeptidases / immunology*
  • Treatment Outcome
  • Young Adult


  • Antibodies, Monoclonal
  • Cholesterol, LDL
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases

Associated data

  • ClinicalTrials.gov/NCT01588496
  • ClinicalTrials.gov/NCT01624142