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.

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.

• Authors: Evan A Stein, Narimon Honarpour, Scott M Wasserman, Feng Xu, Rob Scott, Frederick J Raal
• Journal: Circulation (Circulation) Vol. 128 Issue 19 Pg. 2113-20 (Nov 05 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 24014831 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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