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Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia

Circulation (New York, N.Y.), 2013-11, Vol.128 (19), p.2113-2120 [Peer Reviewed Journal]

2013 by the American College of Cardiology Foundation and the American Heart Association, Inc. ;2014 INIST-CNRS ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/CIRCULATIONAHA.113.004678 ;PMID: 24014831 ;CODEN: CIRCAZ

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Title:
Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia
Author: Stein, Evan A ; Honarpour, Narimon ; Wasserman, Scott M ; Xu, Feng ; Scott, Rob ; Raal, Frederick J
Subjects: Adolescent ; Adult ; Aged ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Child ; Cholesterol, LDL - blood ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Disorders of blood lipids. Hyperlipoproteinemia ; Female ; Homozygote ; Humans ; Hyperlipoproteinemia Type II - blood ; Hyperlipoproteinemia Type II - drug therapy ; Hyperlipoproteinemia Type II - genetics ; Male ; Medical sciences ; Metabolic diseases ; Middle Aged ; Pilot Projects ; Proprotein Convertase 9 ; Proprotein Convertases - immunology ; Receptors, LDL - genetics ; Receptors, LDL - immunology ; Serine Endopeptidases - immunology ; Treatment Outcome ; Young Adult
Is Part Of: Circulation (New York, N.Y.), 2013-11, Vol.128 (19), p.2113-2120
Description: 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. CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifiersNCT01588496 and NCT01624142.
Publisher: Hagerstown, MD: by the American College of Cardiology Foundation and the American Heart Association, Inc
Language: English
Identifier: ISSN: 0009-7322
EISSN: 1524-4539
DOI: 10.1161/CIRCULATIONAHA.113.004678
PMID: 24014831
CODEN: CIRCAZ
Source: Geneva Foundation Free Medical Journals
MEDLINE

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Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia

2013 by the American College of Cardiology Foundation and the American Heart Association, Inc. ;2014 INIST-CNRS ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/CIRCULATIONAHA.113.004678 ;PMID: 24014831 ;CODEN: CIRCAZ

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