Document Detail


Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.
MedLine Citation:
PMID:  22633824     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia.
METHODS: This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876.
FINDINGS: 77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment.
INTERPRETATION: REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder.
FUNDING: Sanofi US and Regeneron Pharmaceuticals Incorporated.
Authors:
Evan A Stein; Dan Gipe; Jean Bergeron; Daniel Gaudet; Robert Weiss; Robert Dufour; Richard Wu; Robert Pordy
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Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-05-26
Journal Detail:
Title:  Lancet     Volume:  380     ISSN:  1474-547X     ISO Abbreviation:  Lancet     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-09     Completed Date:  2012-07-23     Revised Date:  2014-10-20    
Medline Journal Info:
Nlm Unique ID:  2985213R     Medline TA:  Lancet     Country:  England    
Other Details:
Languages:  eng     Pagination:  29-36     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT01266876
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Antibodies, Monoclonal / administration & dosage*,  adverse effects
Anticholesteremic Agents / administration & dosage*,  adverse effects
Azetidines / administration & dosage*,  adverse effects
Cholesterol, LDL / blood
Double-Blind Method
Female
Heterozygote
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Hyperlipoproteinemia Type II / blood,  drug therapy*
Male
Middle Aged
Proprotein Convertases / immunology
Serine Endopeptidases / immunology
Treatment Outcome
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Anticholesteremic Agents; 0/Azetidines; 0/Cholesterol, LDL; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/alirocumab; 163222-33-1/ezetimibe; EC 3.4.-/Proprotein Convertases; EC 3.4.21.-/PCSK9 protein, human; EC 3.4.21.-/Serine Endopeptidases
Comments/Corrections
Comment In:
Lancet. 2012 Jul 7;380(9836):6-7   [PMID:  22633823 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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