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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial
The Lancet, Volume 375, No. 9719, Year 2010
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Description
Background: Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. Methods: This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs ≥50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. Findings: 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11·4 mmol/L (SD 3·6) in the mipomersen group and 10·4 mmol/L (3·7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (-24·7%, 95% CI -31·6 to -17·7) than with placebo (-3·3%, -12·1 to 5·5; p=0·0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Interpretation: Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. Funding: ISIS Pharmaceuticals and Genzyme Corporation. © 2010 Elsevier Ltd. All rights reserved.
Authors & Co-Authors
Raal, Frederick Johan
South Africa, Johannesburg
University of the Witwatersrand
Santos, Raul D.
Brazil, Sao Paulo
Universidade de São Paulo
Blom, Dirk J.
South Africa, Cape Town
University of Cape Town
Marais, Adrian David
South Africa, Cape Town
University of Cape Town
Charng, Mingji
Taiwan, Taipei
National Yang-ming University Taiwan
Cromwell, William C.
United States, Charlotte
Presbyterian Center for Preventive Cardiology
Lachmann, Robin
United Kingdom, London
University College London Hospitals Nhs Foundation Trust
Gaudet, Daniel
Canada, Montreal
University of Montreal
Tan, Ju L.
Singapore, Singapore City
National Heart Centre Singapore
Chasan-Taber, Scott
United States, Cambridge
Genzyme Corporation
Tribble, Diane L.
United States, Carlsbad
Ionis Pharmaceuticals, Inc.
Flaim, Jo Ann D.
United States, Carlsbad
Ionis Pharmaceuticals, Inc.
Crooke, Stanley T.
United States, Carlsbad
Ionis Pharmaceuticals, Inc.
Statistics
Citations: 789
Authors: 13
Affiliations: 10
Identifiers
Doi:
10.1016/S0140-6736(10)60284-X
ISSN:
01406736
Research Areas
Disability
Genetics And Genomics
Maternal And Child Health