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.
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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
ISIS Pharmaceuticals and Genzyme Corporation.
Raal
Frederick J
FJ
Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa. frederick.raal@wits.ac.za
Santos
Raul D
RD
Blom
Dirk J
DJ
Marais
A David
AD
Charng
Min-Ji
MJ
Cromwell
William C
WC
Lachmann
Robin H
RH
Gaudet
Daniel
D
Tan
Ju L
JL
Chasan-Taber
Scott
S
Tribble
Diane L
DL
Flaim
Joann D
JD
Crooke
Stanley T
ST
D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053299:Apolipoprotein B-100 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D005260:Female; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008297:Male; D009841:Oligonucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; D008055:Lipids; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C524142:mipomersen; D000410:Alanine Transaminase