Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease.
BACKGROUND
Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease.


RESULTS
This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (-28.0% [-34.0% to -22.1%] compared with 5.2% [-0.5% to 10.9%] increase with placebo; P<0.001). Mipomersen significantly reduced apolipoprotein B (-26.3%), total cholesterol (-19.4%), and lipoprotein(a) (-21.1%) compared with placebo (all P<0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (P<0.001).


CONCLUSIONS
Mipomersen is an effective therapy to further reduce apolipoprotein B-containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00706849.
Metabolic and Atherosclerosis Research Center, 5355 Medpace Way, Cincinnati, OH 45227, USA. esteinmrl@aol.com
Evan A
EA
Stein
Robert
R
Dufour
Claude
C
Gagne
Daniel
D
Gaudet
Cara
C
East
Joanne M
JM
Donovan
Wai
W
Chin
Diane L
DL
Tribble
Mary
M
McGowan
D000410:Alanine Transaminase / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors*; D001663:Bilirubin / Q000378:metabolism; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000453:epidemiology* / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000453:epidemiology* / Q000378:metabolism; D007279:Injections, Subcutaneous; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C524142:mipomersen; D000410:Alanine Transaminase; D001663:Bilirubin