Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy

PLoS One. 2012;7(11):e49006. doi: 10.1371/journal.pone.0049006. Epub 2012 Nov 13.


Objectives: Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated.

Methods and results: Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n = 58) were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n = 39) or placebo (n = 19) were added to lipid-lowering therapy for 26 weeks.

Main outcome: percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27) reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18) from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001). Mipomersen produced statistically significant (p<0.001) reductions in apolipoprotein B and lipoprotein(a), with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%), 39(100%); serious adverse events, 0(0%), 6(15.4%); discontinuations due to adverse events, 1(5.3%), 8(20.5%) and cardiac adverse events, 1(5.3%), 5(12.8%).

Conclusion: Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a). Mounting evidence suggests it may be a potential pharmacologic option for lowering LDL-C in patients with severe hypercholesterolemia not adequately controlled using existing therapies. Future studies will explore alternative dosing schedules aimed at minimizing side effects.

Trial registration: ClinicalTrials.gov NCT00794664.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / therapeutic use*
  • Cholesterol, LDL / blood
  • Female
  • Humans
  • Hypercholesterolemia / drug therapy*
  • Male
  • Oligodeoxyribonucleotides, Antisense / administration & dosage
  • Oligodeoxyribonucleotides, Antisense / adverse effects
  • Oligodeoxyribonucleotides, Antisense / therapeutic use*
  • Oligonucleotides / administration & dosage
  • Oligonucleotides / adverse effects
  • Oligonucleotides / therapeutic use*
  • Treatment Outcome


  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Oligodeoxyribonucleotides, Antisense
  • Oligonucleotides
  • mipomersen

Associated data

  • ClinicalTrials.gov/NCT00794664

Grant support

This trial was supported by Genzyme Corporation (http://www.genzyme.com/). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.