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

Abstract

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.

• Authors: Mary P McGowan, Jean-Claude Tardif, Richard Ceska, Lesley J Burgess, Handrean Soran, Ioanna Gouni-Berthold, Gilbert Wagener, Scott Chasan-Taber
• Journal: PloS one (PLoS One) Vol. 7 Issue 11 Pg. e49006 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23152839 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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