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

Study Questions:

How safe and effective is mipomersen treatment for lowering low-density lipoprotein cholesterol (LDL-C) in patients with heterozygous familial hypercholesterolemia (HeFH)?


This phase 3 trial randomized patients with HeFH and coronary artery disease (CAD) on maximally tolerated statin and LDL-C ≥100 mg/dl to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary endpoint was change in LDL-C from baseline at week 28. Safety endpoints 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 LDL-C decreased by 28% with mipomersen compared to a 5.2% increase with placebo (p < 0.001). Mipomersen reduced apolipoprotein B (26.3%), total cholesterol (-19.4%), and lipoprotein(a) (21.1%) compared to placebo, all p < 0.001. No change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and flu-like symptoms. Five (6%) mipomersen patients had two consecutive alanine aminotransferases ≥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.


Mipomersen is an effective therapy to further reduce apolipoprotein B-containing lipoproteins in HeFH patients with CAD on statins and other lipid-lowering therapy.


Treatment of LDL with statins is the most effective pharmacologic strategy to reduce cardiovascular (CV) risk. However, not all patients can achieve target LDL with statins, and many patients may benefit from additional LDL lowering. The mechanism by which LDL is lowered may be very important, as not all LDL-lowering strategies appear to translate into reduced CV risk. Mipomersen is an antisense oligonucleotide that inhibits synthesis of apolipoprotein B-100 synthesis in the liver, leading to reduced LDL and lipoprotein(a). This LDL receptor-independent mechanism may be particularly useful in patients deficient in LDL receptors; however, it remains to be demonstrated that this receptor-independent mechanism of LDL lowering will lead to reduced CV risk. The clinical implications of the transaminase and hepatic fat increases in some patients will also need to be determined. Nonetheless, mipomersen may find use in a subset of patients with refractory hyperlipidemia.

Keywords: Coronary Artery Disease, Hyperlipidemias, Mineralocorticoid Receptor Antagonists, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Apolipoprotein A-I, Bilirubin, Receptors, LDL, Cholesterol, Troponin I, Cardiology, Apolipoprotein B-100, Oligonucleotides, Antisense

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