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 (CAD). 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 CAD.
Methods and Results—This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and CAD 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 endpoint was percent change in LDL-C from baseline at Week 28. Safety assessments included adverse events, laboratory tests, and MRI 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 to 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 to placebo, all P<0.001. No significant change occurred in HDL cholesterol. Adverse events included injection site reactions and flu-like symptoms. Five (6%) mipomersen patients had 2 consecutive alanine aminotransferases ≥3 times ULN at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen vs. 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 CAD on statins and other lipid lowering therapy. The significance of hepatic fat and transaminase increases remain uncertain at this time.
Clinical Trial Registration Information—www.clinicaltrials.gov. Identifier: NCT00706849.
- Received March 8, 2012.
- Accepted September 10, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited