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

Heterozygous familial hypercholesterolemia is a common genetic disorder that leads to premature coronary artery disease. Despite aggressive lipid-lowering therapy, many patients with heterozygous familial hypercholesterolemia fail to achieve optimal low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in patients with heterozygous familial hypercholesterolemia with coronary artery disease who were already on maximally tolerated lipid-lowering therapy and had LDL-C 2.6 mmol/L (100 mg/dL). The phase 2, double-blind, placebo-controlled trial randomized 124 patients (41 placebo, 83 mipomersen) 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. Mean LDL-C decreased 28.0% with mipomersen compared with a 5.2% increase with placebo (P 0.001), and 45.1% compared with 4.9% achieved LDL-C 2.6 mmol/L (100 mg/dL), respectively. Mipomersen significantly (P 0.001) reduced apolipoprotein B ( 26.3%) and lipoprotein(a) ( 21.1%) compared with placebo. More frequent and severe injection site reactions occurred with mipomersen, and 5 mipomersen-treated patients (6%) had 2 consecutive alanine aminotransferase levels 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). The clinical implications of such increases in hepatic fat and transaminase elevations are unclear and must be elucidated in longer-term studies. We conclude that mipomersen is effective to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in patients with heterozygous familial hypercholesterolemia with coronary artery disease on statins and other lipid-lowering therapy. See p 2283.