Efficacy of Apolipoprotein B Synthesis Inhibition in Subjects With Mild-To-Moderate Hyperlipidaemia

Study Questions:

How effective is antisense inhibition of apolipoprotein (apo) B in reducing low-density lipoprotein cholesterol (LDL-C) in patients with hyperlipidemia?


Fifty subjects with LDL-C levels between 119 and 266 mg/dl were enrolled into five cohorts with a 4:1 randomization ratio of drug to placebo. Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/wk.


Mipomersen produced dose-dependent reductions in apoB-containing lipoproteins. In the 200 and 300 mg/wk dose cohorts, mean reductions from baseline in LDL-C were -45 ± 10% (p < 0.001) and -61 ± 8% (p < 0.001), corresponding to a -46 ± 11% (p < 0.001) and -61 ± 7% (p < 0.001) decrease in apoB levels. Triglyceride levels were also lowered, with median reductions up to 53% (p = 0.021). The most common adverse events were injection site reactions. Seven of 40 subjects (18%) showed consecutive transaminase elevations >3× upper limit of normal. Five of these subjects received 400 mg/wk, four of whom had apoB levels below the limit of detection. As a consequence, the 400 mg/wk cohort was discontinued.


The authors concluded that mipomersen administered as monotherapy in subjects with mild-to-moderate hyperlipidemia produced potent reductions in all apoB-containing lipoproteins.


Reduction of LDL-C with statins has proven to be effective in reducing cardiovascular events. However, not all patients tolerate statins and not all patients reach target LDL-C goals. Thus, other effective therapies to reduce LDL-C are needed. Previous studies in healthy volunteers and in patients treated with statins have demonstrated that adding mipomersen is effective in reducing LDL-C. The current study adds to previous short-term studies and demonstrates the effectiveness of mipomersen as monotherapy in patients with hyperlipidemia. The effect of mipomersen treatment on cardiovascular events will need to assessed in future trials, as will the implications of transaminase elevations at higher doses.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Hyperlipidemias, Lipoproteins

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