Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials

Abstract

Objective: Lp(a) is an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis. Current pharmacological lipid-lowering therapies do not optimally lower Lp(a), particularly in patients with familial hypercholesterolemia (FH).

Approach and results: In 4 phase III trials, 382 patients on maximally tolerated lipid-lowering therapy were randomized 2:1 to weekly subcutaneous mipomersen 200 mg (n=256) or placebo (n=126) for 26 weeks. Populations included homozygous FH, heterozygous FH with concomitant coronary artery disease (CAD), severe hypercholesterolemia, and hypercholesterolemia at high risk for CAD. Lp(a) was measured 8× between baseline and week 28 inclusive. Of the 382 patients, 57% and 44% had baseline Lp(a) levels >30 and >50 mg/dL, respectively. In the pooled analysis, the mean percent decrease (median, interquartile range in Lp(a) at 28 weeks was significantly greater in the mipomersen group compared with placebo (-26.4 [-42.8, -5.4] versus -0.0 [-10.7, 15.3]; P<0.001). In the mipomersen group in patients with Lp(a) levels >30 or >50 mg/dL, attainment of Lp(a) values ≤30 or ≤50 mg/dL was most frequent in homozygous FH and severe hypercholesterolemia patients. In the combined groups, modest correlations were present between percent change in apolipoprotein B-100 and Lp(a) (r=0.43; P<0.001) and low-density lipoprotein cholesterol and Lp(a) (r=0.36; P<0.001) plasma levels.

Conclusions: Mipomersen consistently and effectively reduced Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. Modest correlations were present between apolipoprotein B-100 and Lp(a) lowering but the mechanistic relevance mediating Lp(a) reduction is currently unknown.

Trial registration: ClinicalTrials.gov NCT00607373 NCT00706849 NCT00770146 NCT00794664.

Keywords: antisense oligonucleotide; coronary artery disease; dyslipidemias; hyperlipoproteinemia type II; hypolipidemic agents.

© 2015 American Heart Association, Inc.

Figures

Figure 1. Study Design for Mipomersen Phase 3 Clinical Trials

R=randomization; PET=Primary Efficacy Timepoint; week 28 or 2 weeks after the last dose.

Figure 2. Frequency distribution of baseline Lp(a) levels in the 4 randomized trials

Histogram of the distribution of Lp(a) levels in the 4 studies. The black line represents the normal curve for the histogram.

Figure 3. Median change in Lp(a) mediated by mipomersen in the pooled data of the 4 trials and in individual trials

Effect of mipomersen (median (IQR) percent change) over time in the pooled 4 Phase III studies and in individual studies.

Figure 4. Waterfall plots of the percent change in Lp(a) from baseleine to the primary efficacy endpoint in the pooled data of the 4 trials and in individual trials

Waterfall plots depicting the distribution of the percent change in Lp(a) levels in reposnse to mipomersen and plabebo in the pooled 4 Phase III studies and in individual studies.

Figure 5. Correlations between percent change in Lp(a), apoB and LDL-C

Spearman Correlations (r-values) between LDL-C and apoB (A), LDL-C and Lp(a) (B) and apoB and Lp(a) (C) in the mipomersen and placebo groups in the pooled 4 Phase III studies.