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.
- antisense oligonucleotide
- coronary artery disease
- dyslipidemias
- hyperlipoproteinemia type II
- hypolipidemic agents
- Received August 29, 2014.
- Accepted January 3, 2015.
- © 2015 American Heart Association, Inc.
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- Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With HypercholesterolemiaRaul D. Santos, Frederick J. Raal, Alberico L. Catapano, Joseph L. Witztum, Elisabeth Steinhagen-Thiessen and Sotirios TsimikasArteriosclerosis, Thrombosis, and Vascular Biology. 2015;ATVBAHA.114.304549, originally published January 22, 2015https://doi.org/10.1161/ATVBAHA.114.304549
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- Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With HypercholesterolemiaRaul D. Santos, Frederick J. Raal, Alberico L. Catapano, Joseph L. Witztum, Elisabeth Steinhagen-Thiessen and Sotirios TsimikasArteriosclerosis, Thrombosis, and Vascular Biology. 2015;ATVBAHA.114.304549, originally published January 22, 2015https://doi.org/10.1161/ATVBAHA.114.304549