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.

• Authors: Raul D Santos, Frederick J Raal, Alberico L Catapano, Joseph L Witztum, Elisabeth Steinhagen-Thiessen, Sotirios Tsimikas
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 3 Pg. 689-99 (Mar 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25614280 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• APOB protein, human
• Anticholesteremic Agents
• Apolipoprotein B-100
• Biomarkers
• Lipoprotein(a)
• Oligodeoxyribonucleotides, Antisense
• Oligonucleotides
• mipomersen

Topics

• Adult
• Aged
• Anticholesteremic Agents (therapeutic use)
• Apolipoprotein B-100 (blood, genetics)
• Biomarkers (blood)
• Cardiovascular Diseases (etiology, prevention & control)
• Clinical Trials, Phase III as Topic
• Down-Regulation
• Female
• Humans
• Hyperlipoproteinemia Type II (blood, complications, drug therapy, genetics)
• Lipoprotein(a) (blood)
• Male
• Middle Aged
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Oligonucleotides (therapeutic use)
• Randomized Controlled Trials as Topic
• Risk Assessment
• Risk Factors
• Treatment Outcome