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 8x 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.