Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With Hypercholesterolemia

Author:

Santos Raul D.1,Raal Frederick J.1,Catapano Alberico L.1,Witztum Joseph L.1,Steinhagen-Thiessen Elisabeth1,Tsimikas Sotirios1

Affiliation:

1. From the Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil (R.D.S.); Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R.); Department of Pharmacological and Biomolecular Sciences, University of Milan, IRCCS Multimedica, Milan, Italy (A.L.C.); Lipid Ambulatory Clinic, Charite-Universitaetsmedizin Berlin, Berlin, Germany (E.S.-T.); and University of...

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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