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Atherosclerosis. 2019 Jan;280:109-117. doi: 10.1016/j.atherosclerosis.2018.11.017. Epub 2018 Nov 10.

Safety and efficacy of mipomersen in patients with heterozygous familial hypercholesterolemia.

Author information

1
Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: l.f.reeskamp@amc.uva.nl.
2
Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
3
Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
4
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.
5
Dipartimento Dieccellenza Scienze Farmacologiche e Biomolecolari, Milano, Italy; IRCCS Multimedica, Milano, Italy.
6
Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil; Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
7
Sections of Cardiology and Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA.

Abstract

BACKGROUND AND AIMS:

Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C-lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile.

METHODS:

In this double-blind trial, HeFH patients (LDL-C >160 mg/dL) on maximal tolerated LDL-lowering therapy were randomized to mipomersen 200 mg once weekly (n = 104), mipomersen 70 mg thrice weekly (n = 102), or placebo in matching frequency (n = 103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment.

RESULTS:

Mipomersen 200 mg once weekly and mipomersen 70 mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p < 0.001). Lipoprotein(a) was significantly lowered by 27.7% (p < 0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200 mg), 17.6% (70 mg), and 5.8% (placebo) of participants. Alanine transaminase was elevated (≥3× upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively.

CONCLUSIONS:

Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits.

KEYWORDS:

Antisense oligonucleotide; Heterozygous familial hypercholesterolemia; Lipoproteins; Mipomersen; Randomized controlled trial; apoB

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