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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.

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Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:
Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.
Dipartimento Dieccellenza Scienze Farmacologiche e Biomolecolari, Milano, Italy; IRCCS Multimedica, Milano, Italy.
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.
Sections of Cardiology and Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA.



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.


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.


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.


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.


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

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