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

Authors :
Reeskamp LF
Kastelein JJP
Moriarty PM
Duell PB
Catapano AL
Santos RD
Ballantyne CM
Source :
Atherosclerosis [Atherosclerosis] 2019 Jan; Vol. 280, pp. 109-117. Date of Electronic Publication: 2018 Nov 10.
Publication Year :
2019

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.<br />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.<br />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.<br />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.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1879-1484
Volume :
280
Database :
MEDLINE
Journal :
Atherosclerosis
Publication Type :
Academic Journal
Accession number :
30500603
Full Text :
https://doi.org/10.1016/j.atherosclerosis.2018.11.017