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

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.

• Authors: Laurens F Reeskamp, John J P Kastelein, Patrick M Moriarty, P Barton Duell, Alberico L Catapano, Raul D Santos, Christie M Ballantyne
• Journal: Atherosclerosis (Atherosclerosis) Vol. 280 Pg. 109-117 (01 2019) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 30500603 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Anticholesteremic Agents
• Apolipoproteins B
• Cholesterol, HDL
• Cholesterol, LDL
• Oligodeoxyribonucleotides, Antisense
• Oligonucleotides
• mipomersen
• Transaminases

Topics

• Adult
• Aged
• Anticholesteremic Agents (therapeutic use)
• Apolipoproteins B (metabolism)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Double-Blind Method
• Female
• Humans
• Hyperlipoproteinemia Type II (drug therapy)
• Male
• Medication Adherence
• Middle Aged
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Oligonucleotides (therapeutic use)
• Risk Assessment
• Transaminases (blood)