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Review
. 2013 Aug;76(2):269-76.
doi: 10.1111/j.1365-2125.2012.04469.x.

Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B

Stanley T Crooke  1 , Richard S Geary
Affiliations
Review

Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B

Stanley T Crooke et al. Br J Clin Pharmacol. 2013 Aug.

Abstract

Mipomersen is a second generation antisense oligonucleotide that targets apolipoprotein B. It has been studied thoroughly in clinical trials (more than 800 subjects), including four randomized double-blind placebo controlled phase 3 studies involving 391 patients, and is in registration for the treatment of severe hypercholesterolaemia. The pharmacokinetic and pharmacodynamic properties of mipomersen are well characterized. Mipomersen is rapidly and extensively absorbed after subcutaneous administration and has an elimination half-life of approximately 30 days across species. It is cleared by nuclease metabolism and renal excretion of the metabolites. Mipomersen reduces all apolipoprotein B containing atherogenic particles and displays dose dependent reductions between 50-400 mg week⁻¹ , both as a single agent and in the presence of maximal lipid lowering therapy. No drug-drug interactions have been identified. Mipomersen is a representative of second generation antisense drugs, all of which have similar properties, and is thus representative of the behaviour of the class of drugs.

Keywords: LDL-cholesterol; antisense inhibitor; familial hypercholesterolaemia; mipomersen.

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Figures

Figure 1
Figure 1
Structure of mipomersen
Figure 2
Figure 2
Sustained reduction in atherogenic lipids. Dose-dependent and prolonged effects of mipomersen on LDL cholesterol and apoB. LDL cholesterol and apolipoprotein B are presented as mean % change from baseline. Error bars represent ± SEM. Time period ranges from day 1 to day 175 . formula image, Placebo; formula image, 50 mg week−1; formula image, 100 mg week−1; formula image, 200 mg week−1; formula image, 300 mg week−1; formula image, 400 mg week−1
Figure 3
Figure 3
Schematic of mipomersen metabolism
Figure 4
Figure 4
Plasma concentration−response relationships for mipomersen. The individual points represents measurements of apoB100 or mipomersen in serum from either the phase 1 study in normal volunteers or phase 2 studies in hypercholesterolaemic patients either as a single agent or in combination with statins , (PD: 14 days after last dose). formula image, Observed; formula image, Predicted
See this image and copyright information in PMC

References

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MeSH terms