Physicians' Academy for Cardiovascular Education

Mipomersen: inhibiting apoB synthesis reduces apoC-III

Literature - Furtado JD; J Lipid Res. 2012 Feb 2

Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins


Furtado JD, Wedel MK, Sacks FM

J Lipid Res. 2012 Feb 2.

Abstract

Mipomersen, an antisense oligonucleotide that reduces hepatic production of apoB, has been shown in phase 2 studies to decrease plasma apoB, LDL-C and triglycerides. ApoC-III inhibits VLDL and LDL clearance, and stimulates inflammatory responses in vascular cells. Concentrations of VLDL or LDL with apoC-III independently predict cardiovascular disease. We performed an exploratory post-hoc analysis on a subset of hypercholesterolemic subjects obtained from a randomized controlled dose-ranging phase 2 study of mipomersen receiving 100, 200, or 300 mg/wk, or placebo for 13 weeks (n=8 each). ApoC-III-containing lipoproteins were isolated by immuno-affinity chromatography and ultracentrifugation. Mipomersen 200 and 300 mg/wk reduced total apoC-III from baseline by 6mg/dL (38-42%) compared to placebo group (p<0.01); and reduced apoC-III in both apoB lipoproteins and HDL. Mipomersen 100, 200, and 300 mg doses reduced apoB concentration of LDL with apoC-III (27%, 38%, and 46%, p<0.05). Mipomersen reduced apoC-III concentration in HDL. The drug had no effect on apoE concentration in total plasma and in apoB lipoproteins. In summary, antisense inhibition of apoB synthesis reduced plasma concentrations of apoC-III and apoC-III-containing lipoproteins. Lower concentrations of apoC-III and LDL with apoC-III are associated with reduced risk of coronary heart disease in epidemiologic studies independent of traditional risk factors.

Background

Apolipoprotein (apo) C-III is a protein present on some apoB-lipoproteins modifying the metabolism in plasma of the lipoprotein particle. Concentration of apoC-III in very-low (VLDL) and low-density lipoproteins (LDL) is very predictive of coronary heart disease, more than TG alone [1]. LDL with apoC-III is most predictive for CVD in Type 2 diabetes [2] and in the general population [3]. Mipomersen is a second generation 20-mer antisense oligonucleotide that reduces hepatic production of apo B-100. Mipomersen dose-dependently reduces plasma total apoB and LDL cholesterol (LDL-C), and reduces plasma non-HDL cholesterol (non-HDL-C) and triglycerides in polygenic and familial hypercholesterolemia [4,5] and in subjects with mild to moderate hyperlipidemia [6]. There are no effects on plasma HDL cholesterol (HDL-C) concentration.
It is suggested that mipomersen reduces the plasma concentration of apoC-III and the concentration of apoB-lipoproteins that contain apoC-III.  The primary aim of the parent study was to determine the effects of mipomersen on concentrations of LDL-C and apoB.


Main results

Mipomersen reduces apoB concentration of LDL with apoC-III Mipomersen 200mg/wk and 300mg/wk reduced total plasma apoC-III from baseline by 6 mg/dL for both doses (p<0.01) a percentage reduction of 38 to 42% (p<0.03).

ApoC-III in total plasma, apoB-lipoproteins, and apoAI-lipoproteins. Placebo-adjusted change (mg/dL ± SEM) * p<0.05 in generalized linear model relating outcome measure to dose variable (SAS PROC GLM). p-value for test for trend across doses is <0.05 for Total apoC-III and apoC-III in apoAI-lipoproteins.

Mipomersen 100, 200, and 300 mg doses reduced apoB concentration of LDL with apoC-III (27%, 38%, and 46%, p<0.05)


Mipomersen reduces apoB concentration of LDL with apoC-III

ApoB in total plasma, and VLDL and LDL with and without apoC-III. Placebo-adjusted change (mg/dL ± SEM). * p<0.05 in generalized linear model relating outcome measure to dose variable (SAS PROC GLM). p-value for test for trend across doses is <0.05 for total plasma and all plasma fractions.

Conclusion

Mipomersen reduces total apoC-III, apoC-III in apoB lipoproteins, and apoC-III in HDL. ApoC-III is an activator of atherogenic processes and apoB-lipoproteins with apoC-III are associated with increased CHD. Mipomersen has no effect on apoE concentrations thereby enriching apoB-lipoproteins with apoE relative to apoC-III, which may facilitate lipoprotein clearance and reduce formation of atherogenic remnants and LDL.



References

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