Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant condition with a population prevalence of one in 300-500 (heterozygous) that is characterized by high levels of low-density lipoprotein (LDL) cholesterol, tendon xanthomata, and premature atherosclerosis and coronary heart disease (CHD). FH is caused mainly by mutations in the LDLR gene. However, mutations in other genes including APOB and PCSK9, can give rise to a similar phenotype. Homozygous FH with an estimated prevalence of one in a million is associated with severe hypercholesterolemia with accelerated atherosclerotic CHD in childhood and without treatment, death usually occurs before the age of 30 years. Current approaches for the treatment of homozygous FH include statin-based lipid-lowering therapies and LDL apheresis. Mipomersen is a second-generation antisense oligonucleotide (ASO) targeted to human apolipoprotein B (apoB)-100. This review provides an overview of the pathophysiology and current treatment options for familial hypercholesterolemia and describes novel therapeutic strategies focusing on mipomersen, an antisense apoB synthesis inhibitor. Mipomersen is distributed mainly to the liver where it silences apoB mRNA, thereby reducing hepatic apoB-100 and giving rise to reductions in plasma total cholesterol, LDL-cholesterol, and apoB concentrations in a dose-and time-dependent manner. Mipomersen has been shown to decrease apoB, LDL-cholesterol and lipoprotein(a) in patients with heterozygous and homozygous FH on maximally tolerated lipid-lowering therapy. The short-term efficacy and safety of mipomersen has been established, however, injection site reactions are common and concern exists regarding the long-term potential for hepatic steatosis with this ASO. In summary, mipomersen given alone or in combination with standard lipid-lowering medications shows promise as an adjunct therapy in patients with homozygous or refractory heterozygous FH at high risk of atherosclerotic CHD, who are not at target or are intolerant of statins.

Keywords: LDL-cholesterol; antisense oligonucleotide; apolipoprotein B; familial hypercholesterolemia; metabolism; mipomersen.

Figure 1

Discrete clinical manifestations of familial hypercholesterolemia. (A) Corneal arcus and xanthelasma; (B) extensor tendon xanthomas; (C and D) Achilles tendon xanthomas. Note: Copyright © 2008, The Australian Association of Clinical Biochemists. Reproduced with permission from Burnett JR, Hooper AJ. Common and rare gene variants affecting plasma LDL cholesterol. Clin Biochem Rev. 2008;29(1):11–26.

Figure 2

Cumulative LDL exposure (expressed as grams of cholesterol per year) over a lifetime in familial hypercholesterolemia patients (HeFH, HoFH) and normal individuals. Note: Coronary heart disease occurs after a theoretical threshold of LDL exposure is exceeded, reached in early childhood in HoFH and early middle-age in HeFH., Copyright © 2009, The American Society for Biochemistry and Molecular Biology. Adapted with permission from Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50 Suppl:S172–S177. Abbreviations: CHD, coronary heart disease; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL, low-density lipoprotein.