Therapeutic potential of mipomersen in the management of familial hypercholesterolaemia.

High levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are associated with early morbidity and mortality caused by cardiovascular disease (CVD). There are hints that a reduction of LDL-C levels beyond currently advocated targets, and the use of drugs that also have Lp(a)-lowering potential, could provide further clinical benefit. Today, LDL apheresis is the only available treatment option to achieve further lowering of apolipoprotein-B (apo-B)-containing lipoproteins, especially Lp(a). Mipomersen is currently being studied in patients with mild to severe hypercholesterolaemia as add-on therapy to other lipid-lowering therapy, as monotherapy in patients who are intolerant of HMG-CoA reductase inhibitors (statins) and who are at high risk for CVD. Patients affected by homozygous or heterozygous familial hypercholesterolaemia (FH), which are inherited autosomal co-dominant disorders characterized by a marked elevation of serum LDL-C concentration, remain a clinical challenge, especially when their CVD risk is aggravated by additionally elevated Lp(a) levels. Mipomersen is a 20-mer oligonucleotide [2'-O-(2-methoxy) ethyl-modified oligonucleotide], a second-generation antisense oligonucleotide (AOS), complementary to the coding region for human-specific apo-B-100 messenger RNA (mRNA). Mipomersen inhibits apo-B-100 synthesis and is consequently a new treatment strategy to lower apo-B-containing lipoproteins like LDL-C and Lp(a) in patients at high risk for CVD not on target or intolerant to statins. This article focuses on mipomersen and gives an overview of the current status of mipomersen as a promising treatment option. Recent studies have shown a decrease in LDL-C levels of 22-42.2% and in Lp(a) of 19.6-31.1% from baseline, depending on study design. Dose-dependent reductions of very low-density lipoprotein cholesterol (VLDL-C) and triglyceride levels have also been observed. Although the short-term efficacy and safety of mipomersen have been proven, side effects like injection-site reactions (up to 90-100%), increased liver enzymes, cephalgias, nasopharyngitis, myalgia, nausea and fatigue must be mentioned and critically discussed. Furthermore, we need more data on the long-term side effects, especially regarding the long-term potential for hepatic steatosis. Data on cardiovascular outcomes with mipomersen are also not yet available.