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March 13, 2010

Antisense inhibitor of apoB synthesis: A new approach for severe hypercholesterolemia

From theheart.org, by Sue Hughes

Johannesburg, South Africa – A novel agent that reduces LDL production by inhibiting apolipoprotein B (apoB) synthesis could be an effective therapy for patients with severe hypercholesterolemia, a new study suggests [1].

The product, mipomersen (ISIS Pharmaceuticals/Genzyme), an antisense inhibitor of apoB synthesis, showed impressive reductions in LDL cholesterol in patients with homozygous familial hypercholesterolemia (FH) in the phase 3 study published online March 13, 2010 in the Lancet. The drug is also in late-stage trials in patients with heterozygous FH and other forms of severe hypercholesterolemia.

The authors, led by Dr Frederick J Raal (University of the Witwatersrand, Johannesburg, South Africa), report that weekly subcutaneous injections of mipomersen lowered LDL by a mean of 25% in FH patients who were already receiving a variety of lipid-lowering drugs, including high-dose statins. Lipoprotein(a) concentrations, which are unresponsive to statin therapy, were similarly reduced.

An accompanying editorial says this new treatment seems to offer patients who would otherwise depend on weekly LDL apheresis a less onerous alternative [2]. However, it cautions that the agent is associated with an increase in hepatic fat and that longer studies with greater numbers of patients are needed to provide reassurance on safety.

In the paper, Raal et al explain that homozygous FH is characterized by very high LDL-cholesterol concentrations and early cardiovascular disease, with untreated patients rarely surviving beyond the age of 30 years. Because LDL receptors are not functional in these patients, statins, which act mainly by upregulating hepatic LDL receptors, are not very effective. LDL apheresis seems to increase survival but is expensive, invasive, and not universally available.

Since patients with homozygous FH are unable to effectively clear LDL particles, therapy aimed to reduce LDL production is an attractive option. Mipomersen targets apoB, which is an essential component of all atherogenic lipoproteins, including LDL. In animal studies and phase 1/2 clinical trials, mipomersen has shown dose-dependent lipid-lowering effects, including reductions in concentrations of apoB, LDL cholesterol, non-HDL cholesterol, and triglycerides.

The current study was conducted in 51 patients with homozygous FH who were already receiving the maximum tolerated doses of lipid-lowering drugs. They were randomized to mipomersen 200 mg subcutaneously (34 patients) every week or placebo (17 patients). Of these, 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo).

Mean concentrations of LDL at baseline were 11.4 mmol/L in the mipomersen group and 10.4 mmol/L in the placebo group. At the end of the treatment period, LDL levels had reduced significantly more in patients in the mipomersen group than in those receiving placebo.

Mean percentage change in LDL (%)

Mipomersen Placebo p

-24.7 -3.3 0.0003

Concomitant significant reductions were also noted in concentrations of apoB, non-HDL cholesterol, VLDL cholesterol, and lipoprotein(a). HDL cholesterol increased by 15% in the mipomersen vs 4% in the placebo group.

Novel therapeutic for reducing Lp(a)

Raal et al comment that in view of the negligible effect of statin therapy on lipoprotein(a), which is now recognized as an independent cardiovascular risk factor, mipomersen could represent a novel therapeutic approach to targeting this lipoprotein.

The most common adverse events were injection-site reactions, which occurred in 26 mipomersen patients (76%) and four (24%) of the placebo group. Increases in alanine aminotransferase concentrations to three times or more the upper limit of normal occurred in four patients (12%) in the mipomersen group but none in the placebo group, but these were not accompanied by abnormalities in other tests of liver function.

The authors note: “Although most patients did not achieve therapeutic targets for LDL-cholesterol concentration, the additional 25% mean reduction and the more than 2.5-mmol/L absolute reduction brought about by mipomersen should benefit patients with homozygous FH. If such effects are maintained, they would be expected to reduce the risk of atherosclerotic cardiovascular complications and improve survival.”

They note that higher doses of mipomersen may have greater effects and that in a small pilot study in patients with homozygous FH, 300-mg mipomersen administered once per week for 11 weeks after a two-week loading period produced a 45% to 51% reduction in LDL.

Watch out for increased hepatic fat

In the editorial, Drs Dermot Neely (Royal Victoria Infirmary, Newcastle upon Tyne, UK) and Margaret Bassendine (Newcastle University, UK) elaborate on the mechanism by which hepatic fat is increased with mipomersen. They explain that synthesis and secretion of apoB is needed to export cholesterol and triglycerides from the liver to peripheral tissues, and mipomersen effectively induces a partial deficiency of apoB analogous to the situation in familial hypobetalipoproteinemia—an inherited disorder of apoB synthesis in which there is a substantial reduction of LDL cholesterol, reduced incidence of cardiovascular events, and an approximate threefold increase in hepatic fat.

In the current study, hepatic-fat increases were measured only in the four participants who developed increases in alanine aminotransferase, of whom one showed a large increase of hepatic fat. The editorialists point out that in a smaller study in patients with heterozygous FH given the same mipomersen regimen for only 13 weeks, liver fat was measured in all participants and a small increase in hepatic lipid content was noted. They add that simple hepatic steatosis, a frequent finding in metabolic syndrome, usually follows a benign course, with coronary artery disease being the most common cause of death. But occasionally nonalcoholic steatohepatitis can develop, which can lead to fibrosis, cirrhosis, and liver-related deaths. Therefore, the potential for this side effect this needs to be ruled out in longer safety studies, especially if mipomersen treatment is extended to common lipid disorders with more heterogeneous underlying causes.

Raal et al note that phase 3 studies with mipomersen in patients with heterozygous FH and severe hypercholesterolemia are incorporating comprehensive measurements of hepatic-fat content, and these studies, in addition to two open-label extension trials, will provide long-term safety and efficacy data.


Nature Reviews Drug Discovery 9, 10 (January 2010) | doi:10.1038/nrd3093

Trial watch: Antisense agent reduces LDL–cholesterol levels in high-risk patients


A Phase III trial of the antisense agent mipomersen in patients with homozygous familial hypercholesterolaemia has demonstrated a 25% reduction (versus 3% for placebo) in levels of low-density lipoprotein (LDL)–cholesterol after 26 weeks of treatment.Mipomersen — which is being developed by Genzyme and Isis Pharmaceuticals — is a synthetic antisense oligonucleotide that targets messenger RNA encoding apolipoprotein B100 (APOB100).