News Release

Mipomersen offers new therapeutic strategy for inherited high cholesterol

Peer-Reviewed Publication

The Lancet_DELETED

A new cholesterol lowering drug, mipomersen, reduces plasma low-density lipoprotein (LDL or bad cholesterol) by about 25% compared with placebo when added to existing therapies in patients who have homozygous familial hypercholesterolaemia (FH). This new type of therapy involving the targeted blocking of apolipoprotein B synthesis* is efficacious in reducing LDL cholesterol, and could lower the risk of heart disease and improve survival in patients with homozygous FH. Thus mipomersen therapy has the potential to become an important treatment for these patients as well as those with other more common lipid disorders. These are the conclusions of an Article published Online First and in this week's edition of The Lancet.

Homozygous FH is a rare genetic disorder affecting one in every million people. Patients have severely elevated LDL cholesterol, a high risk of early cardiovascular disease and, if untreated, rarely live beyond the age of 30. Because LDL receptors do not function in people with homozygous FH they have a poor response to standard lipid-lowering drugs such as statins, and new therapies to reduce LDL levels are needed. Previous phase 2 studies have shown that mipomersen—a second-generation antisense therapy designed to inhibit apolipoprotein B synthesis—can reduce concentrations of LDL cholesterol.

To further evaluate this new therapeutic strategy, Frederick Raal from the University of Witwatersrand, Johannesburg, South Africa and international colleagues did a randomised phase 3 trial to examine the safety, tolerability, and effects of mipomersen on LDL cholesterol levels in patients with homozygous FH already receiving lipid-lowering drugs, including high-dose statins. Patients were randomly assigned mipomersen 200mg every week (34) or placebo (17) for 26 weeks.

Despite treatment with maximum doses of standard lipid-lowering drugs, LDL cholesterol levels at the start of the study were very high. After 26 weeks of treatment, mipomersen significantly reduced mean LDL cholesterol levels compared with placebo (-24.7% vs -3.3%). Treatment with mipomersen resulted in an absolute reduction in LDL concentration from 11.4 mmol/L to 8.4 mmol/L.

Other significant reductions were also noted in concentrations of apolipoprotein B, non-HDL cholesterol, VLDL cholesterol, and lipoprotein(a)—which is unresponsive to statin therapy and an independent cardiovascular risk factor. Additionally, mipomersen treatment resulted in a significant increase in HDL (good) cholesterol concentration, which is inversely linked with cardiovascular risk.

Mipomersen was generally well tolerated. The most common side effects were injection site reactions, which were three times more common with mipomersen than with placebo (76% vs 24%), and flu-like symptoms which did not differ significantly between the two groups.

The authors say: "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 conclude: "Mipomersen could be a valuable addition to the drugs used in the management of homozygous FH and should prove useful in the management of other forms of severe refractory hypercholesterolaemia."

In an accompanying Comment, Dermot Neely from the Royal Victoria Infirmary, Newcastle upon Tyne, UK says that: "This new treatment paradigm appears to offer patients who would otherwise be dependent on weekly LDL apheresis [removal of LDL in a method similar to dialysis] a less onerous alternative."

However, he cautions that longer studies with greater numbers of participants are needed to ensure that more significant fat accumulation and progression to liver damage do not occur if this treatment is extended to more common lipid disorders.

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Professor Frederick Raal, University of Witwatersrand, Johannesburg, South Africa. T) +27 11 488 3538 E) Frederick.raal@wits.ac.za

Dr Dermot Neely, Newcastle upon Tyne Hospitals NHS Trust, Royal Victoria Infirmary, Newcastle upon Tyne, UK. T) +44 (0)191 282 4554 E) Dermot.Neely@nuth.nhs.uk

For full Article and Comment, see: http://press.thelancet.com/mipomersen.pdf

Notes to Editors: *Mipomersen acts by decreasing formation of apolipoprotein B, the main structural protein present in LDL, and its release from the liver or intestine, thereby reducing circulating LDL cholesterol concentrations.


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