Mipomersen in familial hypercholesterolemia

- EAS 2011 Gothenburg, Sweden Monday 27 June -

Mipomersen added to existing lipid-lowering therapy lowers LDL cholesterol, lipoprotein-a (Lp(a)), and other atherogenic lipoproteins, and reduces the need for lipid apheresis in patients with heterozygous familial hypercholesterolemia (HeFH), according to results from two randomized, placebo-controlled phase 3 trials. Mipomersen is a first-in-class apolipoprotein B (apoB) synthesis inhibitor. Other than apheresis, there is no approved treatment that addresses the specific challenges faced by these patients. The data were reported by Dr Elisabeth Steinhagen-Thiessen, Lipid Ambulatory Clinic, University of Berlin, Germany.

One study included 124 HeFH patients with coronary artery disease, and the other included 58 severe HeFH patients. All patients were already taking a maximally tolerated dose of a statin, and most also received additional lipid-lowering drugs. Mipomersen decreased LDL cholesterol by 28 and 36 percent compared with increases of 5 and 13 percent for placebo, respectively (both p<0.001), meeting primary endpoints in both studies.

The presentation also highlighted the efficacy of mipomersen in lowering Lp(a). Most patients in the two trials (71 and 62 percent) had elevated Lp(a) levels >20 mg/dl at baseline. Lp(a) is an independent risk factor for heart disease and cardiovascular events. Elevated Lp(a) levels are recognized to have a strong genetic component and are particularly common in people with FH. In 2010, the EAS Consensus Panel paper recommended screening and treatment for elevated Lp(a).¹ In the trials, mipomersen decreased Lp(a) by a median 21 and 39 percent, compared with zero and five percent for the placebo groups (both p<0.001). Mipomersen lowered Lp(a) by ≥50 percent in 22 percent of mipomersen patients across both studies. The reductions observed were in addition to those achieved with the patients’ existing therapeutic regimens.

Another presentation by Dr KG Parhofer, Ludwig-Maximilians University, Munich, Germany, focused on mipomersen’s potential to reduce the need for lipid-apheresis by lowering LDL cholesterol values below thresholds for apheresis eligibility. Patients with severe forms of FH may be eligible for this treatment. Country-specific LDL cholesterol thresholds to determine eligibility for apheresis can range from ≥100 mg/dL to ≥160 mg/dL. However, many eligible patients are not on apheresis because of lack of availability, high cost and negative impact on quality of life.

In HeFH patients with coronary artery disease, mipomersen reduced the percentage of patients with LDL cholesterol levels:

• ≥160 mg/dL by 95 percent (from 39 percent to 2 percent);
• ≥130 mg/dL by 74 percent (from 62 percent to 16 percent); and
• ≥ 100 mg/dL by 45 percent (from 98 percent to 54 percent).

These reductions were in addition to those achieved with the patients’ existing therapeutic regimens. No significant change in LDL cholesterol was observed in placebo-treated patients. ‘These results suggest that the impact of mipomersen on the treatment landscape could be quite significant. Mipomersen could become an important new treatment option for those who are eligible for apheresis but cannot access it or tolerate its impact on their quality of life,’ said Dr Parhofer.’

The most commonly observed adverse events were injection site reactions and flu-like symptoms. In phase 3 trials, persistent elevations ( at least one week apart) in liver transaminases (ALTs) above 3X ULN were observed in 8 percent of mipomersen-treated patients. No patients had changes in other laboratory tests to indicate hepatic dysfunction.

References

1. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.