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Hypercholesterolemia Drug Kynamro (Mipomersen) Gets ‘Thumbs Down’ in Europe

Drug is currently under FDA review in U.S. (Dec. 14)

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has denied marketing authorization for Kynamro (mipomersen, Genzyme/Isis Pharmaceuticals) for the treatment of patients with homozygous familial hypercholesterolaemia (HoFH).

An application for Kynamro is currently under review by the FDA. In October 2012, an advisory panel ruled that there was sufficient efficacy and safety data to support the marketing of Kynamro for the treatment of patients with HoFH in the U.S.

CHMP’s opinion was based on data from two clinical studies. One study involved 51 patients with HoFH, and the other involved 58 patients with severe heterozygous familial hypercholesterolaemia (HeFH). The two studies compared the effects of Kynamro with those of placebo when added to treatment with other cholesterol-lowering drugs and a low-fat diet for a treatment period of 26 weeks. The primary efficacy measure in both studies was the reduction in the patients’ low-density lipoprotein cholesterol (LDL-C) levels.

CHMP noted that Kynamro was effective at reducing LDL-C levels in patients with either HoFH or HeFH. After 26 weeks, the approximate average LDL-C reduction in patients treated with Kynamro was between 25% and 36%, compared with a reduction of between 3% and 13% in placebo-treated patients.

However, CHMP was concerned about the drug’s safety. The committee noted that a high proportion of patients stopped taking Kynamro within 2 years — even in the restricted group of patients with HoFH — mainly because of side effects, such as flu-like symptoms, injections-site reactions, and liver toxicity. This was considered important because Kynamro is intended for long-term treatment in order to maintain its cholesterol-lowering effect.

CHMP was also concerned by liver-test results in patients taking Kynamro, which showed a build-up of fat in the liver and increased enzyme levels. CHMP was not convinced that the drug’s manufacturer had proposed sufficient measures to prevent the risk of irreversible liver damage.

Moreover, the committee was concerned that a greater proportion of patients taking Kynamro experienced serious cardiovascular events than did patients taking placebo. This prevented CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its cardiovascular risk.

Therefore, CHMP was of the opinion that the benefits of Kynamro did not outweigh its risks and recommended that it be refused marketing authorization.

Kynamro (mipomersen) is an apolipoprotein-B (apo-B) synthesis inhibitor designed to further reduce LDL-C in patients with HoFH who are already maintaining a stable regimen of maximally tolerated lipid-lowering therapies, and who require additional significant lipid lowering treatment. The drug reduces LDL-C by preventing the formation of atherogenic lipoproteins (the particles that carry cholesterol through the bloodstream). Mipomerson acts by blocking the production of apo-B, the protein that provides the structural core for these atherogenic particles, including LDL and lipoprotein-a.

Sources: Genzyme; December 14, 2012; and EMA; December 13, 2012.

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