December 14th, 2012

CHMP Recommends Against Approval for Mipomersen in Europe

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency today recommended that mipomersen (Kynamro; Isis and Genzyme) not be approved for use in Europe. The novel antisense oligonucleotide works by inhibiting the synthesis of apolipoprotein-B and is under development in the United States and Europe for the treatment of familial hypercholesterolemia.

CHMP agreed that mipomersen effectively lowered LDL cholesterol in people with homozygous and severe heterozygous familial hypercholesterolemia (FH). The negative recommendation was based on the committee’s concerns about the safety of mipomersen. Here is the CHMP discussion of the safety issue:

The CHMP was concerned about the medicine’s safety. The Committee noted that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolemia, mainly due to 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 the cholesterol-lowering effect. The CHMP was also concerned by liver test results in patients taking Kynamro showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company 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 (problems with the heart and blood vessels) than patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its cardiovascular risk.

In October, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, voting 9-6 in favor of an approval recommendation. Comments during the panel meeting, however, clearly indicated that committee members were concerned about both the efficacy and safety of the drug.

Another new drug under development for lowering cholesterol in FH patients is lomitapide (Aegerion). The same FDA panel in October gave lomitapide a slightly stronger approval recommendation.

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