On 13 December 2012, the Committee for Medicinal Products for Human Use ( CHMP ) has adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product Kynamro, intended for the treatment of patients with certain forms of familial hypercholesterolaemia.
Kynamro is a medicine that contains the active substance Mipomersen. It was to be available as a solution for injection under the skin.
Kynamro was expected to be used to treat patients with an inherited disease causing high blood cholesterol levels, called familial hypercholesterolaemia. It was initially expected to be used to treat two closely related forms of the disease called severe heterozygous and homozygous familial hypercholesterolaemia.
During the assessment of Kynamro, the indication was restricted to the most severely affected patients with homozygous and compound heterozygous familial hypercholesterolaemia only.
It was expected to be used together with other cholesterol-lowering medicines and a low-fat diet.
The active substance in Kynamro, Mipomersen, is an antisense oligonucleotide, a very short fragment of DNA designed to block the production of a protein called apolipoprotein B, by attaching to the genetic material of cells responsible for producing it. Apolipoprotein B is the main component of low density lipoprotein ( LDL ) cholesterol, and of two closely related types of cholesterol called intermediate density lipoprotein ( IDL ) and very low density lipoprotein ( VLDL ) cholesterol. Patients with homozygous familial hypercholesterolaemia have high blood levels of these types of cholesterol, which increases the risk of coronary heart disease. By blocking the production of apolipoprotein B, Kynamro was expected to reduce the levels of these types of lipoproteins in the blood of patients.
The company ( Genzyme ) submitted the results of two main studies. One involved 51 patients with homozygous familial hypercholesterolaemia and the other involved 58 patients with severe heterozygous familial hypercholesterolaemia. The studies compared the effects of Kynamro with placebo when added onto treatment with other cholesterol-lowering medicines and a low-fat diet, for a treatment period of 26 weeks. The main measure of effectiveness was the reduction in the patients’ LDL cholesterol levels.
In December 2012, the CHMP was concerned that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolaemia, mainly due to side effects. This was considered an important limitation because Kynamro is intended for long-term treatment.
The CHMP was also concerned by the potential long-term consequences of liver test results 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 more cardiovascular events were reported in patients taking Kynamro than in patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its potential cardiovascular risk. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Kynamro did not outweigh its risks and recommended that it be refused marketing authorisation.
During the re-examination in March 2013, the CHMP’s concerns remained unresolved and were not fully addressed by measures proposed by the company. Therefore, the CHMP refusal was confirmed after re-examination. ( Xagena )
Source: European Medicines Agency, 2013