Merck Serono's Kuvan receives European marketing authorization

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, today announced that the European Commission has granted marketing authorization for Kuvan(R) for the treatment of hyperphenylalaninemia (HPA) in phenylketonuria (PKU) or BH4 deficient patients.

Kuvan, which had previously received Orphan Medicinal Product designation from the European Medicines Evaluation Agency (EMEA), is the first drug approved in Europe for HPA due to PKU or BH4 deficiency.

"To date, there has been no drug treatment available in Europe for patients suffering from PKU, a debilitating inherited condition that can cause serious brain damage in children and transient to lasting impairments in adults if a strict diet is not observed throughout life," said Roberto Gradnik, Executive Vice President Commercial Europe at Merck Serono. "With the approval of Kuvan(R), Merck Serono provides patients access to an efficient treatment to better control their blood phenylalanine levels. This will contribute to improving their quality of life and may ultimately reduce the risk of lasting mental impairment," he added.

There are approximately 35,000 patients diagnosed with hyperphenylalaninemia due to PKU or BH4 deficiency in the European Union.(1) PKU and BH4 deficiency are rare diseases caused by genetic defects in the metabolism of the amino acid phenylalanine (PKU), or in the enzymes responsible for the recycling and synthesis of the cofactor BH4 (BH4 deficiency), resulting in hyperphenylalaninemia, i.e. abnormally high levels of phenylalanine in the blood. Hyperphenylalaninemia can cause serious brain damage in infants and children, and transient to lasting neurocognitive impairment in adult patients.

Until today, the only therapy option for PKU patients in Europe to manage their disease was through a diet highly restricted in phenylalanine (food with high levels of phenylalanine include meat, fish, nuts, dairy products and some vegetable and fruits) associated with daily amino-acid supplementation. Non-adherence to the restrictive diet and adequate control of blood phenylalanine levels can result in a decline in mental and behavioral performance.

"Through the approval of Kuvan(R), Merck Serono confirms its commitment to developing and marketing innovative therapeutic solutions for patients suffering from high medical unmet needs. PKU and BH4 deficiency deserve the attention of the whole healthcare industry and we are pleased to provide patients today with the first therapeutic option to treat these rare diseases," said Richard Douge, Executive Vice President Global Marketing at Merck Serono.

The marketing authorization is supported by data from two international, double-blind, randomized, placebo-controlled Phase III clinical trials in patients with hyperphenylalaninemia due to PKU. The data show that treatment with Kuvan(R) reduces blood phenylalanine levels and increases the proportion of patients with blood phenylalanine levels within target range, resulting in a higher dietary phenylalanine tolerance, which may reduce the need to limit phenylalanine intake in patients' diet. The most frequently reported potentially undesirable effects were headache, runny nose, diarrhea, vomiting, sore throat, cough, abdominal pain, stuffy nose and low levels of phenylalanine in the blood. These adverse events were generally mild to moderate and transient.

The European Commission has granted marketing authorization for the 27 countries(2) of the European Union as well as Iceland, Liechtenstein and Norway. As an Orphan Medicinal Product and the first drug approved for the treatment of HPA, Kuvan(R) will receive 10 years of data protection in the European Union for this therapeutic indication. Launch of Kuvan(R) in Europe is expected to start in the first half of 2009.

Kuvan(R)

Kuvan(R) (INN: sapropterin dihydrochloride, formerly known as Sapropterin and Phenoptin(TM)) is developed by Merck Serono and BioMarin Pharmaceutical Inc. (Nasdaq and SWX: BMRN) as an oral therapeutic for the treatment of hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. Kuvan(R) is the synthetic form of 6R-BH4, a naturally occurring enzyme cofactor that works in conjunction with the enzyme phenylalanine hydroxylase (PAH) to metabolize phenylalanine (Phe). Clinical data suggest that Kuvan(R) produces significant reductions in blood Phe levels in the subset of patients who are BH4-responsive. Merck Serono estimates that Kuvan(R) could be a potential treatment option for the approximately 35,000 patients in the European Union who have been diagnosed with HPA, due to PKU or BH4 deficiency and are responsive to BH4 treatment.

Under the terms of the agreement with BioMarin, Merck Serono has exclusive rights to market Kuvan(R) in all territories outside North America and Japan. BioMarin has exclusive rights to market Kuvan(R) in the USA and Canada; in the USA, Kuvan received approval from the Food and Drug Administration for the treatment of BH4-responsive PKU in December 2007. In July 2008, Asubio Pharma Co., Ltd. (a subsidiary of Daiichi Sankyo), received marketing approval from the Japanese Ministry of Health, Labour and Welfare for a label extension of Biopten, which contains the same active ingredient as Kuvan(R), for the treatment of patients with PKU.

Hyperphenylalaninemia (HPA)

Disorders of phenylalanine (Phe) metabolism can lead to abnormal elevations of blood Phe levels, also called hyperphenylalaninemia (HPA). Two inborn errors of metabolism, phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency, account for the majority of cases of HPA.

Phenylketonuria (PKU)

PKU, a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is required for the metabolism of phenylalanine (Phe), an essential amino acid found in all protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and brain, resulting in a variety of complications including severe mental retardation and brain damage, mental illness, seizures and tremors, and cognitive problems. As a result of global newborn screening efforts implemented in the 1960s and early 1970s, virtually all PKU patients in developed countries are diagnosed at birth. The only treatment currently available for PKU patients is a highly restrictive and expensive medical food diet that most patients fail to adhere to the extent needed for achieving adequate control of blood Phe levels. The diet restricts consumption of normal foods such as meat, fish and dairy products.

BH4 deficiency

BH4 deficiency is a very rare inborn error of metabolism, and is estimated to account for 1-2 % of cases of HPA. BH4 deficiency is an autosomal recessive genetic condition and can result from deficiencies of any of the five different enzymes involved in BH4 synthesis and regeneration. BH4 is a necessary co-factor for PAH. Therefore, BH4 deficiency impairs PAH activity leading to a biochemical situation similar to PKU, with HPA resulting from deficient conversion of Phe to tyrosine. In addition, since BH4 is also a necessary co-factor for both tyrosine hydroxylase and tryptophan hydroxylase, BH4 deficiency causes deficiencies in the downstream neurotransmitter products of these amino acids including catecholamines and serotonin. Dietary limitation of whole protein or Phe intake is often not necessary with BH4 treatment. However, since BH4 does not cross the blood brain barrier, concomitant therapy with neurotransmitter precursors, i. e. levodopa and 5-hydroxytryptophan, may be necessary to boost central nervous system substrate levels for catecholamine and serotonin synthesis, respectively.

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