GENEVA, Switzerland, September 26 /PRNewswire/ --

- CHMP Issued Positive Opinion Recommending Marketing Authorization of Kuvan(R) for the Treatment of hyperphenylalaninemia in Patients With phenylketonuria or BH4 Deficiency

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced today that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), issued a positive opinion for Kuvan(R) (sapropterin dihydrochloride) as an oral treatment for hyperphenylalaninemia (HPA) in patients with phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency.(1) With this positive opinion, the CHMP recommends the marketing authorization of Kuvan(R) by the European Commission. Kuvan(R) had previously received Orphan Medicinal Product designation from the EMEA as the first orphan drug for the treatment of HPA.

PKU and BH4 deficiency are rare diseases caused by genetic defects in the metabolism of the amino acid phenylalanine, resulting in hyperphenylalaninemia, i.e. abnormally high levels of phenylalanine in the blood. Hyperphenylalaninemia can cause serious brain damage in infants and children, and neurocognitive impairment in teenagers and adult patients. To date, there is no approved drug for the treatment of this condition in Europe. The only alternative for PKU patients to manage their disease is a diet highly restricted in phenylalanine. Dietary non-adherence can result in a decline in mental and behavioral performance. There are approximately 35,000 patients diagnosed with hyperphenylalaninemia due to PKU or BH4 deficiency in the European Union.(2)

"The efficient therapy of phenylketonuria and BH4 deficiency is still an unmet medical need, and Merck Serono hopes to be able to provide alternative treatments for these rare diseases," said Roberto Gradnik, Executive Vice President Commercial Europe at Merck Serono. "The availability of Kuvan throughout Europe will allow the patients suffering from these serious, debilitating diseases to better control their phenylalanine levels and at the same time improve their quality of life."

Data from two international, double-blind, randomized, placebo-controlled Phase III clinical trials in patients with hyperphenylalaninemia due to PKU show that treatment with Kuvan(R) reduces blood phenylalanine levels and increases dietary phenylalanine tolerance and hence may reduce the need to limit phenylalanine intake in patients' diet. The most frequently reported potential 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 CHMP reviews drug applications for all 27 countries in the European Union(3) as well as Iceland, Liechtenstein and Norway. The CHMP recommendation will now be considered by the European Commission, which will deliver its final decision on the granting of the marketing authorization.

Kuvan(R) is being developed in partnership with BioMarin Pharmaceutical Inc. (Nasdaq and SWX: BMRN). 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, it 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(R), which contains the same active ingredient as Kuvan(R), for the treatment of patients with PKU.


(1) Kuvan(R) is indicated for "the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients of 4 years of age and over with phenylketonuria (PKU) who have been shown to be responsive to such treatment. Kuvan(R) is also indicated for the treatment of HPA in adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency, who have been shown to be responsive to such treatment."

(2) Kuvan(R) is a potential treatment option in those PKU and BH4- deficient patients who are responsive to BH4 treatment. According to published literature, 20 to 50 % of PKU patients are responsive to treatment with Kuvan(R).

(3) Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom


Merck Serono and BioMarin Pharmaceutical are developing Kuvan(R) (INN: sapropterin dihydrochloride, formerly known as Sapropterin and Phenoptin(TM)) 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 repsonsive to BH4 treatment.

Kuvan(R) received Orphan Medicinal Product designation to treat HPA from the EMEA. If Kuvan(R) becomes the first drug therapy approved for the treatment of HPA, sapropterin would receive ten years of data protection in the European Union for this indication.

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 have been 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 or 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.

Merck Serono

Merck Serono is the division for innovative prescription pharmaceuticals of Merck, a global pharmaceutical and chemical group. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, manufactures and markets innovative small molecules and biopharmaceuticals to help patients with unmet medical needs. Its North American business operates in the United States and Canada as EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux(R)), multiple sclerosis (Rebif(R)), infertility (Gonal-f(R)), endocrine and cardiometabolic disorders (Glucophage(R), Concor(R), Euthyrox(R), Saizen(R), Serostim(R)), as well as psoriasis (Raptiva(R)).

With an annual R&D expenditure of around EUR 1bn, Merck Serono is committed to growing its business in specialist-focused therapeutic areas including neurodegenerative diseases, oncology, fertility and endocrinology, as well as new areas potentially arising out of research and development in autoimmune and inflammatory diseases.


Merck is a global pharmaceutical and chemical company with total revenues of EUR 7.1 billion in 2007, a history that began in 1668, and a future shaped by 31,946 employees in 60 countries. Its success is characterized by innovations from entrepreneurial employees. Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds an approximately 70% interest and free shareholders own the remaining approximately 30%. In 1917 the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since.

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