(2) 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. Kuvan®
Kuvan® (INN: sapropterin dihydrochloride, formerly known as Sapropterin and Phenoptin™) 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® 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® produces significant reductions in blood Phe levels in the subset of patients who are BH4-responsive. Merck Serono estimates that Kuvan® 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® in all territories outside North America and Japan. BioMarin has exclusive rights to market Kuvan® 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®, 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. Merck is a global pharmaceutical and chemical company with total revenues of € 7.1 billion in 2007, a history that began in 1668, and a future shaped by 32,458 employees in 59 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.