PKU is an autosomal recessive genetic disorder caused by a defect or a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is required for the metabolism of phenylalanine, an essential amino acid found in all protein-containing foods. It affects approximately 1/10,000 newborns in Europe. If PKU patients are not treated with a phenylalanine-restricted diet, phenylalanine will accumulate in the blood and brain to abnormally high levels, thereby resulting in a variety of complications including clinically significant mental retardation and brain damage, mental illness, seizures and tremors, and cognitive problems. Universal systematic newborn screening programs were developed in the 1960s and early 1970s to enable diagnosis of all patients with PKU patients at birth.
About tetrahydrobiopterin (BH4) deficiency
BH4 deficiency is a very rare inborn error of metabolism, and is estimated to account for 1-2 % of cases of hyperphenylalaninemia (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 phenylalanine 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 phenylalanine 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.
About Kuvan
Kuvan(R) (sapropterin dihydrochloride) is an oral therapy and the first treatment indicated in Europe in conjunction with a phenylalanine-restricted diet, for the treatment of hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) in patients from the age of 4 who have shown to be responsive to Kuvan, or due to tetrahydrobiopterin (BH4) deficiency. Kuvan was developed jointly by BioMarin Pharmaceutical Inc. and Merck Serono. In the US, Kuvan is marketed by BioMarin and is indicated for the treatment of HPA due to PKU without age restriction. The current label states that safety and efficacy of Kuvan in pediatric patients less than 4 years of age have not been established in clinical studies. Kuvan is to be used in conjunction with a phenylalanine-restricted diet.
Kuvan is the synthetic form of 6R-BH4, a naturally occurring co-factor that works in conjunction with the enzyme phenylalanine hydroxylase (PAH) to metabolize phenylalanine into tyrosine. Clinical data show that Kuvan produces significant reductions in blood phenylalanine concentration in a large subset of patients.
Most common adverse reactions reported with the use of Kuvan include headache, runny nose, diarrhea, vomiting, sore throat, cough, abdominal pain, stuffy nose and low levels of phenylalanine in the blood.
Kuvan is approved in 49 countries worldwide, including member states of the European Union and the USA. Under the terms of the agreement with BioMarin, Merck Serono has exclusive rights to market Kuvan in all territories outside the USA, Canada and Japan.
About Merck Serono
Merck Serono is the biopharmaceutical division of Merck. With headquarters in Darmstadt, Germany, Merck Serono offers leading brands in 150 countries to help patients with cancer, multiple sclerosis, infertility, endocrine and metabolic disorders as well as cardiovascular diseases. In the United States and Canada, EMD Serono operates as a separately incorporated subsidiary of Merck Serono.
Merck Serono discovers, develops, manufactures and markets prescription medicines of both chemical and biological origin in specialist indications. We have an enduring commitment to deliver novel therapies in our core focus areas of neurology, oncology, immuno-oncology and immunology.
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Merck is a leading company for innovative and top-quality high-tech products in the pharmaceutical and chemical sectors. With its four divisions Merck Serono, Consumer Health, Performance Materials and Merck Millipore, Merck generated total revenues of EUR 11.1 billion in 2013. Around 39,000 Merck employees work in 66 countries to improve the quality of life for patients, to further the success of customers and to help meet global challenges. Merck is the world's oldest pharmaceutical and chemical company - since 1668, the company has stood for innovation, business success and responsible entrepreneurship. Holding an approximately 70 percent interest, the founding family remains the majority owner of the company to this day. Merck, Darmstadt, Germany is holding the global rights to the Merck name and brand. The only exceptions are Canada and the United States, where the company is known as EMD.
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