GENEVA, Switzerland, November 8 /PRNewswire/ --

- Treatment of Hyperphenylalaninemia Due to Phenylketonuria or BH4 Deficiency is an Important Unmet Medical Need; There is Currently no Approved Drug in Europe to Treat These Inborn Errors of Metabolism

- Sapropterin has Been Granted Orphan Medicinal Product Designation for the Treatment of Hyperphenylalaninemia

Merck Serono, a division of Merck KGaA, announced today that it has submitted an application to the European Medicines Agency (EMEA) for the marketing authorization (MA) of sapropterin (INN: sapropterin dihydrochloride, formerly known as Phenoptin(TM)) as an oral treatment for significant hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. Sapropterin had previously received Orphan Medicinal Product designation for the treatment of HPA from both the EMEA and the Food and Drug Administration (FDA).

"The filing for sapropterin is an important milestone for patients with phenylketonuria or BH4 deficiency. These are serious, debilitating diseases for which there is currently no drug approved in Europe," said Roberto Gradnik, Head of Merck Serono's Operations for Europe. "This submission underscores Merck Serono's commitment to address unmet medical needs."

PKU and BH4 deficiency are 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 young children, and neurological impairment in older patients. There are at least 50,000 people diagnosed with hyperphenylalaninemia due to PKU or BH4 deficiency in the developed world. However, 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.

Data from two international, double-blind, randomized, placebo-controlled Phase III clinical trials in patients with hyperphenylalaninemia due to PKU show that treatment with sapropterin reduces blood phenylalanine levels and may reduce the need to limit phenylalanine 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.

Sapropterin 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 sapropterin in all territories outside the United States and Japan. BioMarin has exclusive rights to market sapropterin in the United States.

About sapropterin

Sapropterin (INN: sapropterin dihydrochloride, formerly Phenoptin(TM)) is an oral therapeutic for the treatment of hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. Sapropterin 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 sapropterin produces significant reductions in blood Phe levels in the subset of patients who are BH4-responsive. BioMarin and Merck Serono estimate that sapropterin could be a potential treatment option for approximately 30-50 % of the estimated 50,000 patients in the developed world who have been diagnosed with HPA, due to PKU or BH4 deficiency.

Sapropterin received Orphan Medicinal Product designation to treat HPA from both the FDA and the EMEA. If sapropterin becomes the first drug therapy approved for the treatment of HPA, sapropterin would receive seven years of market exclusivity in the United States and ten years in the European Union for this indication. Additionally, the FDA has granted sapropterin Fast Track designation, which is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

About 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.

About 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.

About 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.

About Merck Serono

Merck Serono, the new division for innovative small molecules and biopharmaceuticals of Merck, was established following the acquisition of Serono and the integration of its business with the former Merck Ethicals division. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, produces and commercializes innovative products to help patients with diseases with unmet needs. Our North American business operates in the United States and Canada under EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux(R)), multiple sclerosis (Rebif(R)), infertility (Gonal-f(R)), metabolic and cardiometabolic disorders (Glucophage(R), Concor(R), Saizen(R), Serostim(R)), as well as psoriasis (Raptiva(R)). With an annual R&D investment of EUR 1bn, we are committed to growing our business in specialist-focused therapeutic areas such as Neurodegenerative Diseases and Oncology, as well as new therapeutic areas potentially arising out of our research and development in Autoimmune and Inflammatory Diseases.

About Merck

Merck is a global pharmaceutical and chemical company with sales of EUR 6.3 billion in 2006, a history that began in 1668, and a future shaped by 30,962 employees in 61 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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Contacts: Merck Serono, 9 Chemin des Mines, Media Relations, 1202 Geneva, Tel: +41-22-414-36-00, Switzerland