Merck Serono Launches Kuvan(R) in Europe

GENEVA - First Drug in Europe Indicated for the Treatment of Hyperphenylalaninaemia (Hpa) due to Phenylketonuria (Pku) or Tetrahydrobiopterin (BH4) Deficiency, now Commercially Available in France, Germany and the United Kingdom

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, today announced that Kuvan (sapropterin dihydrochloride), indicated for the treatment of hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency, is now commercially available in Europe. Beginning with France, Germany and the United Kingdom, Kuvan will be rolled out in a total of thirteen European countries this year.

“We are pleased to bring Kuvan to the European market, as this treatment can make a difference in the management of HPA for many patients suffering from lifelong PKU or BH4 deficiency, and may contribute to prevent the appearance of potential transient to non-reversible mental impairment. In the US where Kuvan has been available since 2007, we have received positive testimonials from healthcare professionals and from the patients whose quality of life has improved thanks to treatment with Kuvan,” said Roberto Gradnik, Executive Vice President Commercial Europe at Merck Serono. “As part of our commitment to patients, Merck Serono will continue to investigate innovative treatment options for patients with high unmet medical needs.”

Kuvan is the only drug approved in Europe for the treatment of HPA due to PKU or BH4 deficiency, two rare genetic diseases leading to an abnormally high concentration of phenylalanine (Phe) in the blood, which can be harmful for patients. Diagnosed at birth, HPA due to PKU or BH4 deficiency is estimated to affect approximately 35,000 patients in the European Union(1). If left untreated, HPA can result in permanent neurological disorders in pediatric patients and cognitive deficits and psychiatric disorders in adults due to sustained elevations of Phe in the blood(2). Used in conjunction with a restricted Phe diet, Kuvan has been shown to help control blood levels of Phe in patients suffering from PKU or BH4 deficiency. The European health authorities recommend that therapy with Kuvan should be initiated as early as possible to avoid the appearance of non-reversible neurological damages(2).

The marketing authorization for Kuvan soluble tablets was granted by the European Commission in December 2008; it applies to the 27 countries of the European Union as well as Iceland, Liechtenstein and Norway. Merck Serono owns the exclusive rights to market Kuvan in all countries outside North America and Japan.

References

(1) Kuvan is a potential treatment option in 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

(2) Summary of Product Characteristics; accessed via www.emea.europa.eu/humandocs/PDFs/EPAR/kuvan/H-943-PI-en.pdf

About Kuvan(R)

Kuvan (sapropterin dihydrochloride) 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(R), which contains the same active ingredient as Kuvan, for the treatment of patients with PKU.

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 are diagnosed 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 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 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), cetuximab), multiple sclerosis (Rebif(R), interferon beta-1a), infertility (Gonal-f(R), follitropin alfa), endocrine and cardiometabolic disorders (Glucophage(R), metformin); (Concor(R), bisoprolol); (Euthyrox(R), levothyroxine); (Saizen(R) and Serostim(R), somatropin). Not all products are available in all markets.

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.

About Merck

Merck is a global pharmaceutical and chemical company with total revenues of EUR 7.6 billion in 2008, a history that began in 1668, and a future shaped by 32,800 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.

For more information, please visit www.merckserono.com or www.merck.de

Source: Merck Serono

Merck Serono, 9 Chemin des Mines, Media Relations, 1202 Geneva, Tel.: +41-22-414-36-00, Switzerland