Merck Serono Initiates Phase IIIb European Study SPARK in Children Younger Than Four Years, Suffering from Phenylketonuria

By Merck Serono S A, PRNE
Wednesday, June 29, 2011

GENEVA, June 30, 2011 -

Merck Serono, a division of Merck KGaA, Darmstadt, Germany,
today announced the enrollment of the first patients in
SPARK[1]. The SPARK study will
investigate the safety, efficacy and population pharmacokinetics of
Kuvan® (sapropterin dihydrochloride) in patients younger
than four years, who suffer from Phenylketonuria (PKU).

PKU is a rare inborn metabolic disorder causing the toxic
accumulation in brain and blood of an essential amino acid,
Phenylalanine (Phe), found in all protein-containing foods. Until
recently, the only way to prevent or reduce Phe blood level was a
strict, life-long binding diet. In December 2008, Kuvan®
received a European marketing authorization in patients four years
of age and older in PKU indication and in patients of all age in
the indication of Tetrahydrobiopterin (BH4) deficiency.

“Beyond the implementation of SPARK as follow-up measure agreed
with the European Medicines Agency, we want to make
Kuvan® available for patients who could benefit from it,
including children younger than four years suffering from PKU”,
said Dr. Bernhard Kirschbaum, Executive Vice President Global
Research and Development at Merck Serono.  

SPARK is a Phase IIIb, multi-center, open-label, randomized and
controlled study that will be conducted in Europe and in Turkey.
Fifty pediatric patients with PKU, younger than four years old, are
expected to be included in SPARK. They will randomly receive either
Kuvan® therapy in conjunction with a Phe-restricted diet
or the dietary therapy alone, over a period of 26 weeks.

Patients who complete the 26-weeks study period will be eligible
to enter in an extension period, during which all subjects will
undergo continued treatment with Kuvan®, along with a
Phe-restricted diet, over a period of up to three years.

[1] SPARK: Safety
Pediatric EfficAcy PhaRmacokinetic with
Kuvan® (sapropterin dihydrochloride).

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)

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,

About Kuvan®

Developed by Merck Serono and BioMarin Pharmaceutical Inc.
(Nasdaq and SWX: BMRN), Kuvan® (sapropterin
dihydrochloride), is an oral therapeutic and the first treatment
indicated in Europe for the treatment of hyperphenylalaninemia
(HPA) due to phenylketonuria (PKU) in patients over the age of 4,
or due to tetrahydrobiopterin (BH4) deficiency. In the US,
Kuvan® is indicated for the treatment of HPA due
to PKU without age restriction. Kuvan® is to be
used in conjunction with a Phe-restricted diet.

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 show that Kuvan produces
significant reductions in blood Phe levels in the subset of
patients who are BH4-responsive.

Most common side effects 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 32 countries, 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 KGaA,
Darmstadt, Germany, a global pharmaceutical and chemical company.
Headquartered in Geneva, Switzerland, Merck Serono discovers,
develops, manufactures and markets prescription medicines of both
chemical and biological origin in specialist indications. In the
United States
and Canada, EMD Serono operates as a separately
incorporated affiliate of Merck Serono.

Merck Serono has leading brands serving patients with cancer
(Erbitux®, cetuximab), multiple sclerosis (Rebif®, interferon
beta-1a), infertility (Gonal-f®, follitropin alfa), endocrine and
metabolic disorders (Saizen® and Serostim®, somatropin), (Kuvan®,
sapropterin dihydrochloride), (Egrifta™, tesamorelin), as well as
cardiometabolic diseases (Glucophage®, metformin), (Concor®,
bisoprolol), (Euthyrox®, levothyroxine). Not all products are
available in all markets.

With an annual R&D expenditure of over € 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 rheumatology.

About Merck

Merck is a global pharmaceutical and chemical company with total
revenues of € 9.3 billion in 2010, a history that began in 1668,
and a future shaped by more than 40,000 employees in 67 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 or

Merck Serono S.A. – Geneva, 9 Chemin des Mines, 1202 Genf, Schweiz, Media relations, Tel: +41-22-414-36-00

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