Merck Announces Positive Outcome of IIIb Study for Kuvan

Darmstadt, Germany (ots/PRNewswire) -

- Primary endpoint met in SPARK study: significant increase in phenylalanine
tolerance demonstrated after 26 weeks of the study in children less than 4 years of
age with phenylketonuria and responsive to Kuvan treated with Kuvan plus a
phenylalanine-restricted diet, versus diet alone
- SPARK study was conducted as a post-authorization measure and results will be
submitted to EMA this year

Merck, a leading company for innovative and top-quality high-tech
products in the pharmaceutical and chemical sectors, announced today
that the Phase IIIb SPARK* study has met its primary endpoint. The
results of the first 26 weeks of this study demonstrated that the
addition of Kuvan(R) (sapropterin dihydrochloride) to a
phenylalanine-restricted diet in children less than 4 years of age
who have phenylketonuria (PKU) and have been previously shown to be
responsive to Kuvan significantly increased tolerance to
phenylalanine compared with a phenylalanine-restricted diet alone.
The safety profile of Kuvan in this population was consistent with
the safety profile for Kuvan described in the European Summary of
Product Characteristics. The 26-week results will be submitted for
presentation at upcoming international scientific meetings and for
publication in a peer-reviewed journal. SPARK was requested by the
European Medicines Agency (EMA) as a post-authorization measure and
demonstrates Merck's commitment to addressing areas of high unmet
medical need. The positive outcome of the study will enable the
submission of a regulatory application for a label extension later
this year.

Dr John Orloff, Global Head of Clinical Development at Merck's
biopharmaceutical division Merck Serono, underlined the company's
commitment to better management of PKU for all those affected by it:
"PKU is a serious rare disease that has a significant impact on
patients and their families. We are delighted by the positive outcome
of this study, and remain dedicated to further improving our
understanding of PKU in infants and young children."

PKU is an inborn metabolic disorder that causes the toxic
accumulation of phenylalanine, an essential amino acid found in all
protein-containing foods, in the brain and blood.[1],[2] Untreated,
PKU can lead to intellectual disability, seizures and other serious
medical problems.[1],[2] In many countries, implementation of
national newborn screening programs has allowed identification of
children with PKU at birth, enabling the management of the disease to
begin as early as possible in order to avoid potentially severe
neurological damage.[3]

"This is the first time a controlled study such as this has been
conducted in children below 4 years of age with PKU" said Professor
Ania Muntau, Klinikum University Munich, Germany, and lead
investigator for SPARK. "These study findings with Kuvan in addition
to phenylalanine-restricted diet could lead to a new disease
management approach to control blood phenylalanine levels right from
birth."

SPARK is a Phase IIIb, multicenter, open-label, randomized,
controlled study designed to assess the efficacy, safety, and
population pharmacokinetics of Kuvan in patients younger than 4 years
old with PKU and who have been previously shown to be responsive to
Kuvan in a response test. The study was conducted under a Pediatric
Investigational Plan. Patients were randomized to Kuvan (10
mg/kg/day) plus a phenylalanine-restricted diet, or to a
phenylalanine-restricted diet alone, for 26 weeks, and the primary
endpoint of the study was to compare phenylalanine tolerance achieved
in both arms after 26 weeks of treatment. Secondary study endpoints
included change in levels of blood phenylalanine during the study
period, change in dietary phenylalanine tolerance over time (from
baseline to 26 weeks) in both groups, as well as assessment of
neurodevelopmental function, growth parameters and safety. The
long-term efficacy and safety of Kuvan will be assessed in the
study's 3-year extension period, in which all patients will be
offered to receive Kuvan in addition to the phenylalanine-restricted
diet.

European marketing authorization was granted for Kuvan in 2008.
Kuvan was the first, and remains the only, medication in combination
with dietary modifications in Europe designed to reduce the
concentration of phenylalanine in the blood and in the brain in those
patients who are responsive to Kuvan to prevent the debilitating
effects of PKU.[4] Kuvan is indicated in patients of all ages with
tetrahydrobiopterin (BH4) deficiency, and in those aged 4 years and
above with PKU (due phenylalanine hydroxylase enzyme deficiency) who
are responsive to Kuvan. Currently, there is no licensed medication
in Europe for the treatment of PKU in the 0-4 years age group. Kuvan
is marketed by Merck Serono outside the USA, Canada and Japan, by
BioMarin in the USA and Canada, and under the name Biopten(R) by
Asubio Pharma in Japan. In the USA and Europe, Kuvan received orphan
drug designation.

*SPARK: Safety Pediatric EfficAcy PhaRmacokinetic with Kuvan
(sapropterin dihydrochloride)

References:

1) Blau N: Phenylketonuria and BH4 deficiencies. Bremen: Uni-Med; 2010
2) Blau N, van Spronsen FJ, Levy HL: Phenylketonuria. Lancet 2010,376:1417-1427
3) Loeber JG. Neonatal screening in Europe: the situation in 2004. J Inherit
Metab Dis 2007;30:30-38
4) http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000943/human_med_000880.jsp&mid=WC0b01ac058001d124
, Accessed 31.03.2014

About phenylketonuria (PKU)

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 (Phe), an essential
amino acid found in all protein-containing foods. It affects
approximately 1/10,000 newborns in Europe and 1/15,000 in the US. If
PKU patients are not treated with a Phe-restricted diet, Phe 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 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 Kuvan

Kuvan(R) (sapropterin dihydrochloride) is an oral therapy and the
first treatment indicated in Europe in conjuction with a
Phe-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 Phe-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 (Phe) into tyrosine.
Clinical data show that Kuvan produces significant reductions in
blood Phe concentration in a large subset of patients.

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 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.

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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 38,000 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.

ots Originaltext: Merck KGaA
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