Merck Announces Detailed 26-Week Results from Phase IIIb Study with Kuvan in Children with PKU Below 4 Years of Age

Darmstadt, Germany (ots/PRNewswire) -

Not intended for UK based media

- Detailed 26-week results of SPARK study presented at SSIEM Annual
Symposium
- Phenylalanine tolerance significantly increased in children with PKU below 4
years of age, previously shown to be responsive to Kuvan and treated with Kuvan plus a
phenylalanine-restricted diet, versus diet alone (p<0.001)

Merck Serono, the biopharmaceutical division of Merck, announced
today that detailed 26-week data from the Phase IIIb SPARK study are
being presented at the Society for the Study of Inborn Errors of
Metabolism (SSIEM) Annual Symposium, currently taking place in
Innsbruck, Austria. As announced in April, the study met its primary
endpoint. It showed that the addition of Kuvan(R) (sapropterin
dihydrochloride) at a dose of 10 or 20 mg/kg/day to a
phenylalanine-restricted diet significantly increased phenylalanine
tolerance by 30.5 mg/kg/day in children with phenylketonuria (PKU)
who are below 4 years of age and responsive to Kuvan compared with
that of patients on diet alone (p<0.001).

The group of patients receiving Kuvan had an adjusted mean
phenylalanine tolerance of 80.6 mg/kg/day at the end of 26 weeks of
treatment compared with that of 50.1 mg/kg/day in the group of
patients receiving diet alone (increment 30.5 mg/kg/day). The mean
phenylalanine tolerance in the group receiving Kuvan in addition to a
phenylalanine-restricted diet (n=27) increased from a baseline of
37.1 mg/kg/day (standard deviation [SD] 17.3 mg/kg/day) to 80.6
mg/kg/day (SD 4.2 mg/kg/day) after 26 weeks. In the group following a
phenylalanine-restricted diet alone (n=29), the increase was from
35.8 mg/kg/day (SD 20.9 mg/kg/day) to 50.1 mg/kg/day (SD 4.3
mg/kg/day).

The safety profile of Kuvan in this population was consistent with
the safety profile of Kuvan described in the European Summary of
Product Characteristics, which lists the most common adverse
reactions reported with the use of Kuvan, including headache, runny
nose, diarrhea, vomiting, sore throat, cough, abdominal pain, stuffy
nose and low levels of phenylalanine in the blood. The most frequent
Kuvan-related adverse reactions in the SPARK trial were reported as
"amino acid level decreased" (hypophenylalaninemia), rhinitis and
vomiting. 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 trial will enable the submission of an application for a label
extension this year, and study results will be submitted for
publication in a peer-reviewed journal.

"This study was designed to investigate if children below 4 years
of age with PKU could potentially benefit from adding Kuvan to their
phenylalanine-restricted diet," said Professor Ania Muntau,
previously Dr. von Hauner Children's Hospital Ludwig-Maximilians
University, Munich, Germany, and now University Medical Center
Hamburg-Eppendorf, Hamburg, Germany, and lead investigator for SPARK.
"It is the first time a controlled study such as this has been
conducted in this population and the study results have the potential
to significantly change treatment strategies with immediate start of
a pharmacological treatment in newborns diagnosed to have
phenylketonuria responsive to sapropterin dihydrochloride."

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 prevent potentially severe
neurological damage.[3]

Luciano Rossetti, Head of Global Research & Development at Merck
Serono underlined the company's commitment to better management of
PKU for all those affected by it: "Although rare, we know that PKU
can have profound and far-reaching consequences if not managed
appropriately right from birth. These results add to the growing
insights for the medical community around PKU in infants and young
children."

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 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. Subject to a
patient's phenylalanine tolerance after approximately 4 weeks, the
Kuvan dose could be increased in a single step to 20 mg/kg/day. 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 are being assessed in the
ongoing study's 3-year extension period, in which all patients are
offered to receive Kuvan in addition to the phenylalanine-restricted
diet.

The Kuvan European marketing authorization was granted 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 to phenylalanine hydroxylase enzyme deficiency)
who are responsive to Kuvan. Currently, there is no licensed
medication in Europe for the treatment of PKU in children who are
below 4 years of age. 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, 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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