Merck Announces Positive Outcome of IIIb Study for Kuvan
Merck Announces Positive Outcome of IIIb Study for Kuvan
PR56580
DARMSTADT, Germany, Apr. 24 /PRN=KYODO JBN / --
- 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)
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.
SOURCE: Merck KGaA
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