Merck Serono Announces CHMP Positive Opinion to Extend Kuvan Use to Children with PKU Below 4 Years of Age
Merck Serono Announces CHMP Positive Opinion to Extend Kuvan Use to Children with PKU Below 4 Years of Age
PR60601
DARMSTADT, Germany, May 22 /PRN=KYODO JBN/ --
Not intended for UK based media
CHMP recommendation based on results from the Phase IIIb SPARK study
Merck Serono, the biopharmaceutical business of Merck, today announced that
the European Medicines Agency's (EMA) Committee for Medicinal Products for
Human Use (CHMP) has issued a positive opinion on an update to the product
information for its product Kuvan(R) (sapropterin dihydrochloride). Following
review of the data from SPARK[*] , a Phase IIIb clinical study, the CHMP has
recommended that the Kuvan indication is extended to allow its use in children
with phenylketonuria (PKU) below 4 years of age who have shown to be responsive
to such treatment.
Luciano Rossetti, Head of Global Research & Development at Merck Serono,
said, "PKU is a rare disease with significant consequences - but if managed
appropriately, it doesn't have to impair child development or quality of life
for children and adults. We are committed to helping patients with PKU, both at
adult age and during childhood. The positive CHMP opinion is an important step
towards being able to use Kuvan also in children right from diagnosis and
evidence of responsiveness at birth."
Detailed 26-week data from the SPARK study were presented at the Society
for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium in
September 2014. The SPARK study showed that the addition of Kuvan to a
phenylalanine-restricted diet significantly increased phenylalanine tolerance
by 30.5 mg/kg/day in children with PKU below 4 years of age and responsive to
Kuvan, when compared with phenylalanine tolerance in children following a
phenylalanine-restricted diet alone (p＜0.001).
PKU is an inborn metabolic disorder that causes the toxic accumulation of
phenylalanine, an essential amino acid contained in all protein-rich 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] However, in Europe there is currently no licensed
medication for the treatment of PKU in children who are below 4 years of age.
If approval is granted by the European Commission, the Summary of Product
Characteristics (SmPC) will be updated to include details about the extended
use of Kuvan in this younger population.
The original European marketing authorization for Kuvan was granted in
2008. In Europe, Kuvan was the first, and yet remains the only medication in
combination with phenylalanine-restricted diet designed to reduce the
concentration of phenylalanine in the blood and brain in those patients who are
responsive to Kuvan to prevent the debilitating effects of PKU.[4] Kuvan is
currently 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.
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 09.04.2015
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 for the treatment of hyperphenylalaninemia (HPA)
due to phenylketonuria (PKU) in patients from the age of 4 years 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 EU label states that safety
and efficacy of Kuvan in pediatric PKU 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 51 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 the SPARK study
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 requested by
the European Medicines Agency (EMA) as a post-authorization measure and
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. 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
37.1degree(s)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).
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 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. 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.
About Merck Serono
Merck Serono is the biopharmaceutical business 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. For
more information, please visit http://www.merckserono.com.
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SOURCE: Merck Serono
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