Merck Serono Announces CHMP Positive Opinion to Extend Kuvan Use to Children with PKU Below 4 Years of Age

Darmstadt, Germany (ots/PRNewswire) -

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)
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000943/hum
an_med_000880.jsp&mid=WC0b01ac058001d124, 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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