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

PR57758

DARMSTADT, Germany, Sep. 3 /PRN=KYODO JBN/ --

    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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SOURCE: Merck Serono