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)

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 (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