Merck Healthcare

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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Merck is a leading company for innovative and top-quality high-tech products in healthcare, life science and performance materials. The company has six businesses - Merck Serono, Consumer Health, Allergopharma, Biosimilars, Merck Millipore and Performance Materials - and generated sales of around EUR 11.3 billion in 2014. Around 39,000 Merck employees work in 66 countries to improve the quality of life for patients, to foster 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% interest, the founding family remains the majority owner of the company to this day. Merck, Darmstadt, Germany, holds the global rights to the Merck name and brand. The only exceptions are Canada and the United States, where the company operates as EMD Serono, EMD Millipore and EMD Performance Materials.

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