Actualizado 03/09/2014 12:05
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Merck Announces Detailed 26-Week Results from Phase IIIb Study with Kuvan in Children with PKU Below 4 Years of Age (1)

DARMSTADT, Germany, September 3, 2014 /PRNewswire/ --

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?c...
, Accessed 31.03.2014

About phenylketonuria (PKU)

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