Abstract
Introduction: Sapropterin dihydrochloride (Kuvan®), a synthetic 6R-diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged ≥4 years with hyperphenylalaninaemia (HPA) due to BH4-responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency.
Aims/methods: KAMPER is an ongoing, observational, multicentre registry with the primary objective of providing information over 15 years on long-term safety of sapropterin dihydrochloride treatment in patients with HPA. Here we report initial data on characteristics from patients recruited by the time of the third interim analysis and results at 1 year.
Results: Overall, 325 patients from 55 sites in seven European countries were included in the analysis: 296 (91.1%) patients with PAH deficiency (median [Q1, Q3] age, 10.3 [7.2, 15.0] years) and 29 (8.9%) with BH4 deficiency (12.8 [6.6, 18.9] years). Fifty-nine patients (18.2%) were aged ≥18 years; 4 patients were pregnant. No elderly patients (aged ≥65 years) or patients with renal or hepatic insufficiency were enroled in the study. Twelve-month data were available for 164 patients with PAH deficiency and 16 with BH4 deficiency. No new safety concerns were identified as of May 2013.
Conclusions: Initial data from KAMPER show that sapropterin dihydrochloride has a favourable safety profile. Registry data collected over time will provide insight into the management and outcomes of patients with PAH deficiency and BH4 deficiency, including long-term safety, impact on growth and neurocognitive outcomes and the effect of sapropterin dihydrochloride treatment on populations of special interest.
Competing interests: None declared
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Abbreviations
- AE:
-
Adverse event
- BH4 :
-
Tetrahydrobiopterin
- BMI:
-
Body mass index
- CI:
-
Confidence interval
- ECG:
-
Electrocardiogram
- HPA:
-
Hyperphenylalaninaemia
- ICH:
-
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
- KAMPER:
-
Kuvan® Adult Maternal Paediatric European Registry
- PAH:
-
Phenylalanine hydroxylase
- Q:
-
Quarter
- SAE:
-
Serious adverse event
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Acknowledgments
This study (EMR700773_001) was supported by Merck Serono SA Geneva, Switzerland, a subsidiary of Merck KGaA, Darmstadt, Germany. Writing assistance was provided by Alyson Bexfield and Jane Davies of Caudex Medical, Oxford, UK (supported by Merck Serono SA Geneva, Switzerland). The authors thank Charles Edward Jefford of EMD Serono, Inc., Billerica, MA, USA, a subsidiary of Merck KGaA, Darmstadt, Germany, for support in the development of this manuscript.
The authors would also like to thank the KAMPER study investigators: Austria: Michaela Brunner-Krainz, Daniela Karall and Dorothea Möslinger; France: Magalie Barth, Nathalie Bednarek, Antoine Bedu, Thierry Billette de Villemeur, Pierre Broué, Brigitte Chabrol, Dries Dobbelaere, Cécile Dumesnil, Didier Eyer, Alain Fouilhoux, François Labarthe, Delphine Lamireau, Gilles Morin, Jean-Claude Netter, Vassili Valayannopoulos and Kathy Wagner-Mahler; Germany: Philipp Guder, Julia Hennermann, Jürgen Herwig, Ralf Husain, Martin Lindner, Amelie S. Lotz-Havla, Klaus Mohnike, Alexandra Puchwein-Schwepcke, Dagmar Scheible and Michael Staudigl; Italy: Generoso Andria, Milva Orquidea Bal, Roberto Cerone, Daniela Concolino, Antonio Correra, Vincenzo Leuzzi, Concetta Meli, Enrica Riva and Iris Scala; Netherlands: Annet M Bosch, Maria Estela Rubio-Gozalbo and Ans van der Ploeg; Slovakia: Katarina Hálová and Ludmila Potocnakova; Spain: Javier Blasco Alonso, Jaume Campistol Plana, Maria Luz Couce Pico, Maria García Jimenez, David Gil Ortega, Domingo González-Lamuño, Mónica Ruiz Pons, Angeles Rúiz Gomez, Félix Sánchez-Valverde and Pablo Sanjurjo Crespo.
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Communicated by: Nenad Blau, PhD
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Synopsis
Initial data from the ongoing, 15-year, Kuvan® Adult Maternal Paediatric European Registry show that sapropterin dihydrochloride has a good safety profile in patients with phenylalanine hydroxylase deficiency or tetrahydrobiopterin deficiency.
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Conflicts of Interest
F. K. Trefz has served as a member on Merck Serono SA Geneva, Switzerland, advisory boards or similar committees; has current or recent participation in a clinical trial sponsored by Merck Serono SA Geneva, Switzerland; has assisted in the design of and/or participated in clinical studies using products manufactured by Merck Serono SA Geneva, Switzerland; and has received consulting fees or other remuneration including speaker fees from Merck Serono SA Geneva, Switzerland.
A. C. Muntau has participated in strategic advisory boards for Merck Serono SA Geneva, Switzerland; has assisted in the design of and/or participated in clinical studies using products manufactured by Merck Serono SA Geneva, Switzerland; and has received honoraria as a consultant and as a speaker from Merck Serono SA Geneva, Switzerland.
F. B. Lagler has served as a member on Merck Serono SA Geneva, Switzerland, advisory boards and has received research grants from Merck GesmbH, Austria.
F. Moreau is an employee of EMD Serono, Inc., Billerica, MA, USA.
J. Alm has served as a member on Merck Serono SA Geneva, Switzerland, advisory boards or similar committees; has assisted in the design of and/or participated in clinical studies using products manufactured by Merck Serono SA Geneva, Switzerland; and has received honoraria as a consultant from Merck AB Sweden.
A. Burlina has served as a member on Merck Serono SA Geneva, Switzerland, advisory boards or similar committees; has current or recent participation in a clinical trial sponsored by Merck Serono SA Geneva, Switzerland; has assisted in the design of and/or participated in clinical studies using products manufactured by Merck Serono SA Geneva, Switzerland; and has received consulting fees or other remuneration including speaker fees from Merck Serono SA Geneva, Switzerland.
F. Rutsch has served as a member on Merck Serono SA Geneva, Switzerland, advisory boards or similar committees; has assisted in the design of and/or participated in clinical studies using products manufactured by Merck Serono SA Geneva, Switzerland; and has received consulting fees or other remuneration including speaker fees from Merck Serono SA Geneva, Switzerland.
A. Bélanger-Quintana has participated in strategic advisory boards and received grants and fees for presentations from Merck Serono SA Geneva, Switzerland, and Nutricia.
F. Feillet has served as a member on Merck Serono SA Geneva, Switzerland, advisory boards or similar committees; has current or recent participation in a clinical trial sponsored by Merck Serono SA Geneva, Switzerland; has assisted in the design of and/or participated in clinical studies using products manufactured by Merck Serono SA Geneva, Switzerland; and has received consulting fees or other remuneration including speaker fees from Merck Serono SA Geneva, Switzerland.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national), with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice (ICH topic E6, 1996) and with the Helsinki Declaration. Informed consent was obtained from all patients included in the registry.
Contributions of Individual Authors
F.K. Trefz was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
A.C. Muntau was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
F.B. Lagler was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
F. Moreau was substantially involved in the conception and design of the study protocol and the development of the statistical analysis plan; the analysis and interpretation of data; and the preparation, review and approval of the manuscript.
J. Alm was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
A. Burlina was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
F. Rutsch was substantially involved in collection and interpretation of data and the preparation, review and approval of the manuscript.
A. Bélanger-Quintana was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
F. Feillet is the principal investigator of the KAMPER study and was substantially involved in the conception and design of the study protocol; the interpretation of data; and the preparation, review and approval of the manuscript.
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Trefz, F.K. et al. (2015). The Kuvan® Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 23. JIMD Reports, vol 23. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_425
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DOI: https://doi.org/10.1007/8904_2015_425
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