Abstract
Prospectively enrolled phenylketonuria patients (n=485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN®). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5–20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.
Competing interests: None declared.
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Acknowledgements
We are indebted to the PKU patients and families who enrolled this study, as well as doctors and their healthcare staff for their invaluable assistance in the conduct of the clinical studies. We also thank our colleagues, John Tomaro for data collection, Sonia Schnieper-Samec for help with statistical review, Kumar Saikatendu and Katya Kadyshevskaya for the 3D figure preparation, Angela Walker for assistance with manuscript preparation and submission to the journal, Sun Sook Kim and Sabrina Cheng for data revision, and Manyphong Phommarinh and Jacques Mao for assistance with PAHdb. A. Gamez was supported by a research contract from “Ramón y Cajal” program by Ministerio de Ciencia e Innovación and Fundación Ramón Areces.
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Communicated by: Nenad Blau.
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Synopsis
Some PAH mutations causing misfolding of the PAH protein respond to pharmacological doses of sapropterin dihydrochloride (BH4) acting as a chaperone; however, to know genotype is not a robust predictor of therapeutic response, an assumption corroborated by findings reported in Phase II and III clinical trials.
Author Contributions
All co-authors participated in various aspects of the study. CNS and AG organized, corrected, analyzed, and interpreted the data, PS did the genotyping, JD completed the analysis of genotypes, AD compiled the data, CNS, AG and CRS drafted the manuscript, and CNS, AG, AD, RCS, and CRS reviewed it. The final version was seen and approved by all authors. CNS and AG are co-first authors who contributed equally to this work.
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Raymond C. Stevens
Competing Interests Statement
The authors report commercial affiliations and competing financial interests: this study was supported by BioMarin Pharmaceutical Inc., the manufacturer of KUVAN®. AD was an employee of BioMarin Pharmaceutical Inc., and owns stock or stock options in the company. RCS and CRS have consulted (or are consultants) for BioMarin Pharmaceutical Inc. regarding their development of treatments for PKU/HPA.
CNS | AG | PS | JD | AD | CRS | RCS | |
|---|---|---|---|---|---|---|---|
1. Have you in the past 5 years accepted the following from an organization that may in any way gain or lose financially from the results of your study or the conclusions of your review, editorial, or letter: | |||||||
Reimbursement for attending a symposium? | Yes | No | No | No | Yes | Yes | No |
A fee for speaking or for organizing education? | No | No | No | No | Yes | No | No |
Funds for research or for a member of staff? | Yes | No | No | No | Yes | Yes | Yes |
A fee for consulting? | Yes | No | No | No | Yes | Yes | Yes |
2. Have you in the past 5 years been employed by an organization that may in any way gain or lose financially from the results of your study or the conclusions of your review, editorial, or letter? | Yes | Yes | No | Yes | Yes | Yes | Yes |
Do you hold any stocks or shares in such an organization? | No | No | No | No | Yes | No | No |
3. Have you acted as an expert witness on the subject of your study, review, editorial, or letter? | No | No | No | No | No | No | No |
4. Do you have any other competing financial interests? | No | No | No | No | No | No | No |
Funding
This study grew out of clinical trials NCT00104260, NCT00104247, NCT00225615 supported by BioMarin Pharmaceutical Inc., the manufacturer of KUVAN®. The mutations analysis was funded by BioMarin Pharmaceutical Inc.; however, they did not financially support the authors (except for AD who was an employee at the time) in the organization, correction, analysis, and interpretation of the data, drafting of the manuscript and review. BioMarin Pharmaceutical Inc. did not influence the analysis process or outcome of the project.
Ethics Approval
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Ethics approval for this research study was covered as a component of the clinical trials.
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Patient consent for this research study was covered as a component of the clinical trials.
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No vertebrate animals were used.
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Sarkissian, C.N. et al. (2011). Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?. In: JIMD Reports - Case and Research Reports, 2012/2. JIMD Reports, vol 5. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_96
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DOI: https://doi.org/10.1007/8904_2011_96
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