Phenylalanine hydroxylase (PAH) deficiency, traditionally known as phenylketonuria (PKU), is an autosomal recessive inborn error of metabolism caused by mutations in the gene encoding PAH, the enzyme that converts phenylalanine (Phe) to tyrosine. If untreated, Phe accumulates to toxic levels in the brain, which can lead to profound neurocognitive, neuropsychiatric, and developmental problems. PKU occurs in approximately one in every 12,000 to 15,000 infants born in North America, accounting for approximately 300 new cases each year. The main treatment for PKU is a Phe-restricted diet; however, the strict diet imposes economic and social hardships and often leads to non-adherence, especially among adolescents and young adults. PKU places a large burden on patients and their families and has a substantial effect on patients’ quality of life. Patients’ expectations are that sapropterin (SAP) will lower Phe levels and increase Phe tolerance so that patients are able to eat a more varied diet and be less isolated from their peers.

Kuvan (sapropterin dihydrochloride) is a synthetic formulation of tetrahydrobiopterin (BH4), a necessary co-factor for the PAH enzyme that hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU who are responders, treatment with BH₄ can activate residual PAH enzyme, improve the oxidative metabolism of Phe, and decrease Phe blood levels in some patients. Kuvan is available as 100 mg oral tablets and the recommended starting dose is 10 mg/kg/day daily. Prior to treatment, responders are typically identified by evaluating the reduction in blood Phe following treatment with 20 mg/kg/day of SAP for a period of up to four weeks. A 30% reduction from baseline in mean Phe blood levels is often cited as evidence of effective response. Once responsiveness to SAP has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg/day, according to response.

Contents

• Abbreviations
• Executive Summary
• 1. Introduction
  • 1.1. Disease Prevalence and Incidence
  • 1.2. Standards of Therapy
  • 1.3. Drug
• 2. Submission History
  • 2.1. Basis of Resubmission
• 3. Objectives and Methods
  • 3.1. Objectives
  • 3.2. Methods
• 4. Results
  • 4.1. Findings From the Literature
  • 4.2. Included Studies
  • 4.3. Patient Disposition
  • 4.4. Exposure to Study Treatments
  • 4.5. Critical Appraisal
  • 4.6. Efficacy
  • 4.7. Harms
• 5. Discussion
  • 5.1. Summary of Available Evidence
  • 5.2. Interpretation of Results
  • 5.3. Potential Place in Therapy
• 6. Conclusions
• Appendix 1. Patient Input Summary
• Appendix 2. Literature Search Strategy
• Appendix 3. Excluded Studies
• Appendix 4. Detailed Outcome Data
• Appendix 5. Validity of Outcomes
• Appendix 6. Summary of Other Studies
• Appendix 7. Dietary Treatment for Phenylketonuria
• Appendix 8. Proposed Reimbursement Criteria from Ontario Specialists
• References

This review report was prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). In addition to CADTH staff, the review team included two clinical experts in metabolic/biochemical diseases who provided input on the conduct of the review and the interpretation of findings.

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