Safety and Efficacy Study of Phenoptin in Subjects With Hyperphenylalaninemia Due to BH4 Deficiency
Condition: Tetrahydrobiopterin Deficiencies; Hyperphenylalaninemia, Non-Phenylketonuric
MeSH terms: Phenylketonurias
Intervention: Phenoptin
Intervention description: 5mg/kg/day orally, dose may be adjusted to between 5-20 mg/kg/day by investigator at week 6 to control blood Phe levels
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Outcomes were to be evaluated for all subjects with primary BH4 disease. Outcomes were also evaluated based on the type of BH4 deficiency either due to defects in the genes encoding the enzymes involved in BH4 biosynthesis, GTPcyclohydrolase I (GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR); or defects in the genes encoding the enzymes involved in BH4 recycling, pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR)
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the ability of Phenoptin to control blood
      phenylalanine levels in subjects who have hyperphenylalaninemia due to a primary BH4
      deficiency and to evaluate the safety of Phenoptin in this population. Some subjects were
      receiving non-registered formulations of BH4 at enrollment and this treatment was suspended
      after Part 1 and within one day the subjects started Phenoptin at approximately the same
      dose.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Documented history of blood Phe level > 180 µmol/L on at least one occasion

          -  Established diagnosis of hyperphenylalaninemia (HPA) due to primary BH4 deficiency
             with a documented defect in biopterin metabolism with blood or urine tests

          -  Willing and able to provide written informed consent or, in the case of subjects under
             the age of 18 years, provide written assent (if required) and written informed consent
             by a parent or legal guardian

          -  Negative urine pregnancy test at screening for females of child-bearing potential

          -  Male and female subjects of childbearing potential (if sexually active and
             non-sterile) must be using acceptable birth control measures and be willing to
             continue to use acceptable birth control measures, as determined by the Investigator,
             and be willing to continue to use acceptable birth control measures while
             participating in the study

          -  Willing and able to comply with all study procedures

          -  Able to take medication orally

        Exclusion Criteria:

          -  Perceived to be unreliable or unavailable for study participation or, if under the age
             of 18 years, have parents or legal guardians who are perceived to be unreliable or
             unavailable

          -  Use of any investigational agent (other than BH4) within 30 days prior to screening,
             or requirement for any investigational agent or vaccine prior to completion of all
             scheduled study assessments

          -  Positive urine pregnancy test at screening (non-sterile females of child bearing
             potential only), already known to be pregnant or breastfeeding or planning a pregnancy
             in self or partner during the study

          -  Female subjects of childbearing potential not using an effective method of birth
             control, as determined by the PI, or unwilling to continue to use acceptable birth
             control measures.

          -  Alanine aminotransferase (ALT) > 2 times the upper limit of normal (i.e., Grade 1 or
             higher based on World Health Organization Toxicity Criteria) at screening

          -  Concurrent disease or condition that would interfere with study participation or
             safety (e.g., seizure disorder, oral steroid-dependent asthma or other condition
             requiring oral or parenteral corticosteroid administration, insulin-dependent
             diabetes, or organ transplantation)

          -  Serious neuropsychiatric illness (e.g., major depression) not currently under medical
             control

          -  Requirement for concomitant treatment with any drug known to inhibit folate synthesis
             (e.g., methotrexate)

          -  Clinical diagnosis of phenylketonuria (PKU) due to phenylalanine hydroxylase
             deficiency

          -  Any condition that, in the view of the PI, renders the subject at high risk from
             treatment compliance and/or completing the study