Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients

• Evaluate the therapeutic effects of sapropterin dihydrochloride on the symptoms of anxiety and depression compared to placebo, in subjects with a blood Phe level reduction after treatment. [ Time Frame: 13 weeks ] [ Designated as safety issue: No ]
• Evaluate the durability of any therapeutic effects of sapropterin dihydrochloride on neuropsychiatric symptoms and global function of subjects who have a blood Phe level reduction after treatment. [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
• Determine if sapropterin dihydrochloride has a therapeutic effect on neuropsychiatric symptoms in PKU patients who do not have a blood Phe reduction after treatment. [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
• Assess the safety of sapropterin dihydrochloride when administered as therapy to these patients. [ Time Frame: 26 weeks ] [ Designated as safety issue: Yes ]

This double-blind, placebo-controlled, randomized study is designed to evaluate the safety and therapeutic effects of sapropterin dihydrochloride on neuropsychiatric symptoms in subjects with PKU.

Phenylketonuria (PKU) results from deficient phenylalanine hydroxylase (PAH) activity and leads to toxic phenylalanine (Phe) accumulation in patients with PKU causing mental retardation, microcephaly, delayed speech, seizures, psychiatric symptoms and behavioral abnormalities. Although for most PKU patients early initiation of dietary treatment prevents severe complications, discontinuation of dietary restrictions at an early age is associated with poor cognitive development and neuropsychiatric disorders are present even in early-treated and well controlled PKU patients.

This study, PKU-016, will be conducted in PKU patients to evaluate the therapeutic effects of sapropterin dihydrochloride on the symptoms of attention deficit hyperactivity disorder (ADHD), depression, and anxiety.

• Drug: Sapropterin dihydrochloride
  A dose of 20 mg/kg/day will be administered. Route of administration is oral (intact).
  Other Names:

  • Kuvan
  • Phenoptin
  • BH4
  • 6R BH4
• Drug: Placebo
  Placebo (tablet without active ingredient) is dosed once/day for the first 13 weeks of the study.

• Experimental: Sapropterin dihydrochloride
  Intervention: Drug: Sapropterin dihydrochloride
• Placebo Comparator: Tablet without active ingredient
  Intervention: Drug: Placebo

Inclusion Criteria:

• ≥ 8 years of age
• Confirmed diagnosis of PKU
• Willing to continue current diet (typical diet for the 3 months prior to study entry) unchanged while participating in the study
• Willing and able to provide written, signed informed consent or in the case of subjects under the age of 18, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures
• Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study and for at least 30 days following the last dose of sapropterin dihydrochloride
• Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been in menopause at least 2 years, or had tubal ligation at least 1 year prior to screening, or have had total hysterectomy.
• Willing and able to comply with all study procedure

Exclusion Criteria:

• Has known hypersensitivity to sapropterin dihydrochloride or its excipients
• Subject breastfeeding at screening or planning to become pregnant (subject or partner) at any time during the study
• Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to the completion of all scheduled study assessments
• Received sapropterin dihydrochloride within 16 weeks of randomization
• Have initiated or adjusted medication for treatment of ADHD, depression, or anxiety ≤ 8 weeks prior to randomization
• Taking medication known to inhibit folate synthesis (eg, methotrexate)
• Any condition requiring treatment with levodopa or any PDE-5 inhibitor
• Concurrent disease or condition that would interfere with study participation, compliance or safety as determined by the Investigator
• Any condition that, in the view of the Investigator, places the subject at high risk of poor treatment compliance or of not completing the study