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

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.

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