Tetrahydrobiopterin Treatment in Children With Idiopathic Cognitive Developmental Disorders

SUMMARY

PURPOSE: The purpose of this study is to develop biomarkers for central nervous system BH4
concentration in children with autism so they can be easily screened to determine if they
may benefit from BH4 supplementation. Kuvan is a synthetic form of BH4. BH4 is an enzyme
cofactor that is essential for several critical metabolic functions.

Procedures: Consented subjects' behavior, particularly irritability, cognitive and language
function will be assessed at baseline to make sure that the subject meets the inclusion and
exclusion criteria. Parents of subjects will be instructed to give the subjects 20 mg/kg/day
of Kuvan® orally dissolved in 4 - 8oz. of water or apple juice with breakfast. Subjects will
not be permitted to start any new supplement treatments during the study period but will be
allowed to continue previous supplements. Subjects will be permitted to take over the
counter medications or other prescription medications for acute illnesses. Evaluation of
subjects will include three clinic visits for neuropsychological and clinical testing,
completion of study-related questionnaires and telephone follow-up visits.

Course of Study: Subjects will be in the study for up to 16 weeks.

Enrollment: The study will enroll 20 (male and female) subjects, 2-6 years old, with delays
in language and/or social development. Vulnerable populations include children. A pediatric
risk assessment was completed by Ian Butler, MD with an outcome of minimum risks to
subjects.

Recruitment: Subjects will be recruited when their parents present them for care at the
University of Texas medically-based autism clinic.

Known Risks: For the study drug Kuvan, there have been rare associations with
gastroesophageal reflux and a previous form of this compound was associated with seizures in
individuals taking Levodopa concurrently. There is a risk of loss of confidentiality.

Data Safety Monitoring: A DSMB will not be formed for this study. The PI will be responsible
for the data and safety of the study.

Informed Consent: A written parental informed consent form has been submitted for review and
approval. There is no cost for participation, and no remuneration. Confidentiality will be
maintained through the use of unique study codes.

IND#: A request for a pre-IND meeting with the FDA to discuss the possible IND exemption has
been submitted.

Funding Source: This study is being funded by BioMarin Pharmaceuticals.

SCIENTIFIC PRE-REVIEW: The Clinical Research Unit Review Board Committee Scientific Advisory
Committee (SAC) completed the submission with the outcome of CRU - Approved on12/10/2009.