Sapropterin in Individuals With Phenylketonuria

Investigators at Washington University will examine the effects of sapropterin (Kuvan) on
brain and cognition in individuals with phenylketonuria (PKU) using neuropsychological and
neuroimaging procedures. Sapropterin is a medication developed by BioMarin Pharmaceutical
Inc. that is approved by the FDA for treatment of patients with PKU to reduce phenylalanine
(Phe) levels. Patients beginning treatment with sapropterin as standard clinical care will be
enrolled. As a first step, patients with PKU who are ≥ 6 years of age will receive baseline
neuropsychological and neuroimaging evaluations 1 day prior to beginning their treatment with
sapropterin. Screening for response to sapropterin (20mg/kg/day) will then occur over 4 weeks
as standard care for enrolled patients. At the end of 4 weeks, response to sapropterin will
be reviewed. Patients with a reduction of ≥ 20% in blood Phe (i.e., responders) will receive
follow-up neuropsychological and neuroimaging evaluations after 6 months of treatment with
sapropterin. Patients (both responders and nonresponders) will receive long-term follow-up
neuropsychological and neuroimaging evaluations 3 to 5 years after initial enrollment in the
study.

A matched control group of healthy individuals without PKU will receive baseline and
follow-up neuropsychological and neuroimaging evaluations for comparison purposes and to
control for possible practice effects in repeated neuropsychological testing.

The focus of neuropsychological testing will be executive abilities, as these abilities are
particularly susceptible to disruption in individuals with PKU. Specifically, the focus of
neuropsychological assessment will be working memory, strategic processing, and inhibitory
control, as our research group has shown that each of these executive abilities is impaired
in individuals with PKU. (White, D. 2001 Neuropsychol.)(White, D. 2002 J. Int. Neuropsychol.
Soc.)(Christ, S. 2006 Dev. Neuropsychol.) We hypothesize that improvements in these abilities
will occur following treatment with sapropterin.

For neuroimaging assessments, both structural magnetic resonance imaging (MRI) and diffusion
tensor imaging (DTI; mean diffusivity and fractional anisotropy) will be used. Structural MRI
will permit evaluation of changes in the structure and volume of the gray and white matter of
the brain. DTI will permit evaluation of microstructural white matter integrity. Brain
abnormalities have been noted in individuals with PKU, and using DTI our research group
recently identified abnormalities in the integrity of white matter in early and continuously
treated individuals with PKU.

The primary objectives of the proposed study are two-fold. First, we will determine whether
cognition (particularly executive abilities) improves in patients with PKU who have been
treated with sapropterin. Second, we will determine whether the integrity of the brain
improves in patients with PKU who have been treated with sapropterin. In addition, the
interrelationships between changes in cognition and brain will be examined.

Inclusion Criteria:

- Willing and able to provide informed consent or assent.

- Willing and able to comply with study procedures.

- Greater than or equal to 6 years of age.

- For phenylketonuria,intention of physician to prescribe sapropoterin.

- For phenylketonuria,phenylalanine level greater than or equal to 450μmol/L.

- For phenylketonuria, negative pregnancy test if of childbearing potential.

- For phenylketonuria, willing to use contraception if sexually active.

Exclusion Criteria:

- Pregnant, breastfeeding, or planning to become pregnant during study.

- Use of investigational product less than 30 days prior to or during study.

- Concurrent condition that could interfere with participation or safety.

- Any condition creating high risk of poor compliance with study.

- Perceived to be unreliable or unavailable for study.

- Use of L-Dopa, methotrexate, or other drugs that inhibit folate metabolism.

- For phenylketonuria, known hypersensitivity to sapropterin or excipients.