Kuvan® in Phenylketonuria (PKU) Patients Less Than 4 Years Old (SPARK)

Inclusion Criteria:

1. Male or female PKU infants and young children <4 years of age at the scheduled Day 1 visit of the 26-week Study Period (taking into consideration the maximum of 21 days in the Screening Period).
2. Confirmed clinical and biochemical PKU, including at least two previous blood Phe levels ≥ 400 μmol/L obtained on 2 separate occasions.

3. Previously responded, as assessed by the Investigator, to a BH4 test, if all 3 of the following criteria are satisfied:

   1. The BH4 dose was 20 mg/kg/day.
   2. The duration of the test was at least for 24 hours.
   3. A 30% decrease in blood Phe levels.
4. Defined level of dietary Phe tolerance consistent with the diagnosis of PKU;
5. Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods.
6. Maintenance of blood Phe levels within the therapeutic target range of 120-360 μmol/L (defined as ≥120 to < 360 μmol/L) over a 1-month period prior to Screening, as assessed by the Investigator.
7. Parent(s) and/or guardian(s) willing to comply with all study procedures, maintain strict adherence to the diet, and willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study procedures.

Exclusion Criteria:

1. Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test.
2. Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for >30 days.
3. Known hypersensitivity to Kuvan® or its excipients.
4. Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin.
5. Previous diagnosis of BH4 deficiency.
6. Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors.
7. Current use of medications that are known to affect nitric oxide synthesis, metabolism or action.
8. Current use of levodopa.
9. Current use of experimental/other investigational or unregistered drugs that may affect the study outcomes.
10. Inability to comply with study procedures.
11. Inability to tolerate oral intake.
12. History of organ transplantation.
13. Concurrent disease or condition that would interfere with study participation or increase the risk for adverse events, including seizure disorders, corticosteroid administration, active malignancy, diabetes mellitus, severe congenital heart disease, renal or hepatic failure.
14. Other significant disease that in the Investigator's opinion would exclude the subject from the trial.
15. Any condition that, in the view of the Principal Investigator renders the subject at high risk for failure to comply with treatment or to complete the study.