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

• Levels of blood Phe [ Time Frame: 26 weeks (6 months) ] [ Designated as safety issue: No ]
  Phe levels will be measured twice weekly during the 26-week Study Period and will be derived from either filter paper cards/forms or venous blood samples
• Levels of blood Phe [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  Phe levels will be measured every 3 months during the Extension Period and will be derived from either filter paper cards/forms or venous blood samples
• Change from Baseline (prior to enrolment) in dietary Phe tolerance after 26 weeks (6 months) treatment with Kuvan® + a Phe-restricted diet vs. just a Phe-restricted diet alone [ Time Frame: Baseline (prior to enrolment) to 26 weeks (6 months) ] [ Designated as safety issue: No ]
  Phe tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the selected therapeutic target range (defined as ≥120 to < 360 μmol/L).
• Number of subjects with adverse events [ Time Frame: 26 weeks (6 months) ] [ Designated as safety issue: Yes ]
• Number of subjects with adverse events [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
• AUC0-∞ (area under the plasma concentration curve, time 0 to infinity) [ Time Frame: Weeks 5-12, inclusive of the 26 weeks (6 months) period ] [ Designated as safety issue: No ]

The purpose of the study is to evaluate efficacy, safety and population pharmacokinetics of Kuvan® in infants and children with PKU (<4 years of age at the time of entry into the study).

A pharmacogenetic sub-study as optional part of this study will be also conducted.

Approximately 50 children will be enrolled in this study conducted at multiple sites and in several countries in EU and potentially Turkey. The study will last approximately 6 months followed by a up to 3 year follow up period during which all children in the study will be treated with Kuvan® and a Phe-restricted diet therapy.

Extension Period (3 years):

At the end of the study period, all subjects will switch to Kuvan® + Phe-restricted diet

Kuvan®:

• For subjects randomized to the Phe-restricted diet-only group in Study Period, their starting dose of Kuvan® in the Extension period will be 10 mg/kg/day.
• For subjects randomized to Kuvan® + Phe-restricted diet in the Study Period, their starting dose of Kuvan® in the Extension period will be the same dose they received at the end of the Study Period.

During Extension Period, Kuvan® dose can be adjusted at the discretion of the Investigator, but must not exceed 20 mg/kg/day.

Phe-restricted diet:

During Extension Period, Phe intake adjustments will follow the clinical practice standards of each site.

• Drug: Kuvan®

  Kuvan® tablets contain 100 mg of sapropterin dihydrochloride.

  Study Period (26 weeks): Starting Kuvan® dose is 10 mg/kg/day and may be escalated to 20 mg/kg/day if after 4 weeks a subject's Phe tolerance is not increased by at least 20% vs baseline.

  Phe-restricted diet:

  Study Period (26 weeks): Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

• Other: Phe-restricted diet
  During Study Period (26 weeks): Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

• Experimental: Kuvan® + Phe-restricted diet
  Subjects will be treated with Kuvan® tablets once daily + Phe-restricted diet therapy
  Intervention: Drug: Kuvan®
• Phe-restricted diet alone
  Subjects will follow a Phe-restricted diet alone
  Intervention: Other: Phe-restricted diet

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.