This is an open-label, non-comparative, Phase 3 study to evaluate the degree, frequency of response and safety of Kuvan® (sapropterin dihydrochloride) in subjects aged 4 to 18 years who have phenylketonuria and with elevated blood phenylalanine level of greater than or equal to 450 micromole per liter.

Inclusion Criteria:

• Willing and able to provide written informed consent (for children under 18 years old the parent[s]/guardians give informed consent, subjects 14-17 years old give additionally their own written informed consent)
• Age of 4 - 18 years, inclusive
• Confirmed clinical and biochemical hyperphenylalaninemia due to phenylketonuria documented by past medical history with at least 2 blood phenylalanine level greater than or equal to 400 micromole per liter obtained in 2 separate occasions
• Blood phenylalanine level at screening greater than or equal to 450 micromole per liter (mean of two measurements)
• For women of childbearing potential, a negative urine pregnancy test is required at screening and willingness to use a highly effective method of contraception is required while participating in the study
• Subject and/or the parent/guardian willing and able to comply with study procedures
• Subject and/or the parent/guardian willing to continue current diet unchanged during the 8 days response test and to adapt the diet according to phenylalanine therapeutic target range during the 6 week treatment period

Exclusion Criteria:

• Subject already assessed for responsiveness to sapropterin dihydrochloride or other tetrahydrobiopterin (BH4)
• Used any investigational agent other than Kuvan® (sapropterin dihydrochloride) within 30 days of screening, or required any investigational agent or vaccine prior to completion of all scheduled study assessments
• Pregnant or breastfeeding, or considering pregnancy
• Concurrent disease or conditions that would interfere with study participation or safety (for example, seizure disorder, asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation recipient)
• Concurrent use of required concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate), levodopa, phosphodiesterase type-5 (PDE-5) inhibitors (such as, sildenafil, vardenafil or tadalafil), medications that are known to affect nitric oxide synthesis metabolism or action
• Any conditions, 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
• Clinical diagnosis of primary BH4 deficiency
• Known hypersensitivity to Kuvan® (sapropterin dihydrochloride) or its excipients or to other approved or non-approved formulation of tetrabiopterin

Intention to Treat (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.

Baseline up to Week 11

An AE is any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE is an AE resulting in any of following outcomes:death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.