Recruitment challenges

This is a Phase 2a multicenter, double-blind, placebo-controlled, randomized, 2-arm pilot trial designed to assess the effect of sapropterin on cognitive abilities in young adults with Phenylketonuria (PKU) over a 26-week treatment period.

Inclusion Criteria:

• Written informed consent given before any trial-related activities are carried out
• Women or men with documented PKU diagnosed by at least two phenylalanine levels equal or greater than 600 micromole per liter (mcmol/L)
• 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 during the study and follow-up periods
• Aged greater than or equal to (>=) 18 to 29 years, inclusive
• Mean blood phenylalanine levels 600 to 1000 mcmol/L during 12 months preceding inclusion in the study. The mean should be calculated from at least 3 blood phenylalanine values over the last 12 months. Screening blood phenylalanine level can be one of these values. There should be at least one value dated between Month -12 and -6 before Screening and at least one value dated between Month -6 and Screening
• An intelligence quotient (IQ) score greater than or equal to 85, assessed a maximum of 2 years before screening with an age-appropriate Wechsler scale. If no IQ test result is available, IQ testing must be performed as part of Screening using an age-appropriate Wechsler scale before the subject can be included
• Subjects willing to comply with all study procedures, including willingness to continue current dietary recommendations during the whole trial duration

Exclusion Criteria:

• Subjects with tetrahydrobiopterin (BH4) deficiency
• Previous exposure to sapropterin or BH4 for greater than 30 days (or exposure to sapropterin or BH4 for less than or equal to 30 days but within the previous 6 months prior to Screening visit)
• Subjects who, according to the Investigator, will not be able to comply with study procedures and computerized neuropsychological testing
• Any significant illness which, according to the Investigator, might preclude participation in the study (including neurological disease, cardio-vascular disease, history of seizure, predisposition to convulsions, renal or hepatic insufficiency, and active malignancy)
• Any significant illness, medication or substance abuse which, according to the Investigator, might affect cognitive function and cognitive testing (for example, significant visual or motor impairment, history of major head trauma, history of stroke, alcoholism, drug dependency, psychological disorder requiring chronic use of psychotropic medications such as anxiolytics, antidepressants, antipsychotic medication, mood stabilizers, and hypnotics)
• Concomitant forbidden medication as described in the Kuvan® Summary of Product Characteristics, namely, inhibitors of dihydrofolate reductase (for example, methotrexate, trimethoprim), medications that are known to affect nitric oxide synthesis (for example, glyceryl trinitrate, isosorbide dinitrate, sodium nitroprusside, molsidomin, phosphodiesterase type 5 inhibitors, and minoxidil), and levodopa, as it may cause increased excitability and irritability
• Known hypersensitivity to sapropterin or any ingredients in the product's formulation, or to other approved or non-approved formulations of BH4
• Subjects who have undergone cognitive neuropsychological testing similar to that to be performed as part of this trial with the following time limits: tasks with limited practice effect performed in the last 6 months, and tasks with important practice effect (such as tasks involving development of strategies) performed in the year preceding inclusion in the trial. Whether a task falls into one or the other category is left to Investigator judgment
• Female subjects who are pregnant or in the lactation period
• Subjects currently participating to another clinical trial or who participated in a previous clinical trial within 30 days prior to screening
• Legal incapacity or limited legal capacity

Baseline analysis population included all the subjects randomized into 24-Week study period and received least 1 dose of study drug.

Screening up to 24 weeks + 4-week follow-up

The study was prematurely discontinued by the Sponsor due to severe enrolment difficulties as a consequence of the limited availability of treatment naïve patients with a diagnosis of phenyl ketonuria.