To improve outcome for individuals with PKU who must adhere to a complex diet, alternative or adjunctive therapies have been developed. Sapropterin dihydrochoride (sapropterin or Kuvan™) is the pharmaceutical derivative of tetrahydobiopterin (BH₄), which is the co-factor for phenylalanine hydroxylase. Sapropterin has been shown to be safe and effective in improving blood PHE in 20-50% of those tested. It has also been shown to reduce fluctuation in blood PHE, which has been positively correlated with improved outcomes. US protocols for testing responsiveness, dosing, and monitoring have been published. Recommendations for modifying dietary therapy after response to sapropterin, and monitoring nutritional status have been made. European protocols generally have more stringent criteria for responsiveness and some describe using sapropterin as a monotherapy with discontinuation of diet restrictions and medical food. Further studies and reports of clinical use describe a broadening criteria (beyond FDA labeling restrictions) for patient selection, dosing, response indicators, and therapy modifications. However, inconsistencies in study design, cohort characteristics, methods, and outcome measures make comparative conclusions complex. When sapropterin response allows increased tolerance of intact PRO, nutritional status and quality of life may be improved. Sapropterin therapy in special populations is not yet well documented but there is consensus that individualized use may provide nutritional, cognitive, and quality of life benefit in young children and untreated or late-treated adults, especially when blood PHE cannot be adequately controlled by diet alone. Sapropterin therapy that results in lowered maternal blood PHE during pregnancy may safely reduce the risk of MPKU syndrome effects in the fetus.  

Large neutral amino acids (LNAA) are known to inhibit the passage of blood PHE into the brain through competition for carrier sites at the blood brain barrier. Supplementation with LNAA has been described as effective in improving neurocognition in individuals with PKU, but does not significantly lower blood PHE. Research on the use of LNAA in PKU is limited, and consists primarily of studies with small sample sizes or case studies with varying treatment protocols, and different measures of neurocognition and quality of life outcomes. A single clinical trial demonstrated benefit when LNAA were added to ongoing dietary management, but correlations with LNAA-treated individuals on a “relaxed” PHE diet cannot be drawn.