Efficacy of Sapropterin Dihydrochloride in Increasing Phenylalanine Tolerance in Children with Phenylketonuria: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study

Objective: To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU). Study design: This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. Results: The mean (±SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (±15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 μmol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (±4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (±SE) was 17.7 ± 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed. Conclusions: Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.