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 mu mol/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. (J Pediatr 2009;154:700-7)