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).


METHODS
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 micromol/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.
Trefz
Friedrich K
FK
Klinik für Kinder-und Jugendmedizin Reutlingen, Klinikum am Steinenberg, Reutlingen, Germany. ftrefz@ramedis.de
Burton
Barbara K
BK
Longo
Nicola
N
Casanova
Mercedes Martinez-Pardo
MM
Gruskin
Daniel J
DJ
Dorenbaum
Alex
A
Kakkis
Emil D
ED
Crombez
Eric A
EA
Grange
Dorothy K
DK
Harmatz
Paul
P
Lipson
Mark H
MH
Milanowski
Andrzej
A
Randolph
Linda Marie
LM
Vockley
Jerry
J
Whitley
Chester B
CB
Wolff
Jon A
JA
Bebchuk
Judith
J
Christ-Schmidt
Heidi
H
Hennermann
Julia B
JB
D000465:Algorithms; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010649:Phenylalanine / Q000008:administration & dosage / Q000097:blood*; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy*
D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin