title: Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study.
abstract: BACKGROUND
  Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration.
  
  
  METHODS
  We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247.
  
  
  RESULTS
  88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9.7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) micromol/L in patients assigned to receive sapropterin, and 888 (323) micromol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) micromol/L, compared with a 3 (240) micromol/L increase in the placebo group (p<0.0001). After 6 weeks, 18/41 (44%) patients (95% CI 28-60) in the sapropterin group and 4/47 (9%) controls (95% CI 2-20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 micromol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0.0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0.80). Upper respiratory tract infections were the most common disorder.
  
  
  CONCLUSIONS
  In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.
authors: Children's Hospital Boston and Harvard Medical School, Boston, MA, USA. harvey.levy@childrens.harvard.edu
authors: Harvey L
authors: HL
authors: Levy
authors: Andrzej
authors: A
authors: Milanowski
authors: Anupam
authors: A
authors: Chakrapani
authors: Maureen
authors: M
authors: Cleary
authors: Philip
authors: P
authors: Lee
authors: Friedrich K
authors: FK
authors: Trefz
authors: Chester B
authors: CB
authors: Whitley
authors: François
authors: F
authors: Feillet
authors: Annette S
authors: AS
authors: Feigenbaum
authors: Judith D
authors: JD
authors: Bebchuk
authors: Heidi
authors: H
authors: Christ-Schmidt
authors: Alex
authors: A
authors: Dorenbaum
mesh_terms: D000293:Adolescent; D000328:Adult; D001708:Biopterins / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010649:Phenylalanine / Q000097:blood*; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin