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. Findings: 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) μmol/L in patients assigned to receive sapropterin, and 888 (323) μmol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) μmol/L, compared with a 3 (240) μmol/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 μmol/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. Interpretation: 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.
Bibliographical noteFunding Information:
This study was sponsored by BioMarin Pharmaceuticals, the Children's Hospital Boston General Clinical Research Centre, the University of Minnesota General Clinical Research Centre, and grants M01-RR00400 and M01-RR02172 from the National Centre for Research Resources, National Institutes of Health. We thank Emil Kakkis, Stuart Swiedler, and Sandra Shpilberg of BioMarin Pharmaceuticals and Inna Furman of Merck Surono for their help in preparing this report. We also thank the participants in the trial, the study investigators and nurses, and especially the coordinators without whose tireless work this study could not have been accomplished.