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Efficacy of Sapropterin Dihydrochloride (Tetrahydrobiopterin, 6R-BH4) for Reduction of Phenylalanine Concentration in Patients With Phenylketonuria: A Phase III Randomised Placebo-Controlled Study

Efficacy of Sapropterin Dihydrochloride (Tetrahydrobiopterin, 6R-BH4) for Reduction of Phenylalanine Concentration in Patients With Phenylketonuria: A Phase III Randomised Placebo-Controlled Study

Harvey L Levy, Andrzej Milanowski, Anupam Chakrapani, Maureen Cleary, Philip Lee, Friedrich K Trefz, Chester B Whitley, François Feillet, Annette S Feigenbaum, Judith D Bebchuk, Heidi Christ-Schmidt, Alex Dorenbaum, etc.

Lancet. 2007 Aug 11;370(9586):504-10.

PMID: 17693179

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.
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) 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.
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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP69056388	(6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride		69056-38-8	Price

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