Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, 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.
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).
                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.
                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.
                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. 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.
                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.
                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.
                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.
There is evidence of short-term benefit from using sapropterin in some patients with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.
There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.