Sapropterin is safe and effective in patients less than 4-years-old with BH4-responsive phenylalanine hydrolase deficiency.

OBJECTIVE: To assess the safety and efficacy of tetrahydrobiopterin therapy with sapropterin to treat tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency in children aged <4 years compared with those aged ≥4 years. STUDY DESIGN: We analyzed a longitudinal follow-up study conducted in all patients with BH4-responsive PAH deficiency throughout Japan. At the end of 2011, 43 patients were receiving sapropterin, of whom 21 were aged <4 years at the initiation of treatment. The starting dose of sapropterin was ≥10 mg/kg/day in 11 of these 21 patients. The duration of follow-up was ≥4 years in 6 of those 11 patients; 3 of these 6 were followed for ≥10 years. Nine patients were receiving sapropterin monotherapy at the end of 2011. RESULTS: Serum phenylalanine level was maintained within the recommended optimal control range in all 21 patients who started sapropterin treatment before age 4 years. Only 1 nonserious adverse drug reaction occurred, an elevated alanine aminotransferase level in 1 patient. No significant abnormal behavior related to nerve disorders was reported. CONCLUSION: Sapropterin therapy initiated before age 4 years was effective in maintaining serum phenylalanine level within the favorable range and was safe in Japanese patients with BH4-responsive PAH deficiency.

Sapropterin dihydrochloride for phenylketonuria.

BACKGROUND: Phenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with sapropterin dihydrochloride. We examined the evidence for the use of sapropterin dihydrochloride to treat phenylketonuria.   OBJECTIVES: To assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria. SEARCH METHODS: We identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 29 June 2012.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 23 July 2012.We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials. SELECTION CRITERIA: Randomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials and extracted outcome data. MAIN RESULTS: Two placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 µmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 µmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group. AUTHORS' CONCLUSIONS: 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.

Tetrahydrobiopterin therapy for phenylketonuria in infants and young children.

OBJECTIVE: To describe patient selection, treatment administration, response evaluation, and side effect management associated with sapropterin therapy in infants and children aged <4 years. STUDY DESIGN: Six case reports are presented from 4 US metabolic clinics treating phenylketonuria with sapropterin in patients aged 7 months to 4 years. Outcomes included blood phenylalanine (Phe) levels before and during treatment. For 3 of 6 cases, diet records were used to monitor changes in dietary Phe. RESULTS: Severity of phenylketonuria ranged from mild to severe (classic). Treatment with sapropterin was safe and generally well tolerated. Blood Phe levels were reduced, or maximum dietary Phe tolerance was increased in patients with blood Phe that was well controlled by diet. CONCLUSIONS: Given the increasing evidence that maintaining blood Phe levels below 360 µmol/L is important for the normal development of neurocognitive and behavioral function, sapropterin can be combined with a Phe-restricted diet to control blood Phe levels in young patients responsive to sapropterin therapy.