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Sapropterin dihydrochloride (Kuvan), hereafter referred to as sapropterin, is a synthetic formulation of the active 6R-isomer of tetrahydrobiopterin, a naturally occurring cofactor for phenylalanine hydroxylase. In the EU, sapropterin is approved for the treatment of hyperphenylalaninaemia in patients >or=4 years of age with tetrahydrobiopterin-responsive phenylketonuria (PKU) and in adults and children with tetrahydrobiopterin deficiency who have been shown to be responsive to such treatment. In the US, it is approved to reduce blood phenylalanine levels in patients with hyperphenylalaninaemia due to tetrahydrobiopterin-responsive PKU. Oral sapropterin effectively lowers blood phenylalanine levels in a proportion of patients with PKU; to date, there are no published efficacy trials of the specific sapropterin formulation under review in patients with tetrahydrobiopterin deficiency. Sapropterin was well tolerated in patients with PKU, although longer-term tolerability data are required. Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels. Thus, sapropterin provides a promising treatment option for patients with PKU who are tetrahydrobiopterin-responsive. PHARMACOLOGICAL PROPERTIES: The mechanism of action of sapropterin in lowering blood phenylalanine levels in patients with PKU has not been fully elucidated, but appears to be related, in part, to its effect in augmenting and stabilizing mutant phenylalanine hydroxylases, resulting in increased clearance of phenylalanine from the body. In tetrahydrobiopterin deficiency, its mechanism of action is presumed to be secondary to replacement of endogenous tetrahydrobiopterin. In healthy adults, orally-administered sapropterin is absorbed into the bloodstream, reaching maximum concentrations in 3-4 hours. It has a mean elimination half-life of approximately 4 hours in healthy adults and, based on a population pharmacokinetic study, 6.7 hours in patients with tetrahydrobiopterin-responsive PKU. Age, from 9 to 49 years, had no effect on key pharmacokinetic parameters. THERAPEUTIC EFFICACY: In an 8-day screening study in patients aged >or=8 years with PKU, approximately 20% of patients responded to sapropterin 10 mg/kg/day (i.e. were tetrahydrobiopterin responsive). Tetrahydrobiopterin-responsive patients from this study were entered into a randomized, double-blind, placebo-controlled trial in which they received sapropterin 10 mg/kg/day or placebo. At the end of 6 weeks of treatment, sapropterin recipients experienced a significant 28% decrease from baseline in mean blood phenylalanine level, while there was no significant change in placebo recipients. The difference in mean blood phenylalanine level between sapropterin and placebo groups was statistically significant at -245 micromol/L. In an extension of this trial, significantly greater reductions in blood phenylalanine levels were observed with sapropterin dosages of 10 and 20 mg/kg/day than with sapropterin 5 mg/kg/day (each dose administered for 2 weeks), indicating a dose dependent effect. During 12 weeks of treatment with the sapropterin dosage individualized to the patient according to the earlier response to sapropterin 5, 10 or 20 mg/kg/day, reductions in plasma phenylalanine were observed in all dosage groups. In a randomized, double-blind trial in children aged 4-12 years with tetrahydrobiopterin-responsive PKU, patients treated with sapropterin 20 mg/kg/day had reduced blood phenylalanine levels after 3 weeks of treatment. Over the full 10-week trial, sapropterin and placebo recipients experienced a significantly increased tolerance to dietary phenylalanine (20.9 mg/kg/day in sapropterin and 2.9 mg/kg/day in placebo recipients). TOLERABILITY: Sapropterin was well tolerated in patients with PKU. In clinical trials in patients with PKU, the following adverse events were identified: headache, rhinorrhoea (both at a frequency of >or=10%), pharyngolaryngeal pain, nasal congestion, cough, diarrhoea, vomiting, abdominal pain and hypophenylalaninaemia (all at a frequency of >or=1% to <10%). There were no serious adverse events that were thought to be related to sapropterin treatment.