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Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria
Author(s) -
Lee Phillip,
Treacy Eileen P.,
Crombez Eric,
Wasserstein Melissa,
Waber Lewis,
Wolff Jon,
Wendel Udo,
Dorenbaum Alex,
Bebchuk Judith,
ChristSchmidt Heidi,
Seashore Margretta,
Giovannini Marcello,
Burton Barbara K.,
Morris Andrew A.
Publication year - 2008
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.32562
Subject(s) - tetrahydrobiopterin , hyperphenylalaninemia , medicine , phenylalanine hydroxylase , discontinuation , adverse effect , placebo , phenylalanine , gastroenterology , chemistry , biochemistry , nitric oxide synthase , alternative medicine , amino acid , pathology , nitric oxide
Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation, which can lead to neurocognitive and neuromotor impairment. Sapropterin dihydrochloride, an FDA‐approved synthetic formulation of tetrahydrobiopterin (6R‐BH4, herein referred to as sapropterin) is effective in reducing plasma Phe concentrations in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)‐responsive PKU, offering potential for improved metabolic control. Eighty patients, ≥8 years old, who had participated in a 6‐week, randomized, placebo‐controlled study of sapropterin, were enrolled in this 22‐week, multicenter, open‐label extension study comprising a 6‐week forced dose‐titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 weeks each), a 4‐week dose‐analysis phase (10 mg/kg/day), and a 12‐week fixed‐dose phase (patients received doses of 5, 10, or 20 mg/kg/day based on their plasma Phe concentrations during the dose titration). Dose‐dependent reductions in plasma Phe concentrations were observed in the forced dose‐titration phase. Mean (SD) plasma Phe concentration decreased from 844.0 (398.0) µmol/L (week 0) to 645.2 (393.4) µmol/L (week 10); the mean was maintained at this level during the study's final 12 weeks (652.2 [382.5] µmol/L at week 22). Sixty‐eight (85%) patients had at least one adverse event (AE). All AEs, except one, were mild or moderate in severity. Neither the severe AE nor any of the three serious AEs was considered related to sapropterin. No AE led to treatment discontinuation. Sapropterin is effective in reducing plasma Phe concentrations in a dose‐dependent manner and is well tolerated at doses of 5–20 mg/kg/day over 22 weeks in BH4‐responsive patients with PKU. © 2008 Wiley‐Liss, Inc.