Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: a two-year analysis of safety and efficacy

Longo, Nicola; Siriwardena, Komudi; Feigenbaum, Annette; Dimmock, David; Burton, Barbara K.; Stöckler, Sylvia; Waisbren, Susan E.; Lang, W. R.; Jurecki, Elaina; Zhang, Charlie; Prasad, Suyash

doi:10.1038/gim.2014.109

Cited by 18 publications

(20 citation statements)

References 31 publications

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“…These results were consistent with those seen in children aged 4–12 years treated with 20 mg/kg/day sapropterin, in whom the mean amount of Phe supplement tolerated had increased at 10 weeks of treatment [23]. The results were also consistent with those reported in a study from the USA and Canada in children aged 0–6 years old, in whom 20 mg/kg/day sapropterin treatment lowered blood Phe concentrations, enabling, in some cases, an increase in dietary Phe intake [24]. …”

Section: Discussionsupporting

confidence: 84%

“…Previous reports have shown that neurocognitive function was preserved and no neurodevelopmental penalty was reported in patients who started sapropterin therapy between 0 and 6 years of age [24], and that treatment with BH 4 may enable relaxation of the dietary regimen, leading to improved quality of life [26]. Patients with mild HPA, who comprised almost a half of the population in this study, retain substantial enzyme activity and will, therefore, likely respond to sapropterin treatment.…”

Section: Discussionmentioning

confidence: 72%

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Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Muntau

Burlina

Eyskens

et al. 2017

Orphanet J Rare Dis

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BackgroundSapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.ResultsIn total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.ConclusionsThe addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria.Trial registrationClinicalTrials.gov, NCT01376908. Registered June 17, 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0600-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 72%

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Muntau

Burlina

Eyskens

et al. 2017

Orphanet J Rare Dis

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“…Previous studies have shown sapropterin to be well tolerated and have an acceptable safety profile consistent with the findings in this analysis [10,12,17,18]. In the registry, long-term safety follow-up shows that the rate of sapropterin-related AEs is low (6%) and that most are non-serious (91%), with no unexpected events.…”

Section: Discussionsupporting

confidence: 84%

“…In the registry, long-term safety follow-up shows that the rate of sapropterin-related AEs is low (6%) and that most are non-serious (91%), with no unexpected events. The most common drug-related AEs were gastrointestinal disorders (3%), nervous system disorders (2%), followed by respiratory, thoracic and mediastinal disorders (0.3%), consistent with adverse reactions seen in the sapropterin clinical trials [8,10,12,19]. The AEs were similar in type and rate across all age groups.…”

Section: Discussionsupporting

confidence: 56%

“…Sapropterin dihydrochloride (KUVAN®, BioMarin Pharmaceutical Inc., Novato CA, USA), a synthetically-prepared salt of naturally occurring BH 4 , at a dose of 20 mg/kg/day can reduce Phe levels in 56% to 75% of pediatric PKU subjects (20% of subjects at 10 mg/kg/day) [8][9][10]. In BH 4 -responsive subjects sapropterin reduces blood Phe levels in adults [8] and in children [10] in a dose-dependent manner [11].…”

Section: Introductionmentioning

confidence: 98%

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Long-term safety and efficacy of sapropterin: The PKUDOS registry experience

Longo

Arnold

Pridjian

et al. 2015

Molecular Genetics and Metabolism

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The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 μmol/L at baseline to 392 ± 239 μmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.

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Tetrahydrobiopterin Therapy for Phenylketonuria

Jurecki

2015

Nutrition Management of Inherited Metabolic Diseases

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Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: a two-year analysis of safety and efficacy

Cited by 18 publications

References 31 publications

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Long-term safety and efficacy of sapropterin: The PKUDOS registry experience

Tetrahydrobiopterin Therapy for Phenylketonuria

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