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

Abstract

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.

Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0–4 years of age

“…The effectiveness of BH 4 treatment has been demonstrated in a number of short-term [ 16 – 19 ] and long-term studies [ 18 , 20 – 24 ], which have included patients aged 0–4 years and shown the benefit of treatment in this age range. The advantages of initiating BH 4 therapy at an early age include increasing natural protein intake during a critical time of growth and development and increasing the likelihood of adherence to treatment [ 22 ]. Accordingly, in 2015, approval of sapropterin was extended in Europe to children aged 0–4 years [ 15 , 22 , 25 ].…”

“…The advantages of initiating BH 4 therapy at an early age include increasing natural protein intake during a critical time of growth and development and increasing the likelihood of adherence to treatment [ 22 ]. Accordingly, in 2015, approval of sapropterin was extended in Europe to children aged 0–4 years [ 15 , 22 , 25 ].…”

“…In clinical trials of children aged 4 years and above, adverse events with an incidence of ≥10% were headache and rhinorrhea; those occurring with an incidence of ≥1% to < 10% were pharyngolaryngeal pain, nasal congestion, cough, diarrhea, vomiting, abdominal pain and hypophenylalaninemia [ 15 ]. In children aged below 4 years who received treatment with sapropterin (10 or 20 mg/kg/day), the most commonly reported adverse reactions were hypophenylalaninemia, vomiting and rhinitis [ 22 ]. Hypersensitivity reactions, including serious allergic reactions and rash, were also reported.…”

“… Mean blood Phe concentration < 360 μmol/L: increase Phe intake by 20% or, if the child is already on a normal diet, decrease the dose of sapropterin by 2 mg/kg/week or do not increase the sapropterin dose in response to the child gaining weight. Mean blood Phe concentration > 360 μmol/L: reduce Phe intake by 10–30%, depending on the degree of elevation of the blood value [ 21 , 22 , 34 ]. …”

“…Mean blood Phe concentration > 360 μmol/L: reduce Phe intake by 10–30%, depending on the degree of elevation of the blood value [ 21 , 22 , 34 ].…”