Long-term safety of sapropterin in paediatric and adult individuals with phenylalanine hydroxylase deficiency: Final results of the Kuvan® Adult Maternal Paediatric European Registry multinational observational study

Abstract

Phenylketonuria is a rare inherited disorder that disrupts the metabolism of phenylalanine (Phe) to tyrosine by phenylalanine hydroxylase (PAH). Sapropterin dihydrochloride (Kuvan®) is approved for use in Europe to reduce blood Phe levels and improve Phe tolerance in sapropterin-responsive individuals. KAMPER (NCT01016392) is an observational, multinational registry assessing long-term safety and efficacy of sapropterin. Five hundred and seventy-six participants with PAH deficiency were enrolled from nine European countries (69 sites; December 2009-May 2016). Participants were aged <4 years (n = 11), 4 to <12 years (n = 329), 12 to <18 years (n = 141), and ≥18 years (n = 95) at enrolment. Overall, 401 (69.6%) participants experienced a total of 1960 adverse events; 61 events in 42 participants were serious, and two were considered sapropterin-related by the investigator. Mean (standard deviation) actual dietary Phe intake increased from baseline across all age groups: 957 (799) mg/day to a maximum of 1959 (1121) mg/day over a total study period of 11 years. Most participants exhibited an increase in Phe tolerance while blood Phe levels remained in the target range for their age (120-360 μmol/L for <12 years; 120-600 μmol/L for ≥12 years). Most participants exhibited normal growth for height, weight, and body mass index. No additional safety concerns were identified. As an observational study, limitations include variability in routine care practices and inconsistent availability of data. Long-term sapropterin use demonstrates a favourable safety profile in real-world settings and increases Phe tolerance in participants with PAH deficiency while maintaining blood Phe levels in the target ranges.

Keywords: BH4; KAMPER; hyperphenylalaninaemia; phenylalanine hydroxylase deficiency; phenylketonuria; sapropterin dihydrochloride.

FIGURE 1

Participant disposition by age group at enrolment. BH₄, tetrahydrobiopterin; PAH, phenylalanine hydroxylase.

FIGURE 2

Mean (SD) blood Phe levels and mean (SD) actual dietary Phe intake at baseline and at year of time on study by age group at enrolment. Participants remained within their respective age groups throughout the study. (A) <4 years; (B) 4 to <12 years; (C) 12 to <18 years; (D) ≥18 years. ‘n’ represents the number of participants with blood Phe level or actual dietary intake data available at each time point. N/A, not available; Phe, phenylalanine; SD, standard deviation.

FIGURE 3

Mean (SD) actual dietary Phe intake at baseline and at Year 5 of time on study stratified by age group at enrolment. Participants remained within their respective age groups throughout the study. ‘n’ represents the number of participants with actual dietary intake data available at each time point. To assess the efficacy of treatment, data includes 5 years of time on study. Phe, phenylalanine; SD, standard deviation.

FIGURE 4

Proportion of participants with a dietary Phe intake increase of ≥100% from baseline. ‘n’ represents the number of participants in each age group at enrolment. Participants remained within their respective age groups throughout the study. Phe, phenylalanine.

FIGURE 5

Mean (SD) daily dose of sapropterin at baseline and at year of time on study stratified by age group at enrolment. (A) <4 years; (B) 4 to <12 years; (C) 12 to <18 years; (D) ≥18 years. Participants remained within their respective age groups throughout the study. ‘n’ represents the number of participants with sapropterin dose data available at each time point. N/A, not available; SD, standard deviation.