Sepiapterin Enables Liberalisation of Natural Protein Intake While Improving Metabolic Control in Adolescents with Phenylketonuria

Background: Sepiapterin is a synthetic precursor of tetrahydrobiopterin (BH4) that increases intracellular BH4 availability and has demonstrated greater phenylalanine-lowering efficacy than sapropterin. We evaluated its effect on dietary liberalisation and metabolic control in adolescents with phenylketonuria (PKU). Methods: Seven adolescents with PKU (median age of commencing sepiapterin: 13 years, range 12–17 years), including five previously responsive to sapropterin, were studied. Median natural protein intake, protein equivalent from protein substitute, and total protein intake were compared during diet-only treatment, sapropterin treatment (where applicable), and after 12 months of sepiapterin. Blood phenylalanine (Phe) and tyrosine (Tyr) concentrations were assessed over 12 months for each treatment period. Results: Median natural protein intake increased from 6.5 g/day (range 4.5–15) during diet-only treatment (n = 7) to 20 g/day (10–25) with sapropterin (n = 5) and 70 g/day (34–90) after 12 months of sepiapterin (n = 7). This represented a median increase of 218% (70–471%) compared with sapropterin and 600% (200–1900%) compared with diet alone. Median total protein intake on sepiapterin was 90 g/day (70–114), equivalent to 1.4 g/kg/day, and four participants discontinued protein substitute completely. Mean (±SD) blood Phe concentrations were lower with reduced variability on sepiapterin (303 ± 157 µmol/L during diet-only treatment; 321 ± 136 µmol/L with sapropterin; 260 ± 116 µmol/L with sepiapterin), while Tyr concentrations remained stable. The percentage of blood Phe concentrations within target improved with sepiapterin (≤360 µmol/L: 83%, range 77–100) compared with diet alone (68%, range 17–100) and sapropterin (66%, range 40–91). Most participants incorporated high-protein foods into their diets, including meat (7/7), fish (6/7), cheese (6/7), and milk or yoghurt (5/7). Conclusions: Twelve months of sepiapterin enabled marked dietary liberalisation while improving metabolic control in adolescents with PKU. These findings suggest that sepiapterin may substantially reduce treatment burden and represent an important advance in the management of this challenging age group.