Sepiapterin: From sapropterin to next-generation therapy

Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenylalanine hydroxylase (PAH), the aromatic amino acid hydroxylases, and nitric oxide synthases, whereas 7,8-dihydrobiopterin (BH2) reflects pterin redox balance and can antagonize BH4-dependent nitric oxide signaling. This review integrates historical and chemical perspectives with current biochemical and clinical understanding of BH4 homeostasis, including de novo synthesis, recycling/oxidation, and the sepiapterin salvage pathway. Sepiapterin is taken up by cells through equilibrative nucleoside transport mechanisms and is intracellularly converted through sepiapterin reductase and dihydrofolate reductase to expand BH4 pools. In healthy volunteers, oral sepiapterin produced marked systemic BH4 exposure with minimal parent-drug exposure (geometric mean Cmax 640 ng/mL for BH4 versus 1.74 ng/mL for sepiapterin after 60 mg/kg) and increased cerebrospinal fluid BH4 after 7 days of 60 mg/kg/day dosing. In phenylketonuria (PKU), the Phase 3 APHENITY trial showed a placebo-adjusted least-squares mean blood phenylalanine reduction of 395.9 μmol/L at Week 6 among sepiapterin-responsive participants, and the Phase 3 AMPLIPHY trial showed greater lowering with sepiapterin 60 mg/kg/day than with sapropterin 20 mg/kg/day (least-squares mean difference 180.4 μmol/L; 95% CI 131.4-229.5; p < 0.0001). Together, these data position sepiapterin as a next-step therapy beyond sapropterin, while underscoring the importance of biomarker studies that quantify BH4, BH2, and the BH4/BH2 ratio in plasma and cerebrospinal fluid.