A phase 1/2 dose-escalation study of sepiapterin in patients with PTPS deficiency with hyperphenylalaninemia

Oral sepiapterin (PTC923), a precursor of tetrahydrobiopterin (BH₄), was evaluated in patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency in a phase 1/2, multicenter, open-label, randomized, intra-individual dose-escalation study. Patients stopped sapropterin (used to control hyperphenylalaninemia) for 2-4 days before being randomized 1:1 into two cohorts receiving sepiapterin at two doses (cohort 1: 2.5 and 10 mg/kg/day; cohort 2: 5 and 20 mg/kg/day) each for 7 days, separated by a 2- to 4-day washout period. Eight participants (five male, three female, aged 2.2-20.0 years) completed the study (four in each cohort). Overall, 7/8 participants (87.5%) experienced a total of 35 treatment-emergent adverse events; none were severe, serious, or led to discontinuation. Mean phenylalanine levels increased (up to 800-1,200 μmol/L) after discontinuation of sepiapterin or sapropterin and normalized (<130 μmol/L) with sepiapterin at all tested doses by day 2. Blood BH₄ concentrations increased with increasing single doses of sepiapterin, reaching a peak at approximately 3-4 h, which was 2-3 h after the sepiapterin peak. These results show that in patients with PTPS deficiency, sepiapterin is rapidly converted to BH₄ and normalizes blood phenylalanine concentrations, with no dose-limiting toxicity or dose-related adverse events.