No QTcF Prolongation with Sepiapterin: Results From a Thorough QT Study in Healthy Subjects at Therapeutic and Supratherapeutic Doses

Abstract Sepiapterin and its major metabolite 6R ‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH 4 ) bind to distinct variants of phenylalanine hydroxylase (PAH), which converts excess phenylalanine to tyrosine, thereby stabilizing, enhancing, and prolonging PAH activity. Sepiapterin was recently approved in Europe and the USA for the treatment of hyperphenylalaninemia patients with phenylketonuria, an inherent metabolic disease caused by PAH deficiency. A thorough QT study of sepiapterin in healthy volunteers at therapeutic (60 mg/kg) and supratherapeutic (120 mg/kg) doses was conducted to assess potential cardiovascular risks. Thirty‐two participants were randomized into one of 12 sequences and received single doses of sepiapterin (60 or 120 mg/kg), moxifloxacin 400 mg, or placebo in separate periods. Sepiapterin had no effect on heart rate or cardiac conduction (PR/QRS interval). Saturable sepiapterin absorption was observed, which resulted in less than dose‐proportional increase of sepiapterin and BH 4 and limited the maximum plasma concentrations clinically achievable. Using concentration‐QT analysis, the placebo‐corrected change from baseline in QT interval corrected using Fridericia's formula (ΔΔQTcF) was −2.11 (90% CI: −3.44, −0.79) ms at geometric mean baseline‐corrected BH 4 C max (728 ng/mL) and −1.9 (−3.25, −0.56) ms at sepiapterin C max (2.08 ng/mL) at the supratherapeutic dose of 120 mg/kg. An effect on ΔΔQTcF exceeding 10 ms was excluded within the observed concentration range of baseline‐corrected BH 4 up to 1088 ng/mL and sepiapterin up to 5.77 ng/mL. The consistency of results from this study and the previous concentration‐QTc analysis based on pooled data from multiple clinical studies demonstrated the reliability of using concentration‐QTc for assessing cardiovascular risks in early clinical development.