Efficacy, Safety, and Pharmacokinetics of Sepiapterin in Phenylketonuria: A Systematic Review and Meta-Analysis

Background: Sepiapterin is a novel therapeutic agent for phenylketonuria (PKU) with a unique mechanism of action. Its short-term safety and pharmacokinetic evidence is still fragmentary, necessitating a systematic synthesis. Objective: The study aims to assess the short-term safety, tolerability, and pharmacokinetic profile of oral sepiapterin in PKU patients and healthy volunteers. Methods: : Following PRISMA 2020 guidelines, we systematically searched PubMed, Google Scholar, Cochrane, and ClinicalTrials.gov up to October 2025. Five studies (four RCTs, one cohort) involving 365 participants were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias using Cochrane RoB 2.0 and ROBINS-I. Meta-analysis was performed using RevMan 5.4 and Comprehensive Meta-Analysis software. GRADE was applied by one author. Results: : Sepiapterin did not significantly increase the risk of overall adverse events (RR 1.04, 95% CI 0.67–1.61) or treatment-emergent adverse events (RR 0.59, 95% CI 0.22–1.59). Side effects such as headache and diarrhea were comparable to controls. Pharmacokinetically, Tmax was significantly shorter with sepiapterin (mean difference –1.48 hours, 95% CI –2.12 to –0.84), indicating faster absorption, while Cmax showed no significant difference. Conclusion: Sepiapterin is well-tolerated in the short term, with a good absorption profile. However, small sample sizes, short duration, and lack of pediatric data limit the evidence. Long-term safety and efficacy need to be confirmed in large-scale longitudinal studies.