Real-world experience with sepiapterin in phenylketonuria: A single-center retrospective analysis

BackgroundPhenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Sepiapterin, the most recently FDA-approved therapeutic for PKU, is indicated for sepiapterin-responsive PKU in individuals >1 month of age. Real-world experience is needed to characterize clinical impact across patient subsets.MethodsA retrospective chart review was conducted for PKU patients at Lurie Children's Hospital prescribed sepiapterin from August 2025 through January 2026. Baseline characteristics, genotypic phenotype values (GPV), historical sapropterin responsiveness, and treatment outcomes were analyzed.ResultsOf 63 patients prescribed sepiapterin, 53 initiated treatment. The cohort included 34 sapropterin-responsive, 12 non-sapropterin-responsive, and 7 treatment-naïve patients. Of 50 patients who submitted blood samples, 74% (n=37) responded to sepiapterin. Mean Phe reductions were 46% (GPV ≤2.7), 53% (GPV 2.8-6.6), and 41% (GPV >6.6). Notably, a mean 46% reduction occurred in sapropterin-responsive patients already receiving sapropterin compared to 56% in non-sapropterin responsive patients who responded to the drug. Dietary liberalization occurred in 64% of patients, with 88% increasing natural protein intake and 5 patients discontinuing medical nutrition therapy. The discontinuation rate was 10% due to inadequate response. Side effects were predominantly gastrointestinal (loose stools 8%, abdominal pain 9%).ConclusionsReal-world experience with sepiapterin demonstrates a 76% response rate in the group of PKU patients tested which included a disproportionate number of sapropterin-responsive subjects. Clinical benefit was observed in individuals across the PKU severity spectrum, including a proportion of patients with classical PKU and those historically non-responsive to cofactor therapy. The favorable safety profile and potential for dietary liberalization support sepiapterin as a valuable treatment option for individuals with PKU.