PKU Mechanism of Disease
In PKU, pathogenic variants in the PAH gene result in misfolded or unstable PAH enzymes, leading to a deficiency in the conversion of Phe to Tyr and the subsequent toxic accumulation of Phe in the blood.1
Untreated PKU2,3
Liver/Brain/Kidney Cells
SEPHIENCE, a natural precursor to BH4, is thought to work via two distinct, complementary, and additive mechanisms to enhance PAH enzymatic activity and lower blood Phe levels.1,4
SEPHIENCE Offers a Distinct Mechanism of Action
Proposed Dual MOA: Stabilizes PAH, boosts BH41,2,4
Liver/Brain/Kidney Cells
Due to its bioavailability, SEPHIENCE crosses cell membranes and the blood-brain barrier, leading to higher intracellular BH4 levels in key tissues such as the liver, brain, and kidneys.2,4
No conclusions regarding the benefits or risks of SEPHIENCE can be established based on the following data. The data are theoretical, and clinical relevance has not been established.
Stay informed
Sign up to receive updates, clinical insights, and resources straight to your inbox.
BH4: Tetrahydrobiopterin; PAH: Phenylalanine hydroxylase; Phe: Phenylalanine; PKU: Phenylketonuria; MOA: Mechanism of action; Tyr: Tyrosine.
References: 1. Muntau AC, Longo N, Ezgu F, et al. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2024;404(10460):1333–1345. doi:10.1016/S0140‐6736(24)01556‐3 2. Bratkovic D, Margvelashvili L, Tchan MC, Nisbet J, Smith N. PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi‐center, three‐period crossover, open‐label, active controlled, all-comers study. Metabolism. 2022;128:155116. doi:10.1016/j.metabol.2021.155116 3. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417–1427. doi:10.1016/S0140-6736(10)60961-0 4. SEPHIENCE. Package Insert. PTC Therapeutics, Inc; 2025.