Phenylketonuria (PKU) is a rare, autosomal recessive inborn error of metabolism caused by genetic variants of the PAH gene, which encodes phenylalanine hydroxylase (PAH). In PKU, the PAH enzyme has reduced affinity for its substrate phenylalanine (Phe) or cofactor tetrahydrobiopterin (BH4), shows decreased substrate activation or becomes destabilized owing to protein misfolding. Approximately 3500 PAH variants have been identified that vary in residual PAH activity and thus disease severity and BH4 responsiveness. Burdensome, lifelong dietary restriction remains the standard of care for PKU. Until recently, only two pharmacological therapies were approved for PKU: sapropterin and pegvaliase; however, the need for additional treatment options remained. In 2025, sepiapterin (Sephience™), a novel oral treatment for children and adults with PKU, was approved in several countries, including the USA. Sepiapterin has pharmacological and clinical properties unique from existing therapies. A key differentiating factor is that it has two distinct mechanisms of action: it acts as an independent chaperone for PAH, stabilizing misfolded enzyme variants, and it serves as a bioavailable precursor to BH4, increasing intracellular BH4 levels. Preclinical studies demonstrate that sepiapterin increases PAH activity across a broad range of genetic variants, including those associated with severe phenotypes and BH4-nonresponsiveness. Clinical trials (e.g., phase 3 APHENITY, AMPLIPHY) show that sepiapterin can significantly lower blood Phe versus placebo and sapropterin, with efficacy observed in both classic PKU and BH4-nonresponsive participants. In clinical studies, sepiapterin is consistently well tolerated, with limited side effects and a convenient oral formulation. On the basis of its dual mechanism of action and favorable safety and tolerability profile, sepiapterin has the potential to treat a broad range of individuals with PKU across the spectrum of disease severities and ages. Thus, all individuals should be considered for an initial treatment trial with sepiapterin to establish responsiveness, regardless of genetic variant or phenotypic severity. Sepiapterin: how it works and its potential benefits for people with phenylketonuria Phenylketonuria is a rare genetic condition that causes changes in the enzyme phenylalanine hydroxylase, stopping it from working. As a result, the body cannot break down the amino acid phenylalanine, leading to a buildup of phenylalanine in the blood and brain. Without treatment, phenylketonuria can affect the way the brain develops and how people think or behave. Currently, the main treatment is a specialized, restrictive, low-protein diet. Two medicines, sapropterin and pegvaliase, are also available; however, they are not beneficial for many individuals with phenylketonuria because of age restrictions, side effects, or lack of effectiveness. So, new treatment options are needed. Sepiapterin (Sephience™) is a new treatment approved in 2025 in several countries for children and adults with phenylketonuria. Sepiapterin works differently from existing treatments. It works in two ways: it interacts directly with phenylalanine hydroxylase to make the enzyme work better, and it turns into a substance called tetrahydrobiopterin in the body, which also helps phenylalanine hydroxylase work better. Here, clinicians summarize how sepiapterin works and its demonstrated benefits across the full range of phenylketonuria disease severities. Clinical trials show that sepiapterin lowers phenylalanine levels, including in many individuals with “classic” phenylketonuria (the most severe type). In addition, sepiapterin is well tolerated with minimal potential side effects. Overall, these data suggest that all individuals with phenylketonuria should be considered for treatment with sepiapterin to assess potential benefits.
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