Sepiapterin for the treatment of phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Untreated, PKU may result in severe and irreversible intellectual impairment due to marked hyperphenylalaninemia (HPA). Guidelines recommend lifelong reduction in Phe levels, usually achieved via a strict low-protein diet and sometimes medications.

We discuss the role of tetrahydrobiopterin (BH₄), an essential PAH cofactor in Phe metabolism, describe the pharmacodynamics, pharmacokinetics, and metabolism of sepiapterin, as well as reporting on its efficacy and safety in children and adults with PKU.

Sepiapterin, an oral synthetic form of a natural precursor of BH₄, can reduce HPA in some patients with PKU. In relatively short-term studies, sepiapterin has been shown to be safe, well tolerated, and like the BH₄ analog sapropterin dihydrochloride effective in reducing blood Phe levels in responsive individuals. The reductions in blood Phe observed with sepiapterin in the phase III APHENITY trial has the potential to allow more PKU patients to attain Phe treatment targets or alternatively easing of the onerous dietary Phe restrictions. Results of longer-term studies in patients with PKU, including neurocognitive and functional outcomes, nutritional status, and quality of life are awaited.