Phenylketonuria: Approval for Sepiapterin

There's a new medication for children and adults with phenylketonuria. The orphan drug sepiapterin can significantly reduce phenylalanine levels in the blood. It may even allow for relaxation of the very strict diet.

Congenital metabolic disorders such as phenylketonuria are now usually detected through newborn screening. / © Adobe Stock/Kati Finell

Sepiapterin (Sephience™, PTC Therapeutics International), a member of the pteridine class, is approved for the treatment of hyperphenylalaninemia in adults and children with phenylketonuria (PKU). This is a rare inherited disorder of amino acid metabolism in which the essential amino acid phenylalanine cannot be metabolized to tyrosine due to a deficiency of phenylalanine hydroxylase.

This results in a neurotoxic accumulation of phenylalanine, leading to severe and irreversible symptoms such as intellectual disability, seizures, developmental delays, memory loss, and behavioral and emotional disturbances. Diagnosis is usually made during newborn screening . An estimated 58,000 people worldwide are living with PKU.

Patients usually have to adhere to a strictly low-protein diet for life. Sapropterin (Kuvan®) , a synthetically produced tetrahydrobiopterin, has been approved since 2009, but it does not replace the diet. In 2019, the pegylated, recombinant form of the enzyme phenylalanine ammonia lyase, pegvaliase (Palynziq®) , was launched as the first enzyme replacement therapy for patients 16 years of age and older.

Sepiapterin is available as an oral powder (sachets of 250 mg and 1000 mg). The recommended daily dose depends on age and body weight and is 60 mg/kg/day for patients two years and older. This is also the recommended maximum dose. The product information contains comprehensive tables for individual dosage.

The medication should be taken once daily with a meal. The powder is mixed with water, apple juice, or a small amount of soft food such as applesauce or jam and stirred thoroughly. The liquid can be administered to small children using a dosing syringe. The powder can also be administered via an enteral feeding tube after mixing with water.

Sepiapterin is a precursor of tetrahydrobiopterin (BH4) that is rapidly absorbed and converted intracellularly into BH4. BH4 is an important cofactor for the enzyme phenylalanine hydroxylase (PAH). Sepiapterin also acts as a pharmacological chaperone, improving the stability and activity of defective PAH.

The drug therefore works in two ways: It improves the conformational stability of misfolded PAH and increases intracellular BH4 concentrations. As a result, phenylalanine (Phe) levels in the blood decrease significantly.