Phenylalanine hydroxylase: assessing the underlying enzymatic defect in PKU

In PKU, elevated Phe levels arise from defects in the phenylalanine hydroxylase (PAH) enzyme, which is involved in the metabolism of Phe to tyrosine.⁴

Normal phenylalanine hydroxylation primarily takes place in the liver.⁴ The cofactor tetrahydrobiopterin (BH4) stimulates PAH to convert Phe to tyrosine, making it an essential part of Phe metabolism. This triggers the hydroxylation reactions for the production of catecholamines and neurotransmitters (namely, the metabolism of tyrosine to dopamine and, subsequently, norepinephrine and epinephrine). BH4 is also a cofactor for the enzyme involved in the metabolism of tryptophan to serotonin.⁴

In PKU, the underlying defect in the PAH enzyme interrupts Phe metabolism, leading to a higher Phe level than normal, as shown in the diagram below.⁴ The resulting elevation in blood Phe level can result in brain toxicity.⁴

There is a secondary Phe metabolism pathway that converts Phe to phenylpyruvate, a phenylketone, and is catalyzed by aminotransferases. In the absence or underactivity of PAH, an abnormal amount of Phe is converted to phenylpyruvate, resulting in a buildup of phenylpyruvate in bodily fluids. It is the abundance of this phenylketone that gives the disease its name.¹⁶

Long-term studies of neurocognitive outcomes with KUVAN treatment have not been conducted. BioMarin is implementing a trial to evaluate long-term neurocognitive outcomes in PKU patients treated with KUVAN.

Indication

KUVAN^® (sapropterin dihydrochloride) Tablets is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). KUVAN is to be used in conjunction with a Phe-restricted diet.

Important Safety Information

Prolonged exposure to elevated blood Phe levels in PKU patients can result in severe neurologic damage. The initiation of KUVAN therapy does not eliminate the need for careful monitoring of blood Phe levels and ongoing dietary management.

Some patients receiving KUVAN can experience significant drops in blood Phe levels. Patients should be monitored closely to ensure that blood Phe levels do not fall too low.

Not all patients with PKU respond to treatment with KUVAN. Response to treatment can only be determined by a therapeutic trial of KUVAN.

KUVAN has not been studied in patients with liver or renal impairment. Patients who have these conditions should be carefully monitored when receiving KUVAN. Caution should be used with the administration of KUVAN to patients who are receiving levodopa and drugs that affect nitric oxide–mediated vasorelaxation or folate metabolism.

The most serious adverse reactions reported during KUVAN administration (regardless of relationship to treatment) were gastritis, spinal cord injury, streptococcal infection, testicular carcinoma, and urinary tract infection. Mild to moderate neutropenia was also noted. The most common adverse reactions were headache, diarrhea, abdominal pain, upper respiratory tract infection, pharyngolaryngeal pain, vomiting, and nausea.

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