KUVAN stimulates the activity of the residual PAH enzyme

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.

PKU is caused by a defect in the PAH enzyme, leading to elevated blood Phe levels.⁴ The mutations in the PAH gene result in defective PAH enzyme activity and reduced ability to convert Phe to tyrosine.² Therefore, if left unmanaged, defects in Phe metabolism allow high levels of Phe to occur.²¹ The consequential elevation in blood Phe level can result in cognitive and psychological problems.⁴

KUVAN is a pharmaceutical formulation of BH4 that interacts with the PAH enzyme in the same way that natural BH4 does. KUVAN stimulates the activity of the residual PAH enzyme in PKU patients to metabolize Phe to tyrosine.¹

Theories on why KUVAN works

Arguably, the greatest disadvantage of existing therapies for elevated Phe lies in the fact that none directly address the underlying defect in the PAH enzyme.⁴ The addition of BH4 activates the defective PAH enzyme to improve the body’s natural metabolism of Phe.^22,23 While the exact mechanisms remain unclear, the use of BH4 may activate phenylalanine hydroxylation by increasing BH4 levels for its cofactor in hepatic cells and compensating for the reduced affinity of the defective PAH enzyme.^22,24 Experimental data also suggest that cofactor treatment with BH4 may work by facilitating the formation of functional PAH tetramers or by acting as a chemical chaperone to protect a misfolded enzyme from degradation.²⁵

KUVAN stimulates the activity of the residual PAH enzyme

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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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