TIPS TO REMEMBER Kuvan
- The recommended starting dose of Kuvan is 10 mg/kg/day.
- While taking Kuvan, blood levels of phenylalanine should be monitored.
- Kuvan should be dissolved in 4 to 8 ounces of water or apple juice prior to administration and taken within 15 minutes.
- All patients should be treated with a Phe-restricted diet while taking Kuvan.
There has never been a drug used to treat phenylketonuria (PKU), a genetic disorder caused by a deficiency of the enzyme phenylalanine
hydroxylase (PAH), until now. Last month, the Food & Drug Administration gave its approval to sapropterin dihydrochloride
(Kuvan, BioMarin), a new molecular entity indicated to reduce blood phenylalanine levels in patients with hyperphenylalaninemia
due to tetrahydrobiopterin (BH4)-responsive PKU. The orphan drug will offer some hope to about 30,000 PKU patients in the
United States and 50,000 worldwide.
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According to Barbara Burton, M.D., director of the PKU clinic at Children's Memorial Hospital in Chicago, sapropterin helped
control blood levels of phenylalanine in PKU patients during clinical trials. Burton, a clinical investigator in the Phase
II and Phase III studies for the drug, said that for the first time, a drug therapy option exists to help manage the disease.
Left untreated, PKU is toxic to the brain and can lead to mental retardation and other neurological problems.
Composition of drug
Sapropterin is a synthetic form of BH4, the cofactor for the enzyme PAH, which is normally responsible for hydroxylating Phe
to form tyrosine. But in patients with PKU, PAH activity is absent or deficient. According to BioMarin, treatment with BH4
can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.
But not all PKU patients will respond to sapropterin.
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The efficacy and safety of sapropterin was evaluated in four clinical trials. The first study, which was designed to identify
responders (defined as ≥30% decrease in blood Phe from baseline), showed the drug worked in 20% of patients who were treated
for eight days. In a second study of the responsive patients, mean blood Phe level dropped from 843 micromoles/L to 607 micromoles/L,
while the placebo group stayed about the same. According to FDA's Daniel Shames, M.D., deputy director of the Office of Drug
Evaluation III, sapropterin is useful in 20% to 50% of patients, and is due to the fact that many mutations exist for PKU.
Also, a higher dosage may mean a better response. In the drug studies, patients taking 20 mg/kg/day rather than the lower
recommended starting dose of 10 mg/kg/day were more likely to respond to the therapy.
Precautions to watch
Once treatment is initiated, blood Phe should be monitored routinely. Sapropterin should be taken with food to increase its
absorption and also should be dissolved in four to eight ounces of water or apple juice prior to administration. The mixture
should then be consumed within 15 minutes. All patients receiving sapropterin should also be simultaneously maintained on
a Phe-restricted diet.
The most common adverse reactions during clinical trials included abdominal pain, diarrhea, headache, upper respiratory infection,
vomiting, nausea, and pharyngolaryngeal pain. As part of several postmarketing commitments, the manufacturer will implement
a PKU registry program along with several clinical trials, including one in children eight years of age and younger.
According to BioMarin, sapropterin was co-developed with Merck Serono and will be available in nine specialty pharmacies immediately
at a price of $29 per 100-mg tablet. The company expects 2008 sales of the drug to reach $35 to $70 million. Kuvan will be
available through a specialty pharmacy limited distribution network, including Accredo, Aetna, Caremark, Curascript, Fairview,
McKesson, Pharmacare, Precision Rx, and Tel-Drug.
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