Orphan Drug Gets FDA Nod for Phenylketonuria

By Belden, Heidi | Drug Topics, February 11, 2008 | Go to article overview

Orphan Drug Gets FDA Nod for Phenylketonuria


Belden, Heidi, Drug Topics


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.

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 notmal oxidative metabolism of Phe, and decrease Phe levels in some patients. But not all PKU patients will respond to sapropterin.

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.

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Orphan Drug Gets FDA Nod for Phenylketonuria
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