Currently Enrolling Trials
The FDA has approved Orfadin (nitisinone) capsules for the treatment of hereditary tyrosinemia type I (HT-1), a rare pediatric disease. HT-1 is a genetic metabolic disorder that results from an inability to break down the amino acid tyrosine. Because of resulting liver failure and liver cancer, children with HT-1 rarely survive into their twenties without a liver transplant.
Orfadin was designated an Orphan Drug in May 1995 by the Office for Orphan Product Development. Orphan products are developed to treat rare diseases - there are less than 100 children in the United States with HT-1.
Orfadin capsules are to be used in conjunction with a diet restricted in tyrosine and phenylalanine.
Orfadin was evaluated in an open-label study conducted at 87 hospitals in 25 countries. Data was obtained from over 180 subjects with a diagnosis of HT-1, with a median age at enrollment of nine months. Results showed that Orfadin treatment resulted in a four-year survival probability of 88% for children under two months of age at the time of HT-1 diagnosis (subjects also received dietary restrictions). In contrast, historical controls showed that children presenting with HT-1 under two months of age who only received dietary restrictions had a survival rate of 29%.
In clinical testing with Orfadin, transient thrombocytopenia (decreased number of platelets) and leukopenia (decreased number of white blood cells) were reported.
Mechanism of Action
Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1. (from Orfadin Prescribing Information)
For additional information on Orfadin, please visit Orphan Pharmaceuticals.