Long-Term Study of Nitisinone to Treat Alkaptonuria

Alkaptonuria is a rare metabolic disease in which homogentisic acid (HGA), an intermediary metabolite in tyrosine catabolism, accumulates due to deficiency of the enzyme homogentisic acid oxidase. Patients with alkaptonuria exhibit homogentisic aciduria and ochronosis, or dark pigmentation of various tissues due to binding of HGA and its oxidized metabolites. The ochronosis results in debilitating destruction of cartilage, arthritis, lumbosacral ankylosis, limitation of motion, and bone deterioration in later life. No effective therapy exists for alkaptonuria. However, a compound named 2-(2-nitro-4-trifluoromethylbenzoyl) - 1, 3-cyclohexanedione (nitisinone, NTBC, Orfadin) inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone, at doses of approximately 1 mg/kg/day, has proven safe and effective in tyrosinemia type I, which causes fatal liver disease in infants and children. Under protocol 97-HG-0201, we treated 9 alkaptonuria patients with nitisinone; for the 7 who received 1.05 mg twice daily, the HA fell from 4.0 plus or minus 1.8 g/24h to 0.2 plus or minus 0.2 g/24h (normal 0.028 plus or minus 0.015 g/24h, n=10). Plasma tyrosine levels rose from 67 plus or minus 18 micro M to 760 plus or minus 181 micro M. The current protocol (05-HG-0076) is a randomized, controlled clinical trial to determine if nitisinone (2 mg daily) is beneficial for the joint symptoms of alkaptonuira. Patients are examined at the NIH Clinical Research Center every 4 months for 3 years. Hip joint range of motion (ROM) serves as the primary outcome parameter, and nitisinone (Orfadin) is provided by Swedish Orphan International through an Investigational New Drug Application (IND), obtained by William A. Gahl. Forty patients (20 with nitisinone treatment and 20 untreated) have been enrolled for at least 16 months, and an interim analysis shows promising results. Serious adverse events in patients on nitisinone have included a death from myocardial infarction, keratopathy, and elevated liver function tests related to gallstones.