Alkaptonuria (AKU) is caused by the dysfunction of an enzyme in the tyrosine breakdown pathway. A simple diagram of this pathway is included on this page. Tyrosine enters your body as protein in your diet, and is essential for processes such as growth and healing. However, your body also needs to recycle excess tyrosine, and does so by breaking it down piece-by-piece through a series of enzymes, until it finally leaves the body in breath and urine.
AKU patients lack one enzyme in this pathway (homogentisic dioxygenase), which means that instead of removing tyrosine from their body, the pathway stops at the production of homogentisic acid (HGA). HGA then builds up in the body of AKU patients, and causes the symptoms associated with the disease, for example by binding to and weakening cartilage.
Nitisinone is an enzyme inhibitor. It acts to interrupt the action of another enzyme in the tyrosine breakdown pathway. By stopping the breakdown at a safe point, AKU patients should not produce HGA, and can potentially avoid the symptoms of the disease. Clinical research in the US suggests that nitisinone is capable of reducing levels of HGA by up to 95%
While the action of nitisinone is thought to be well-understood, it must be studied and proven through clinical trials in order to provide clinical evidence that it has benefit for AKU patients. Only if the results from DevelopAKUre provide evidence of effectiveness will we be certain if it can be used to treat AKU.
Use in Hereditary tyrosinaemia type I
Nitisinone is currently licensed for the treatment of another disease: hereditary tyrosinaemia type I (HT-1). For use in HT-1, nitisinone is marketed as Orfadin®. The European Commission granted a marketing authorisation to Sobi
, which is valid throughout the European Union, on 21 February 2005.
HT-1 is a rare genetic disorder in which newborn children lack the ability to break down the amino acid, tyrosine. This causes toxic substances to build up in the child, leading to liver failure, kidney dysfunction and neurological problems. Without treatment by Orfadin, HT-1 is a fatal disease.
Nitisinone acts to treat HT-1 by interrupting the same tyrosine breakdown pathway as in AKU. HT-1 patients also lack an enzyme in this pathway which causes the disease. By safely blocking the pathway, nitisinone provides an effective treatment for HT-1 patients.
While evidence of effectiveness in one disease, does not mean that the drug is effective in another disease; the use of nitisinone in HT-1 does indicate that the drug is safe to use in human patients over extended periods of time.