The maintenance therapy of Wilson's disease is now well covered with the recent FDA approval of zinc acetate. However, the initial therapy of patients presenting with neurologic disease is problematic. Zinc is rather slow-acting and the disease of the acutely ill patient may progress prior to zinc controlling copper toxicity. The copper chelator that has been used the longest for Wilson's disease, penicillamine, is extremely dangerous for these patients. We've shown that half of penicillamine treated patients deteriorate neurologically, with many failing to recover, probably due to redistribution of copper into the brain. The copper chelator, trientine, has seen limited use, but seems to have fewer side effects than penicillamine. Initial worsening has not yet been reported, although it is a theoretical risk with trientine.We have introduced a new orphan drug (tetrathiomolybdate, or TM) for the initial treatment of these patients. TM has ideal properties of fast action, and doesn't cause initial worsening. Supported by grants from the Orphan Products Office, we have carried out an open study of an initial 8 weeks of therapy in 51 patients. We have shown excellent initial preservation of neurological function, and excellent recovery at 1 and 2 years. Side effects have been minimal and have occurred primarily at high doses. Here we propose a 3 year, phase II/III double blind, two site, study comparing TM to trientine for initial therapy of neurologically presenting patients. We project a trial of 90 patients, 45 in each arm, but power calculations show that we can get very useful data with 60 patients. The major questions to be answered are: Is there a difference in the rate of initial neurological deterioration? Is there a difference in degree of neuological recovery at years 1 and 2? Are there differences in the incidence of serious side effects? At the completion of the study, we will not only have answered the questions relating to TM vs. trientine, but we will have characterized the efficacy and toxicity of trientine, a drug already on the market, in the initial treatment setting.
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