Treatment of Wilson's disease with tetrathiomolybdate: V. control of free copper by tetrathiomolybdate and a comparison with trientine

It has become clear that serum “free” copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance—if they worsen neurologically as often happens with penicillamine or trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than trientine. In the trientine arm of study 2, mean free copper levels actually went up during trientine therapy. The 5 patients who neurologically worsened on trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way “away from food” tetrathiomolybdate was given.