Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease

Background & AimsIn Wilson Disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may have a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated the effects of TTM on copper absorption and biliary excretion.MethodsIn a double-blind randomized setting, hepatic 64Cu activity after orally administered 64Cu was examined by PET/CT in 16 healthy volunteers before and after 7 days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered 1 h after final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four WD patients, distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain were followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/d), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion.ResultsIn healthy subjects TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In WD patients, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time points and significantly reduced cerebral 64Cu activity 2 h after the intravenous 64Cu dose.ConclusionsWhile we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting 64Cu exposure to organs like the liver and the brain.Impact and implicationsBis-choline tetrathiomolybdate (TTM) is an investigational copper chelator for treatment of Wilson Disease. In animal studies of Wilson Disease models, TTM has been shown to facilitate biliary copper excretion.In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree.Our study improves the understanding of human copper metabolism and the mechanism of action of TTM.Clinical trial numberData is presented from two clinical trials:Absorption study: EudraCT 2020-005832-31Excretion study: EudraCT 2021-000102-25.