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

Abstract

Background & aims: In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with 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 its effects on copper absorption and biliary excretion.

Methods: In a double-blind randomized setting, hepatic ⁶⁴Cu activity was examined after orally administered ⁶⁴Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral ⁶⁴Cu was administered one hour after the final TTM dose. Changes in hepatic ⁶⁴Cu activity reflected changes in intestinal ⁶⁴Cu uptake. Additionally, in four patients with WD, the distribution of ⁶⁴Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. ⁶⁴Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder ⁶⁴Cu activity was taken as evidence of increased biliary ⁶⁴Cu excretion.

Results: In healthy volunteers, TTM reduced intestinal ⁶⁴Cu uptake by 82% 15 hours after the oral ⁶⁴Cu dose. In patients with WD, 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 two hours after the intravenous ⁶⁴Cu dose.

Conclusions: While 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 the exposure of organs like the liver and brain to ⁶⁴Cu.

Impact and implications: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, 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 builds on our understanding of human copper metabolism and the mechanism of action of TTM.

Keywords: 64 copper; ALXN1840; Copper absorption; PET; WTX-101; copper chelation; copper excretion; placebo; randomized; rare disease; tetrathiomolybdate.