Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study

Summary Background Wilson's disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Therapies are limited by efficacy, safety concerns, and multiple daily dosing. Bis-choline tetrathiomolybdate (WTX101) is an oral first-in-class copper-protein-binding molecule that targets hepatic intracellular copper and reduces plasma non-ceruloplasmin-bound copper (NCC) by forming tripartite complexes with albumin and increasing biliary copper excretion. We aimed to assess the efficacy and safety of WTX101 in the initial or early treatment of patients with Wilson's disease. Methods We did this open-label, phase 2 study at 11 hospitals in the USA and Europe. We enrolled patients (≥18 years) with Wilson's disease who were untreated or had received no more than 24 months of treatment with chelators or zinc, had a Leipzig score of 4 or more, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol/L). Eligible patients received WTX101 monotherapy at a starting dose of 15–60 mg/day on the basis of baseline NCC concentrations for the first 4–8 weeks, with response-guided individualised dosing for the remaining weeks up to week 24. Investigators, other hospital personnel, and patients were aware of the identity of the treatment. The primary endpoint was change in baseline NCC concentrations corrected for copper in tetrathiomolybdate-copper-albumin complexes (NCC corrected ) at 24 weeks, with treatment success defined as achievement or maintenance of normalised NCC corrected (≤2·3 μmol/L [upper limit of normal]) or achievement of at least a 25% reduction in NCC corrected from baseline at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT02273596. Findings Between Nov 24, 2014, and April 27, 2016, 28 patients were enrolled and received WTX101; 22 (79%) patients completed the study up to week 24. At 24 weeks, 20 (71%, 95% CI 51·3–86·8; p corrected concentrations and 4 (14%) had at least a 25% reduction from baseline NCC corrected . Mean NCC corrected was reduced by 72% from baseline to week 24 (least squares mean difference −2·4 μmol/L [SE 0·4], 95% CI −3·2 to −1·6; p Interpretation Our findings indicate that WTX101 might be a promising new therapeutic approach for Wilson's disease, with a unique mode of action. In view of its once-daily dose and favourable safety profile, WTX101 could improve the treatment of patients with this debilitating condition. Funding Wilson Therapeutics AB.