Wilson's disease is an autosomal recessive disorder of impaired copper transport that leads to copper accumulation in the liver, brain, and other tissues.1 The disease is caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase.2 Decreased ATP7B function leads to reduced copper incorporation into ceruloplasmin and impaired biliary copper excretion.1, 2 Wilson's disease affects about one in 30 000 people, but prevalence varies among populations3 and there might be considerable underdiagnosis.2, 4 Clinical presentation differs widely, and includes forms of liver disease, neurological and psychiatric manifestations, and Kayser–Fleischer corneal rings.1, 5 Abnormal laboratory findings include raised concentrations of free non-ceruloplasmin-bound copper (NCC) in plasma and low concentrations of circulating ceruloplasmin.1, 5
If left undiagnosed and untreated, Wilson's disease is universally fatal.1, 6 Oral treatments approved several decades ago to reduce copper concentrations include chelators (penicillamine and trientine), which increase urinary excretion of copper, or zinc, which inhibits gastrointestinal copper absorption.1 Few, if any, prospective studies have been done with these treatments, and there are considerable unmet needs with respect to efficacy, safety, and simplicity of dosing regimens.4, 7, 8 Furthermore, patients with neurological presentation who initiate treatment with penicillamine or trientine can have paradoxical early worsening of neurological disease, with rapid appearance of new neurological signs or worsening of existing neurological signs, which leads to marked disability.8, 9, 10, 11, 12 In clinical studies,8, 9, 10, 11, 12 the proportion of patients with neurological Wilson's disease affected by early worsening after chelator initiation ranges from 19% to 35%. Early neurological worsening can be irreversible11 and might be due to rapid mobilisation of free copper.8
Research in context
Evidence before this study
Approved treatments for Wilson's disease include zinc and the chelators penicillamine and trientine. We searched PubMed on June 10, 2017, with no date or language restrictions, using the terms “Wilson disease” and “Wilson's disease” limited to clinical trial article types. This search identified only one prospective trial of these treatments. The trial was a small pilot study of once-daily treatment with trientine, which is currently given in multiple divided dosages. We also identified two articles that described studies of ammonium tetrathiomolybdate, which rapidly controlled copper levels in patients with Wilson's disease, but this compound was later found to be too unstable for clinical use. In studies with ammonium tetrathiomolybdate, patients only had limited exposure for 8 weeks, were given concomitant zinc, and were followed on zinc monotherapy after 8 weeks. On the basis of results from retrospective studies and our own clinical experience, considerable unmet needs exist in the treatment of Wilson's disease. Approved treatments can take several months or years to improve symptoms and there is paradoxical early worsening of neurological symptoms after initiation of chelator therapy in up to 35% of patients with neurological presentation. Many patients develop adverse events, some of which are serious, frequently leading to discontinuation and changes in treatment. Furthermore, regimens are complex (multiple divided doses with several hours of fasting for each dose) and non-adherence is a substantial problem with this lifelong condition.
Added value of this study
In this proof-of-concept phase 2 clinical trial of a newly stabilised form of tetrathiomolybdate, bis-choline tetrathiomolybdate (WTX101), concentrations of free copper levels were rapidly lowered and this was accompanied by reduced disability, improved neurological status without apparent initial paradoxical worsening, and stable liver function after mostly once-daily administration for 24 weeks. Unlike currently available treatments, WTX101 appears to bind copper and albumin to form an inert tripartite complex in the circulation and has direct intracellular activity in hepatocytes, whereby it binds excess copper and promotes biliary copper excretion. These actions might explain the rapid biochemical and clinical improvements we observed.
Implications of all the available evidence
Our findings indicate that WTX101 might be a promising new therapeutic approach with a unique mode of action, and in view of its once-daily dose and favourable safety profile, it could improve the treatment of this debilitating condition. Further large-scale studies with WTX101 are warranted.
Bis-choline tetrathiomolybdate (WTX101) is an oral first-in-class copper-protein-binding molecule under investigation as once-daily monotherapy for Wilson's disease. A previous form of the drug, ammonium tetrathiomolybdate, rapidly controlled copper concentrations in clinical studies; however, it is too unstable for routine use.4, 13 The bis-choline moiety is a major advance since it has improved stability14 and, unlike other available treatments, WTX101 seems to have direct intracellular activity in hepatocytes, in which it binds excess copper and promotes biliary copper excretion.15 WTX101 also rapidly binds free plasma copper, creating a stable tripartite complex of tetrathiomolybdate with copper and albumin.16 In this study, we assessed the efficacy and safety of WTX101 in the initial or early treatment of patients with Wilson's disease.