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

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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 (NCCcorrected) at 24 weeks, with treatment success defined as achievement or maintenance of normalised NCCcorrected (≤2·3 μmol/L [upper limit of normal]) or achievement of at least a 25% reduction in NCCcorrected 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<0·0001) of 28 patients met the criteria for treatment success: 16 (57%) treated with WTX101 either achieved or maintained normalised NCCcorrected concentrations and 4 (14%) had at least a 25% reduction from baseline NCCcorrected. Mean NCCcorrected 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<0·0001). No cases of paradoxical drug-related neurological worsening were recorded. Liver function was stable in all patients, although reversible increased concentrations of asymptomatic alanine or aspartate aminotransferase, or γ-glutamyltransferase, without increased bilirubin, occurred in 11 (39%) of 28 patients who received at least 30 mg/day. 11 serious adverse events were reported in seven (25%) patients and included psychiatric disorders (six events in four patients), gait disturbance (one event), elevated liver aminotransferases (two events in two patients, one with agranulocytosis), and decline in neurological functioning (one event, likely due to natural disease progression although causality could not be ruled out). The seven serious adverse events categorised as psychiatric disorders and as gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related.

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.

Introduction

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.

Section snippets

Study design and patients

We did this open-label, phase 2 study at 11 hospitals in the USA, UK, Germany, Poland, and Austria. Eligible patients were aged 18 years or older, with a diagnosis of Wilson's disease established by a Leipzig score of 4 or more.6, 17 At enrolment, patients had received no previous treatment for Wilson's disease or had been treated with chelation or zinc for no longer than 24 months, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol/L).13 We excluded

Results

Between Nov 24, 2014, and April 27, 2016, 28 patients were enrolled and treated with WTX101; 22 (79%) patients completed the study up to week 24 (figure 1). At baseline, 15 (54%) patients were women and the mean age was 34·1 years (SD 11·86) and ranged from 18 to 64 years. Nine (32%) patients had received no previous treatment for Wilson's disease. Nine (32%) patients had been treated for less than 28 days, and ten (36%) patients had been treated for between 28 days and 2 years (median 100 days

Discussion

Our results show that WTX101 induced rapid copper control with significant NCCcorrected reductions after approximately 3 months, and this was accompanied by significant early improvements in neurological symptoms and function in most patients. To our knowledge, this study is the first multinational prospective trial done in patients with Wilson's disease and aimed to assess treatment with a newly stabilised form of tetrathiomolybdate, WTX101.

Clinical improvement in patients with Wilson's

References (31)

  • W Masełbas et al.

    Persistence with treatment in patients with Wilson disease

    Neurol Neurochir Pol

    (2010)
  • EA Roberts et al.

    Diagnosis and treatment of Wilson disease: an update

    Hepatology

    (2008)
  • P Ferenci

    Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing

    Hum Genet

    (2006)
  • AJ Coffey et al.

    A genetic study of Wilson's disease in the United Kingdom

    Brain

    (2013)
  • EASL Clinical Practice Guidelines: Wilson's disease

    J Hepatol

    (2012)
  • Cited by (0)

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