Monitoring and treatment of Wilson disease: progress and challenges

In The Lancet Gastroenterology & Hepatology, Michael L Schilsky and colleagues report the results of a multicentre, randomised, open-label, non-inferiority, phase 3 trial on the copper chelator trientine tetrahydrochloride (TETA4), 1 Schilsky ML Czlonkowska A Zuin M et al. Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2022; (published online Sept 29.)https://doi.org/10.1016/S2468-1253(22)00270-9 Summary Full Text Full Text PDF Scopus (3) Google Scholar a new trientine formulation that is stable at room temperature, compared with penicillamine in patients with Wilson disease. The study included 53 patients with Wilson disease with both hepatic and neuropsychiatric manifestations who were considered to be stable according to clinical presentation and copper metabolism parameters, particularly 24 h urinary copper excretion and non-caeruloplasmin-bound copper (NCC) serum levels. Patients either continued on penicillamine, the first-line copper chelator, or were switched to TETA4 using a mg-for-mg dose conversion strategy. Patients were assessed for copper metabolism and clinical stability at 24 weeks and 48 weeks, with the primary outcome being NCC levels at 24 weeks. The study showed that TETA4 is non-inferior to penicillamine in maintaining NCC levels as a reflection of efficacy of copper balance control (mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was –9·1 μg/L [95% CI –24·2 to 6·1], with the lower limit of the 95% CI within the defined non-inferiority margin). This finding is important because, although drug regulatory agencies are still indicating penicillamine as first-line treatment for patients with Wilson disease, many, if not most, clinicians will actually prescribe trientine formulations at the time of diagnosis or switch from penicillamine to trientine to prevent or limit side-effects. Numerous reports indicate that penicillamine is associated with side-effects in up to 40% of patients, and side-effects can be observed even after years of treatment, particularly nephropathy, autoimmune conditions, and interference with collagen metabolism with consequent skin changes. 2 Weiss KH Thurik F Gotthardt DN et al. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013; 11: 1028-1035 Summary Full Text Full Text PDF PubMed Scopus (148) Google Scholar , 3 Medici V Trevisan CP D'Incà R et al. Diagnosis and management of Wilson's disease: results of a single center experience. J Clin Gastroenterol. 2006; 40: 936-941 Crossref PubMed Scopus (114) Google Scholar Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trialThe efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease. Full-Text PDF