P21 Monitoring maintenance therapy with D-Penicillamine for Wilson’s Disease: lessons from screening for a randomized trial

Background

Wilson’s disease (WD) is a genetic condition that leads to the accumulation of copper in the body. The goal of therapy in WD is to prevent the accumulation of copper by controlling the circulating free copper by chelation. D-penicillamine (DPA) is first line therapy for WD. Monitoring is conducted by performing 24-hour urinary copper excretions (UCE) and titrating the dose depending on the amount of copper excreted. Patients screened for the CHELATE (NCT03539952) study had laboratory and UCE investigations performed on treatment. The aim of this study was to describe the results of these investigations in physician selected ‘stable’ patients.

Methods

CHELATE was a multicentre, non-inferiority randomized trial comparing trientine tetrahydrochloride with DPA in stable WD adult patients receiving DPA. From the 77 screened, 53 were randomized after a 12-week run in period to fulfil eligibility criteria. Protocol defined stability was determined clinically by treating physicians and independent committee and by laboratory measures; (i) serum non-caeruloplasmin bound copper (NCC) using EDTA chelation (NCC-Ex) (ii) 24-h urinary Cu excretion (iii) serum alanine aminotransferase (ALT) < 2x ULN. NCC measured by chromatography and inductively coupled plasma mass spectroscopy developed by Orphalan (NCC-Sp) was used as the primary endpoint and retrospectively on all specimens collected. Data analysis is limited to initial and repeat laboratory findings from the screening visits.

Results

Data was available in 76 (37 female) patients; with maximum87 laboratory specimens analysed (table 1). Compared to current guidance, only 39% of UCE (34/87) were within range; 11% (10) and 49% (43) suggesting either over-treatment or under-dosing/poor adherence (< 200 and > 500 mcg/day) respectively. NCC-Ex and NCC-Sp were both skewed to the lower end of therapeutic range.. Synthetic liver function tests > ULN were common (% of all specimens); ALT (21%), AST (16%), GGT (17%), bilirubin (23%). No evidence of copper deficiency was identified.

Conclusion

In stable WD patients receiving maintenance DPA therapy, there was a wide range (46–2172 mcg/day) of urinary copper excretion accompanied by a proportion with lower-than-expected NCC. This suggests possible under dosing/over treatment/poor adherence in patients identified as having stable disease. Current methods to assess copper balance with DPA therapy are challenging to interpret. Further studies comparing or correlating clinical signs, symptoms, adherence, transient elastography, and novel biomarkers reflecting copper balance are needed to guide appropriate therapeutic dosing of chelation therapy.

Reference

Schilsky ML, Czlonkowska A, Zuin M, Cassiman D, Twardowschy C, Poujois A, Gondim FAA, Denk G, Cury RG, Ott P, Moore J, Ala A, D’Inca R, Couchonnal-Bedoya E, D’Hollander K, Dubois N, Kamlin COF, Weiss KH; CHELATE trial investigators. Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2022 Dec;7(12):1092–1102. doi: 10.1016/S2468–1253(22)00270–9. Epub 2022 Sep 30. PMID: 36183738.