Abstract

Background: NCC and UCE are recommended for treatment monitoring in Wilson Disease (WD)(1). NCC is assumed to reflect the bioavailable copper (Cu) in plasma and is in equilibrium with the pool of stored Cu. UCE reflects body stores of Cu and is also influenced by the cupriuretic effect of therapy. Current methods to estimate NCC are flawed. The novel assay, NCC-Sp, is an accurate and reproducible method for NCC determination, and therefore was used as the primary endpoint in the CHELATE trial (NCT03539952, sponsor, Orphalan, France) (2). Our aim was to compare NCC-Sp and UCE in the study population.

Methods: We performed a secondary analysis on measurements from all specimens from 53 adults with stable WD on d-penicillamine (DPA). Samples were collected for NCC every 4 weeks after screening until the primary endpoint (24w post-randomization) and end of the extension period (48w). UCE was collected at -12w, -8w, -4w, randomization (0w), 4w, 24w and 48w. After a 12-week run-in period, patients were randomized to continue DPA (N=27) or switched to trientine tetrahydrochloride (TETA4; N=26) mg-for-mg and followed for 24 weeks. Cu was measured by ICP mass spectrometry. NCC-Sp is the total serum Cu minus ceruloplasmin-Cu as separated by anion exchange chromatography (2).

Results: Data from 496 NCC-Sp and 296 UCE measurements were analyzed. A large fraction of NCC-Sp (27%) and UCE (58%) values (Figure) were outside recommended target ranges for stable patients (1). Following randomization NCC-Sp declined from 84.4±22.3 to 53.4±18.3 µg/L in the DPA arm and from 67.0±33.1 to 57-6±29.8 µg/L in the TETA4 arm, likely due to further de-coppering, but without correlation between UCE and change in NCC-Sp.

UCE and NCC-Sp were weakly correlated, but the correlation was statistically significant (DPA arm: r²= 0.04, P=0.001; TETA4: r²=0.12, P=0.0001). UCE did not correlate with dose (mg/kg) overall; however, UCE/mg dose was higher with DPA (mean±SD 0.66±0.35 µg/24H/mg dose) compared with TETA4 (0.33±0.18; P<0.001). Following randomization there was no correlation with either NCC-Sp or change in NCC-Sp to dose prescribed. NCC-Sp and not UCE correlated positively to AST (Figure). The relationship to ALT was similar but weaker (UCE: DPA r²=0.008, NS; TETA4 r²=0.17, P=0.04. NCC-Sp: DPA: r²=0.017, P=0.04; TETA4 r²=0.023, P=0.02).

Conclusion: Though different cupriuretic effects of TETA4 and DPA were observed in the study, a similar overall effect on NCC-Sp indicated copper balance was maintained. NCC-Sp but not UCE correlated with ALT and AST, suggesting its greater utility for monitoring chelator therapy. The large fraction of treated patients outside recommended target ranges for UCE and NCC suggests re-evaluation of target ranges is necessary including correlation with clinical and biochemical outcomes.

1. Schilsky ML et al. Hepatology 2022.

2. Schilsky ML et al Lancet Gastroenterol Hepatol 2022.