Evaluation of novel assays of non-ceruloplasmin copper to monitor chelation treatment in patients with Wilson disease.

BACKGROUND &

aimsWe examined the use of two newer measures of non-ceruloplasmin-bound copper (NCC) and 24-h urinary copper excretion (UCE) to monitor chelation therapy in clinically stable Wilson disease (WD).

methodsWe post hoc analyzed data from the CHELATE study, in which 77 patients with clinically stable WD taking penicillamine (DPA) entered a 12-week screening phase after which 53 were randomized to continued DPA or same dose trientine-tetrahydrochloride (TETA4) (weeks 12-60). Data included NCC measured by protein speciation (NCC-Sp), exchangeable copper (NCC-Ex), and UCE.

resultsIn 32/53 patients with unchanged dose from week 1 to 60, NCC-Sp decreased from 57.9 ± 21.1 μg/L to 39.6 ± 16.25 μg/L (p = 0.0002), whereas NCC-Ex decreased from 56.4 ± 20.3 μg/L to 46.2 ± 11.5 μg/L (p = 0.01), likely because of improved adherence during participation in a clinical trial. UCE dropped by ∼50% after switching to TETA4 and gradually decreased in the DPA arm. Biomarker values did not reach steady state until Week 60. The visit-to-visit coefficient of variance was 30% for NCC-Sp, 20% for NCC-Ex, and 52% for UCE. Including all 45 patients who completed Week 60, those with lower tertile values of NCC-Sp (16.3-30.9 μg/L) and NCC-Ex (18.7-43.1 μg/L) had lower and more stable aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and higher and more stable S-albumin and S-protein compared with those with higher values. No neurological changes were noted despite these differences in NCC. Copper deficiency was not observed.

conclusionsNon-ceruloplasmin by protein speciation and exchangeable copper have the potential to guide chelation in patients with WD taking maintenance therapy. Specific target ranges should be established, and we hypothesize these could include values below normal ranges. Further studies are required to improve our understanding of the responses to dose changes and non-adherence and if standardization of sampling conditions can reduce visit-to-visit variability. IMPACT AND IMPLICATIONS: The use of biomarkers of copper metabolism (NCC and UCE) to monitor chelating treatment in WD is poorly supported by data, and development of newer methodologies (NCC-Ex and NCC-Sp) further supports re-evaluation in longitudinal studies. Our study suggests that, in patients with stable WD, the response of NCC-Sp and NCC-Ex to a dose change can take as long as 6-12 months to achieve and, with an intraindividual visit-to-visit variation coefficient of ∼20-25%, this will impact clinical practice and decision-making (requiring serial measurements) and estimation of sample size and length of clinical trials. Steady-state NCC-Ex and NCC-Sp below the commonly recommended 50-150 μg/L range were associated with stable ALT, AST, S-albumin, and S-protein compared with values >50 μg/L, where ALT and AST increased and S-albumin and S-protein decreased, suggesting that future prospective studies could lead to re-evaluation and changes to ranges for treatment goals for NCC-Ex and NCC-Sp. The lack of a similar association of UCE and clinical outcome and high variation (51%) question the current use of UCE to guide dosing in patients with stable WD. CLINICAL TRIAL: NCT03539952.