Lessons in Monitoring Chelation Therapy in "Stable" Wilson Disease Patients Screened for a Randomized Trial

Introduction: The goal of therapy in Wilson Disease (WD) is to prevent the pathologic accumulation of copper by controlling circulating free copper [non-ceruloplasmin copper;(NCC)]. Copper chelation with d-penicillamine (DPA) is first line therapy with monitoring more intense at initiation of treament, reducing to twice annually once stable. The aim of this study is to describe the distribution of laboratory values from those screened for trial enrolment. Methods: CHELATE (NCT03539952) was a multicenter, non-inferiority randomized trial comparing trientine tetrahydrochloride with DPA in stable adult patients with WD receiving DPA. From the 77 screened, 53 were randomized after a 12-week run in period to fulfil eligibility criteria. Stability was determined clinically by treating physicians and independent adjudication committee and by laboratory measures; (i) serum NCC using EDTA chelation (NCC-Ex) (ii) 24-h urinary Cu excretion (UCE) (iii) serum alanine aminotransferase (ALT) < 2x ULN. NCC measured by chromatography and ICP mass spectroscopy developed by Orphalan (NCC-Sp) was used as the primary endpoint and retrospectively on all specimens collected. Data analysis here is limited to initial and repeat laboratory findings from the screening visit(s). Results: Data was available in 76 (37 female) patients, with up to 87 laboratory specimens analysed (summarized in Table 1). Compared to current guidance1, only 39% of UCE (34/87) samples were within range;11% (10) and 49% (43) suggesting over-treatment or under-dosing/poor adherence (< 200 and > 500 mcg/day) respectively (Figure 1). NCC-Ex and NCC-Sp were both skewed to the lower end of therapeutic range with only 57% and 58% of measurements in range1. 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: Clinician selected stable adults with WD on maintenance DPA showed wide variations in UCE and a proportion with lower-than-expected NCC; patterns suggesting possible under dosing/ poor adherence or possible over-treatment. Current methods to assess copper balance with DPA therapy are challenging to interpret. Further studies comparing [or correlating] clinical signs, symptoms, transient elastography, and novel biomarkers with accurate laboratory measures of copper balance are needed to guide therapeutic dosing to help with clinical optimization and guide future intervention trials.Figure 1.: Screening Laboratory Measures of NCC-Ex, NCC-Sp, ALT and 24 hour UCE From Adults with WD Selected by Physicians and Considered Stable. Normal or recommended therapeutic range are highlighted in light green. Table 1. - Descriptive statistics of common laboratory measures used to determine clinical stability in adults with Wilson Disease (WD) Parameter (unit) N Mean SD Median Range (min, max) DPA dose (mg/kg) 76 13.7 4.7 13.1 4.4, 29.8 UCE (mcg/kg) 87 600.5 414.1 497 46.8, 2172 NCC-Ex (mcg/L) 79 57.8 24.03 54.8 13.1, 124 NCC-Sp (mcg/L) 77 56.6 26.0 56.6 16.2, 149 Cu (mcg/L) 84 298.1 232.2 224 54, 884.4 Ceruloplasmin (mg/L) 87 80.8 47.6 52 52, 240.2 ALT (U/L) 86 35.3 24.5 26.5 6, 110 AST (U/L) 86 25.9 10.1 24 12, 79 GGT (U/L) 87 47.7 65.1 27 10, 425 INR 86 1.06 0.16 1.03 0.76, 2.2 Bilirubin (mmol/L) 86 15.3 8.8 13.1 5.8, 58.4 Albumin (g/L) 87 43.4 3.3 44 35, 50 Creatinine (mmol/L) 87 73.4 14.8 72.9 44, 110.9 Urea Nitrogen (mmol/L) 87 5.5 1.7 5.1 2.7, 13.4 GFR (mL/min) 87 117.9 33.7 114 37, 213 Proteinuria (g/L) 87 71.2 4.7 72 55, 80 Hemoglobin (g/dL) 86 14.3 1.2 14.4 11.7, 16.8 Leucocytes (x109/L) 86 5.5 1.7 5.3 2.9, 12.1 Neutrophils (x109/L) 86 3.3 1.3 3.04 1.5, 8.4 Platelets (x109/L) 86 199 64.7 199 48, 362 Reference 1. Schilksy, ML., et al. 2023 Hepatology 77(4).