P3803 - Lessons in Monitoring Chelation Therapy in “Stable” Wilson Disease Patients Screened for a Randomized Trial

Valentina Medici, ¹, Reginald Gonzales Peralta, MD², C.Omar F. Kamlin, MD, FRCPC³, Michael Heifets, MD⁴, Michael L. Schilsky, MD^5
1University of California Davis, Sacramento, CA; ²AdventHealth for Children, Orlando, FL; ³Orphalan, London, England, United Kingdom; ⁴Orphalan, Chicago, IL; ⁵Yale University Medical Center, New Haven, CT

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). 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). 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.

Discussion: 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.
1. Schilksy, ML., et al. 2023 Hepatology 77(4)



Disclosures:


Valentina Medici, ¹, Reginald Gonzales Peralta, MD², C.Omar F. Kamlin, MD, FRCPC³, Michael Heifets, MD⁴, Michael L. Schilsky, MD⁵. P3803 - Lessons in Monitoring Chelation Therapy in “Stable” Wilson Disease Patients Screened for a Randomized Trial, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.