Bioavailable Copper as a Monitoring Tool in Wilson Disease

Non-ceruloplasmin bound copper measured by speciation (NCC-Sp) declined across chelator, zinc, and combination therapy in patients with biochemically unstable Wilson disease, suggesting the blood test could track treatment response regardless of therapy, according to data presented by Michael Schilsky, MD, at The Liver Meeting 2026 in Denver, Colorado.

NCC-Sp reflects bioavailable copper, the loosely bound pool that moves in and out of tissues, Schilsky, professor of medicine at Yale School of Medicine, told HCPLive. Urinary copper excretion varies with therapy, dose, and medication timing, but the speciation assay “is actually agnostic to treatment, agnostic to dose,” he said.

What Did the REASON Study Show?

The prospective, noninterventional REASON study enrolled 42 adults at 9 US sites who had been treated for more than 1 year but remained biochemically unstable. NCC-Sp was measured after study completion, with treating physicians blinded to results. Over 12 months, mean NCC-Sp fell by 26.0 ng/mL with chelators, 14.1 ng/mL with zinc, and 40.6 ng/mL with combination therapy, although variability between patients was high. Chelators produced the most consistent liver enzyme improvements, while urinary copper excretion moved in different directions depending on therapy.¹

The findings build on the phase 3 CHELATE trial, which used NCC-Sp as its primary end point and found trientine tetrahydrochloride noninferior to penicillamine in clinically stable patients.² Separate research found that many stable patients fall outside recommended targets for non-ceruloplasmin copper or urinary copper.³

How Could NCC-Sp Change Monitoring?

Schilsky estimates that clinically significant nonadherence affects at least 20% to 30% of patients. A simple blood test could help flag undertreatment and potentially spare patients repeated 24-hour urine collections, though larger studies are needed to define treatment targets.¹

Watch the full interview to hear Schilsky discuss how NCC-Sp could help personalize dosing and why a related copper ratio may also aid in diagnosing Wilson disease.

Relevant disclosures for Schilsky include Vivet Therapeutics, Orphalan, DepYmed, Arbomed, Eton Pharma, Prime Medicine, and others.

References

1. Schilsky M, Gonzalez-Peralta R, Cheung A, et al. Real world evidence of therapy impact in unstable Wilson disease using non-ceruloplasmin bound copper by speciation as a novel monitoring tool. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.
2. Schilsky ML, Czlonkowska A, Zuin M, et al. Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2022;7(12):1092-1102. doi:10.1016/S2468-1253(22)00270-9
3. Ott P, Sandahl T, Ala A, et al. Non-ceruloplasmin copper and urinary copper in clinically stable Wilson disease: alignment with recommended targets. JHEP Rep. 2024;6(8):101115. doi:10.1016/j.jhepr.2024.101115