Scientific Director Calvagone SAS Esplugues de Llobregat, Spain
Disclosure(s):
Andreas Lindauer, PhD: No financial relationships to disclose
Objectives: Wilson’s disease (WD) is a severe genetic disorder of copper homeostasis caused by ATP7B copper transporter dysfunction, leading to impaired biliary copper excretion and low circulating ceruloplasmin (CP). VTX-801, an adeno-associated viral (AAV) gene therapy encoding a miniATP7B gene, aims to restore ATP7B activity in the liver. A mechanistic minimal physiologically based pharmacokinetic (PBPK) model was developed using radiocopper data from literature and from a study performed in healthy volunteers (CNL002). Additionally, dose-response models based on preclinical mouse data quantified the ATP7B activity required for a meaningful response. The model was used to simulate other relevant clinical outcome measures in humans based on non-labelled (“cold”) copper to evaluate the potential treatment effect of VTX-801.
Methods: Plasma kinetics and fecal excretion data from radioactive copper isotopes were digitized from publications of studies in healthy volunteers (HV), heterozygote carriers, and WD patients following oral or intravenous (i.v.) administration. The study CNL002 provided additional human data from six subjects receiving i.v. [64Cu]CuCl2. A minimal PBPK model was developed, incorporating plasma, tissue, and liver compartments, with elimination via kidney, skin, and gut (saliva, bile), including partial re-absorption, and eventual fecal elimination. The biliary elimination rate and the binding rate to CP are the parameters affected by the disease, with an activity factor (AF) representing ATP7B function. Of 29 parameters, 8 were fixed to physiological values; others were estimated via NONMEM (7.4.3). Model validation used an external dataset assessing 48h (or 24h)/2h plasma radioactivity ratios in HV, carriers, and WD patients [1]. Mouse studies quantified CP activity and fecal copper across VTX-801 doses, allowing derivation of a dose-dependent AF. Simulations were conducted using campsis [2] to explore which biomarkers based on “cold” copper (e.g., the ratio of exchangeable copper to total copper in blood (REC), urinary copper) would be most sensitive to identify a treatment effect. REC is the fraction of plasma copper that is not tightly bound to CP which is elevated (>15%) in untreated WD patients [3].
Results: Despite variability in literature data, parameters were estimated with good precision. Carriers required separate activity factors for CP-binding (AFcp=0.369) and biliary excretion (AFbil=0.101). WD patients exhibited altered liver and tissue copper kinetics, possibly due to saturation of uptake/binding given the excess copper already existing in these patients. Simulations of cold copper outcomes suggested that urinary copper excretion rate is rather insensitive to determine a treatment effect. On the other hand, REC showed an excellent sensitivity to changes in AF as it directly quantifies the fraction of unbound copper in circulation, which is tightly linked to ATP7B functioning.
Conclusions: A comprehensive mechanistic minimal PBPK model was developed capable of describing the time-course of copper – radioactive or not – in the body. Simulations illustrated the lack of sensitivity to changes in ATP7B activity for urinary copper but confirmed the validity of REC as a biomarker.
Citations: [1] Członkowska, A., Rodo, M., Wierzchowska‐Ciok, A., Smolinski, L., and Litwin, T., Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. Liver International (2018), 38(10): p. 1860-1866. [2] Luyckx N, PAGE 30 (2022) Abstr 9991 [www.page-meeting.org/?abstract=9991] [3] Trocello JM, El Balkhi S, Woimant F, et al. Relative exchangeable copper: a promising tool for family screening in Wilson disease. Mov Disord 2014;29:558-62
