Andreas Lindauer2, Bernard Benichou1, Gloria González Aseguinolaza3, Jean-Philippe Combal1
1Calvagone SAS, 2Vivet Therapeutics SAS, 3Vivet Therapeutics SL
Introduction/Objectives: Wilson’s disease (WD) is a severe genetic disorder of copper homeostasis caused by ATP7B transporter dysfunction, leading to impaired biliary copper excretion and low circulating ceruloplasmin (CP). The main hallmark of WD is toxic copper accumulation in tissues which cause hepatic and neurological disfunctions. VTX-801, an adeno-associated viral (AAV) gene therapy encoding a miniATP7B gene, aims to restore ATP7B activity in the liver. Key development questions include the efficacious human dose and early identification of responders to safely withdraw background therapy in clinical trials. A mechanistic minimal physiologically based pharmacokinetic (PBPK) model was developed using radiocopper data from literature and from a study performed in healthy volunteers (CNL002). Dose-response models based on preclinical mouse data quantified the required ATP7B copper transporter activity for a meaningful response using radiocopper. Before initiating the GATEWAY study in WD patients, simulations were to be conducted to define responder criteria based on radiocopper plasma ratios. Methods: Plasma kinetics and fecal excretion data from radioactive copper isotopes (65Cu, 64Cu, 67Cu) were digitized from publications of studies in healthy volunteers, heterozygote WD carriers, and WD patients following oral and intravenous (i.v.) radiocopper administration. The study CNL002 provided additional human data from six subjects (3 homozygous (ATP7B+/+) and 3 heterozygotes (ATP7B+/-) i.e. carriers) receiving i.v. [64Cu]CuCl2 with radioactivity measured in plasma and feces for up to 96 hours. 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 (HV=1, WD=0 (theoretically), heterozygotes ~0.5). Eight of the 29 parameters were fixed to physiological values, with the remaining estimated using NONMEM (7.4.3). For model validation, an external dataset was available where the plasma ratio of the radioactivity at 48 (or 24) hours over 2 hours was assessed in HV, carriers, and WD patients for diagnostic purposes [1]. Two preclinical studies in WD-mice quantified CP activity and fecal copper excretion as a function of dose, where a hyperbolic equation was used to derive a dose-dependent activity factor (AF): AF=(dose^n)/(dose^n+ED50^n ) Simulations were conducted using campsis [2] to determine the optimal responder criterion based on the 48/2-hour plasma radiocopper ratio. Results: Despite variability in literature data, parameters were estimated with good precision (most RSE <20%). Carriers required separate activity factors for CP-binding (AFcp=0.369) and biliary excretion (AFbil=0.101); a single factor worsened the model fit. 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. The 48/2-hour and 24/2-hour ratios of radiocopper levels in plasma derived from simulations and external observations reported by Czlonkowska et al. [1] were in excellent agreement confirming the validity of the model. Simulations showed that for an AFcp of 0.4 (corresponding to an effective dose in mice based also on transduction level and biomarkers) a 48/2-hour ratio cut-off of 0.4 would correctly identify responders in >80% of the cases. This also matched closely with the diagnostic cut-off value of 0.395 that accurately separated carriers from homozygotes [1]. Conclusion: A mechanistic PBPK model was developed to characterize copper kinetics and ATP7B function. Model simulations were used to define responder criteria for a clinical study with the gene therapy product VTX-801 based on the 48/2-hour radiocopper ratio in plasma.
[1] Czlonkowska, 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]
Reference: PAGE 33 (2025) Abstr 11542 [www.page-meeting.org/?abstract=11542]
Poster: Drug/Disease Modelling - Other Topics