Julia Lund 1, Anna Lundahl 1, Pablo Forte Soto 2, Gerben Bouma 3, Steven Eck 4, Anna Strömbeck 1, Michael Eberhardson 1, David Bock 1, Daniel J.B. Marks 3, Joachim Almquist 1
1 AstraZeneca, Biopharmaceuticals R&D (Gothenburg, Sweden), 2 Parexel Early Phase Clinical Unit (London, United Kingdom), 3 AstraZeneca, Biopharmaceuticals R&D (Cambridge, United Kingdom), 4 AstraZeneca, Biopharmaceuticals R&D (Gaithersburg, United States)
Introduction
AZD7798 is a CCR9+ T-cell-depleting monoclonal antibody, recently evaluated in a first-time-in-human study and in development for treatment of chronic inflammation in Crohn’s disease. Following administration of AZD7798, rapid, complete, and sustained CCR9+ T-cell depletion in blood was observed across all doses and participants.
Objectives
The main objective of this study was to develop a popPKPD model to describe the impact of AZD7798 on CCR9+ T-cell dynamics in blood and the target tissue (gut).
Methods
The first-time-in-human study (NCT05452304) included 12 single-dose cohorts and 1 multiple dose cohort where PK and PD (CCR9+ T-cell depletion in blood) were measured for at least 85 days after dosing. A popPKPD model was developed sequentially with a dataset including in total 758 PK observations and 1302 PD observations. Using the developed popPKPD model, simulations were performed to compare depletion patterns for different dosing regimens. NONMEM (version 7.4.4 (ICON, Hanover, MD, USA)) was used for modeling and simulations, and R (version 4.1.3) was used for post processing.
Results
The PK of AZD7798 was described by a two-compartment disposition model with first-order absorption. Body weight was included as a covariate with fixed allometric exponents (i.e., 0.75 for clearances, 1 for volumes) and inter-individual variability was included on the main PK parameters.
Another two-compartment model was developed for PD, to characterize the migration of CCR9+ memory T cells between blood (central compartment) and tissue including the gut (peripheral compartment). It was assumed that AZD7798-mediated cell depletion only occurred in blood, which was described by a turn-over model with a stimulatory effect on kout.
The PD was characterized by a continuous influx and efflux of cells between the systemic circulation and the gut. The estimated half-life of CCR9+ T-cell degradation in the absence of AZD7798 was 270 days [RSE 17%]). The migration from tissue to blood was estimated to be much slower (12 days [RSE 9%]) in comparison to the opposite direction (0.14 days [RSE 9%]), as expected for these gut-homing cells. In the absence of AZD7798, the net flux of cells between the two compartments was zero, but in presence of AZD7798 the depletion of cells in the blood was heavily accelerated (Emax 2.4×104 [RSE 22%], EC50 0.056 mg/L [RSE 18%]), consistent with the observed complete and rapid depletion already at low doses.
The developed popPKPD model characterized PK data and the AZD7798-mediated depletion of CCR9+ T cells well for all cohorts. Simulation of depletion in blood and tissue following repeated dosing showed that it takes up to 12 weeks of treatment for steady-state depletion to occur in both blood and peripheral tissue. Since it was assumed in the model that depletion can only occur in the central compartment, the rate-limiting step of depletion in gut becomes the slow re-migration to blood.
To maintain the blood-to-gut cell gradient until full gut-depletion is achieved, it can be hypothesized that AZD7798 exposure in circulation needs to exceed a certain threshold long after blood-depletion is complete.
Conclusion
The developed popPKPD model from the first-time-in-human study was able to capture the fast onset, slow return to baseline, and the variability observed in the data. Simulations indicate that a dosing regimen achieving stable PK concentrations over time is key for stable CCR9+ T-cell suppression in the gut. The popPKPD model will be used to guide dose selection in the development program, and data from ongoing clinical studies will be used to confirm the predictability of cell depletion in blood and tissue.
Reference: PAGE 34 (2026) Abstr 11903 [www.page-meeting.org/?abstract=11903]
Poster: Drug/Disease Modelling - Other Topics