PII-220 - RESPONSE TO LYMPHOCYTE DEPLETING AND LYMPHOCYTE MODULATING THERAPIES IN DIFFERENT POPULATIONS OF PATIENTS WITH MULTIPLE SCLEROSIS INVESTIGATED BY QUANTITATIVE SYSTEMS PHARMACOLOGY MODEL

T. Karelina¹, M. Myshkina², O. Demin³; ¹InSysBio CY, ²InSysBio, ³INSYSBIO UK Ltd, Edinburgh, UK.

Background: Therapies targeting B- and T-cells are applied for multiple Sclerosis (MS) patients to deplete cells in the blood or to prevent their migration to CNS and demonstrate significant efficacy for the patients with relapsing remitting MS (RRMS). Inhibition of Bruton’s tyrosine kinase (BTKi) is another promising approach, affecting the activation state of the cells without their depletion, and, in addition, modulating brain resident glial cells, which contribute to pathology, especially at progressive stage. Our goal was to develop systems pharmacology model describing effects of therapies on the MS biomarkers in populations with different stages of MS.

Methods: Model describes the dynamics of B- and T-lymphocytes: proliferation, activation through interaction between B- and T-cells, migration, apoptosis. Migration of cells is linked to BBB leakage and correlates to probability of Gd+ lesions. Model includes activation of glia and its influence on axonal degeneration and appearance of T2 lesions.
The model was calibrated across the data for cell concentrations in plasma and CNS in healthy and MS subjects, data for markers of microglia activation at RRMS and PMS in CSF [1] and their correlation with different types of lesions. PK for natalizumab, rituximab and tolebrutinib (BTKi)[3] was described, in vitro and preclinical data were used to estimate efficacy on T-, B-cells and glia.
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Results: Results. Model describes differences between populations with RRMS and PMS in T2 lesion volumes and CSF GFAP. Model describes efficacy of lymphocyte-depleting therapy on biomarkers in plasma and CSF [2]. Assumption that BTKi prevent activation and so, reduce migration to CNS, accounts for elevation of lymphocyte count in plasma by tolebrutinib [3]. Dose-dependent reduction of T2 lesions volume is predicted to be higher for BTKi inhibitor than for rituximab in PMS population. High variability of response is explained by the variability of T-lymphocyte dynamics in population

Conclusion: The model can be used for prediction of therapy efficacy in different MS populations and to analyze the contribution of different mechanisms to the disease progression.
References
1. Momtazmanesh, et al, (2021). Rev Neurosci, 32(6), 573–595.
2. Piccio et al, (2010) Arch Neurol, 67(6), 707-14.
3. Owens et al, (2022) Clin Transl Sci, (2022), 15(2), 442-450.