(W-060) Quantitative systems pharmacology model for distinguishing efficacy of anti-CD20 therapy variants in populations of Multiple Sclerosis patients
Tatiana Karelina, PhD: No financial relationships to disclose
Oleg Demin Jr: No financial relationships to disclose
Objectives: Multiple Sclerosis (MS) is a chronic neurological disease characterized by the presence of demyelinated lesions in the central nervous system (CNS). Migration of T- and B-cells across the disrupted blood-brain barrier (BBB) from peripheral blood (PB) to CNS initiates the immune reaction to myelin and leads to inflammation, demyelination and neurodegeneration [1]. Anti-CD20 antibodies are considered to be a promising approach in MS treatment, mediating apoptosis of CD20+ cells B-cells [2]. However, it is not exactly clear how observed depletion of B-cells in plasma affects processes in CNS. Goal of our quantitative systems pharmacology model was to describe an influence of B-cell targeting therapy on the cell populations in the brain and markers of disease progression in patients at different stages of MS.
Methods: The model incorporates processes related to different populations of T- and B-cells, including activation, migration through the BBB, proliferation in PB and CNS, and accumulation in the CNS with disease progression. Influence of B-cells on oligodendrocytes, microglia and T-cells is also described. The model was calibrated using data from healthy individuals and patients at different stages of MS: levels of T- and B-cells populations in PB and CNS, microglia and oligodendrocytes in lesions, concentration of activation markers in cerebrospinal fluid (CSF), brain atrophy rate. Datasets on cell interaction from in vitro studies were also used to retrieve some of the model parameters. Pharmacokinetic models for Rituximab and Ocrelizumab were calibrated on available data. The effects of these drugs were calibrated using in vitro, preclinical mouse and clinical human data.
Results: The model describes the dynamics of demyelination in patients with RRMS and SPMS. The difference between these patients is driven by the increase in proportion of proinflammatory microglia and its contribution to demyelination. Variability of influx of peripheral cell into CNS (limited by cell count data) appeared to be sufficient to describe much higher variability in the rate of MS progression. Model captures the dynamics of B-cell populations in patients at different stages of MS after anti-CD20 therapy: after initiation of a treatment there is a rapid depletion of B-cells with consequent gradual repletion. Model captures the reduction of microglia activation and change in T2 lesion volume (T2V) in these groups. Ocrelizumab is predicted to be more effective in decreasing T2V in comparison to Rituximab, due to higher microglia deactivation, explained by more efficient B-cell depletion. This difference is reproduced both in RRMS and SPMS patients. Efficacy in SPMS patients is lower, due to remaining significant microglial-dependent demyelination independent of B-cell contribution.
Conclusions: The model can be used for further exploration of effects and interpretation of distinct efficacy of variants of anti-CD20 therapy at different stages of MS.
