(S-049) Understanding PK/PD relationship of CD19 CAR-T (BMS-986353) in Systemic Lupus Erythematosus (SLE) using a mechanistic quantitative pharmacology framework

Huilin Ma – Quantitative Pharmacology and Data Analytics, Translational Medicine and Clinical Pharmacology – Bristol Myers Squibb; Sharmila Das – Clinical Pharmacology, Translational Medicine and Clinical Pharmacology – Bristol Myers Squibb; Ben Knapp – Quantitative Pharmacology and Data Analytics, Translational Medicine and Clinical Pharmacology – Bristol Myers Squibb; Kristin Taylor – Precision Medicine, Bioanalytical and Translational Sciences – Bristol Myers Squibb; Jerill Thorpe – Translational Research CT TRC – Bristol Myers Squibb; Alisha Desai – Early Clinical Development – Bristol Myers Squibb; Alexis Melton – Early Clinical Development – Bristol Myers Squibb; Ashley Koegel – Early Clinical Development – Bristol Myers Squibb; Panagiota Foteinou – Quantitative Pharmacology and Data Analytics, Translational Medicine and Clinical Pharmacology – Bristol Myers Squibb

Objectives: CD19 CAR-T therapy has revolutionized the treatment landscape for B cell-mediated autoimmune diseases [1]. BMS-986353 (CD19 NEX-T) is an investigational CAR-T cell product, which may lead to durable treatment-free responses in severe-and-refractory-to-treatment autoimmune-diseases and is manufactured using the NEX-TTM process. This process shortens manufacturing-times and optimizes CAR-T cell phenotypic attributes. Despite the remarkable efficacy of CD19 CAR-T therapy in autoimmunity [2], the pharmacokinetics (PK) and pharmacodynamics (PD) exhibit complex and often non-linear behaviors, complicating the prediction of therapeutic outcomes and optimal dosing strategies. Quantitative Systems Pharmacology (QSP) modeling offers a powerful framework to address these challenges by integrating mechanistic insights with clinical data to predict the behavior of BMS-986353 under different scenarios. Here we present a case study by applying a clinically calibrated and validated QSP/BMS-986353 framework to explore what if dosing scenarios.

Methods: A mechanistic QSP model was developed to recapitulate key cellular mechanisms of BMS-986353 by integrating relevant emerging clinical PK/PD data to predict clinically meaningful outcomes. The model is multiscale in design, linking dose and PK to mechanism of action/target engagement and downstream PD across multiple biological compartments (plasma, lymph node, spleen and peripheral tissues). During the model development, emerging clinical PK/PD datasets from the ongoing CA061-1001 study in SLE (NCT05869955) were used to calibrate the model including literature-derived parameters. Literature parameters include size and diffusion rates of T and B cells, T - B cell synapse association/dissociation rates, CD19 expression in B cells, CAR expression in T cells and T cell transmigration rates into tissues. Another key aspect of the calibration workflow is the incorporation of variability as seen in the clinical study using our in-house QSP toolbox algorithm. Upon validation, the proposed model was then applied to project dose/exposure and downstream PD under various clinically meaningful scenarios.

Results: A mechanistic QSP framework has been developed for BMS-986353 and successfully calibrated against relevant clinical data. A key feature of this framework is the explicit binding of BMS-986353 to CD19+ B cells, followed by T cell activation, proliferation and downstream effects on cytotoxicity (B cell depletion) and cytokine release (e.g., IL-6, TNF-α). Drug biodistribution is predicted by a customized physiologically based pharmacokinetic (PBPK) model. With regards to application, the model predicts dose dependency in the duration of B cell depletion (≤ 2 cells/µL), with complete depletion (median ≥ 3 months) post-dose for all clinically tested doses. Further analysis indicates saturation of cytokines (for both IL-6 and TNF-alpha) with increasing clinically tested doses which in turn allows for in silico therapeutic window assessment.

Conclusions: A robust multiscale QSP/CD19 CAR-T framework has been successfully implemented to understand better the counter-intuitive PK/PD relationship of BMS-986353 and thereby optimize dosing considerations.

Citations: 1. Mackensen A, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132.
2. Müller F, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med. 2024 Feb 22;390(8):687-700.

Keywords: CD19/CAR-T, SLE, QSP