Evaluate Dynamics of IL-6 Release during Step-up Dosing of Subcutaneous Administration of Odronextamab Via a Quantitative Systems Pharmacology Modeling Approach

Abstract

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. T-cell activation following odronextamab administration can result in a transient but clinically significant increase in circulating cytokine concentrations. This may lead to cytokine release syndrome (CRS), one of the most important safety concerns with T-cell engaging therapies. As most cytokine release occurs during the early weeks of treatment, a step-up dosing strategy prior to administration of a full treatment dose appears to be a successful strategy to mitigate the level of cytokine release and attenuate the occurrence of CRS. This study was performed to evaluate interleukin (IL)-6 profiles following odronextamab subcutaneous (SC) injection during Cycle 1 step-up dosing (Weeks 1-3) in patients with B-cell non-Hodgkin lymphoma (B-NHL). A quantitative systems pharmacology (QSP) model, which is an emerging mathematical modeling approach that can help improve our understanding of drug-disease interactions and can be used to evaluate hypothetical scenarios in preclinical and clinical settings, was developed and applied to identify SC step-up doses of odronextamab suitable for investigating in clinical studies. Methods A QSP model that can describe IL-6 profiles (a surrogate cytokine associated with CRS) following intravenous (IV) odronextamab was previously developed and calibrated using pharmacodynamic data from the Phase I ELM-1 study (NCT02290951; Toroghi MK. ACoP11 2020. Poster TUE-054). The IV QSP model was updated by adding relevant components (e.g. drug absorption compartment, lymph node compartment) to enable the description of IL-6 profiles following SC administration of odronextamab. Model parameters were calibrated using IL-6 concentration data of other CD20×CD3 bispecific antibodies under SC administration reported in the literature (Matasar M. ASH 2020. Poster 2096). Odronextamab SC step-up doses of interest were proposed and IL-6 profiles of these regimens were simulated with the SC QSP model. In each dosing scenario, IL-6 profiles were simulated in 300 virtual patients. The cytokine release criterion for regimen selection was that the peak IL-6 concentrations of a SC step-up regimen should be lower than peak IL-6 concentrations observed with the previously tested IV regimens. Results Simulation results indicated that the predicted IL-6 profiles were similar with or without split dosing; the former was effectively used in the IV regimen for management of CRS. The predicted highest peak IL-6 value in Week 1 with SC dose of 2 mg was considerably lower than that of IV dosing of 0.7 mg (split 0.2 mg and 0.5 mg over 2 days in Week 1). The predicted highest IL-6 concentration with 2 mg SC was 150 pg/mL and that for 0.7 mg IV was 2,100 pg/mL, indicating a reduction of more than 90%. The predicted IL-6 profiles in Week 4 were similar with 160 mg IV or 400 mg SC doses. Based on the comparison of IL-6 profiles of multiple SC dosing scenarios, SC step-up doses of 2 mg in Week 1, 26 mg in Week 2, and 100 mg in Week 3 were selected, followed by a full dose of 400 mg. The proposed SC regimen is being tested in the clinical study ELM-1 for safety and efficacy evaluations. Conclusion The QSP modeling supported the selection of the odronextamab SC step-up dosing regimen to be evaluated in a clinical study in patients with B-NHL. The selected step-up regimen for SC odronextamab allows adequate step-up to effective therapeutic doses while simplifying and improving overall convenience. The simulations suggest that no split dosing is necessary for SC administration, which may further reduce overall hospital resource burden and requirements for in-patient monitoring.