Modeling and Simulation in Support of Odronextamab Subcutaneous Dose Selection for Adult Patients with Indolent or Aggressive Non-Hodgkin Lymphoma

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. Phase I (ELM-1; NCT02290951; Bannerji R, et al. Lancet Haematol. 2022;9:e327-39) and II (ELM-2; NCT03888105) studies of intravenous (IV) odronextamab in patients with previously treated CD20-positive B-cell malignancies are ongoing and showed promising efficacy. The IV regimen includes step-up dosing in Cycle 1 with doses of 0.7/4/20 mg administered over 3 weeks (each dose split over 2 days), to mitigate the risk of cytokine release syndrome (CRS). Odronextamab is subsequently administered during Cycles 2-4 at 80 mg once weekly (QW) for indolent non-Hodgkin lymphoma (NHL) and at 160 mg QW for aggressive NHL. For further improvement of tolerability, patient convenience, and reduced hospital resource utilization, subcutaneous (SC) administration of odronextamab is being explored in the ELM-1 study. This analysis, based on modeling and simulation, was performed to determine SC regimens for clinical investigation.

Methods

The analysis included 6 steps: 1) A population pharmacokinetic (PK) model was developed to estimate IV odronextamab PK parameters with observed concentration data from patients with B-cell NHL participating in ELM-1 and ELM-2; 2) A projected absorption rate constant (based on data from Regeneron IgG4-based antibodies) and a projected SC bioavailability parameter (based on a study of SC odronextamab in cynomolgus monkeys) were added for the model to be used for SC PK profile simulation; 3) An exposure-response analysis was performed to identify target exposure parameters for clinical efficacy with IV regimens in patients with indolent and aggressive NHL; 4) SC PK profiles were simulated to identify regimens achieving target exposures for efficacy without exceeding maximum concentration (C_max) of the highest evaluated IV doses; 5) A quantitative systems pharmacology (QSP) model was developed to predict interleukin (IL)-6 profiles following SC step-up dosing (Toroghi MK. ASCPT 2021. Poster PIV-051); and 6) Odronextamab SC regimens were simulated for selection of those with IL-6 levels not predicted to exceed those of IV regimens.

Results

Based on the modeling and simulation results, the proposed SC regimen selected for step-up dosing was 2/26/100 mg in Cycle 1 (no split dosing) for both indolent and aggressive NHL. The simulated median C_max during the first week was lower with 2 mg SC than with 0.7 mg IV with split dosing (0.2/0.5 mg). The predicted time to C_max was ~4 days with SC, much later than with IV (where C_max occurs near the end of the infusion). A longer time to C_max may reduce the risk of CRS, which mostly occurs within 1-2 days after split-dose IV administration. The proposed SC dose is 400 mg every 3 weeks (Q3W) after Cycle 1 for indolent NHL, and 400 mg QW in Cycle 2 and 400 mg Q3W after Cycle 2 for aggressive NHL. Additional SC regimens for indolent and aggressive NHL were proposed for testing in ELM-1, to enable optimization based on clinical observations.

According to the simulation results, the proposed SC regimens maintain the required efficacious odronextamab concentrations over the initial 4 cycles of treatment when most tumor responses are expected to occur. Simulated IL-6 profiles, obtained using the SC QSP model, showed the peak IL-6 values during Cycle 1 with the proposed SC step-up dosing regimen (2/26/100 mg) would not exceed those of 0.7/4/20 mg IV.

Conclusion

SC administration of odronextamab may be simpler and more convenient than IV dosing. PK and IL-6 modeling and simulation analyses enabled the identification of SC regimens for clinical evaluation, which may improve the tolerability while preserving the efficacy for the treatment of patients with B-cell NHL.

Zhu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Khaksar Toroghi:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Yan:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Davis:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.

Odronextamab for the treatment of patients with B-cell non-Hodgkin lymphoma.