Background: Obexelimab is a bifunctional, non-cytolytic, humanized monoclonal antibody that binds CD19 and FcγRIIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. Obexelimab has demonstrated the potential to provide clinical benefits across multiple autoimmune disorders.

Objectives: The objectives of this analysis were to 1) develop a population pharmacokinetics (PK) and pharmacodynamics (PD) model of obexelimab from clinical studies following intravenous (IV) or subcutaneous (SC) administration; and 2) conduct simulations using this PK/PD model to support the proposed obexelimab Phase 3 dosing regimen in patients with immunoglobulin G4-related disease (IgG4-RD).

Methods: A population PK/PD model, which described obexelimab serum PK and PD [absolute B cell (ABC) count or CD19 receptor occupancy (RO)] following single and multiple IV or SC administration to healthy subjects, and IV administration to patients with rheumatoid arthritis (RA) or IgG4-RD, was established based on 4 clinical studies: 1) a first-in-human, single-ascending dose study with obexelimab in healthy volunteers (0.03 to 10 mg/kg IV); 2) a multiple-ascending dose study in patients with RA (0.3 to 10 mg/kg IV every other week); 3) an open-label study assessing the effect of obexelimab on disease activity in patients with IgG4-RD (5 mg/kg or 90/180 mg IV every other week); and 4) a PK and relative bioavailability study of obexelimab given IV or SC (125 to 375 mg SC or 250 mg IV every other week or 125 mg SC weekly).

Population PK analyses were performed using nonlinear mixed effects modeling software (NONMEM ^® ). The final population PK/PD model was used to simulate obexelimab PK exposures and changes in ABC counts and in CD19 RO following various SC dosing regimens.

Results: A population PK/PD model was successfully developed which described the PK (concentrations) and PD (both ABC and CD19 RO) of obexelimab following single and multiple IV or SC administration to healthy subjects, and patients with RA or IgG4-RD. The final PK model was a two-compartment model with first-order absorption for SC administration and first-order elimination. The parameters were well estimated with successful model convergence.

Intrinsic and extrinsic subject factors were assessed as covariates in population PK full model development. These covariates included age, gender, and ethnic-related covariates race and body weight. The population PK analysis demonstrated that none of these covariates impacted the PK of obexelimab. The average difference in CL among the race or ethnic groups was <15%.

PK simulation was conducted for weekly SC doses ranging from 15.625 mg to 250 mg. Among all doses, optimal PK was achieved with 250 mg SC weekly. Compared with 5 mg/kg IV Q2W (biweekly) which demonstrated promising clinical efficacy in the IgG4-RD study, 250 mg SC weekly provides comparable total exposure (AUC) or improved trough concentration.

The PD simulation predicts a 250 mg SC weekly dosing will achieve the complete (~100%) CD19 RO and the maximum reduction in ABC count of approximately 50% of baseline during the entire dosing interval. Following discontinuation of the 250 mg SC weekly dosing, approximately 8 and 10 weeks is required for CD19 RO and ABC counts to return to baseline levels, respectively.

Conclusion: The population PK analysis of obexelimab demonstrates the ethnic insensitivity of obexelimab PK. Optimal PK, robust RO and PD following 250 mg SC weekly further supports clinical development of obexelimab to treat B-cell mediated autoimmune diseases.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Xiaodong Wang Holds stock/options in Zenas Biopharma, Employee of Zenas Biopharma, Rachel Kirk Holds stock/options in Zenas Biopharma, Employee of Zenas Biopharma, Hua Mu Holds stock/options in Zenas Biopharma, Employee of Zenas Biopharma, Tanya Fischer Holds stock/options in Zenas Biopharma, Employee of Zenas Biopharma.