15182 Population pharmacokinetic modeling and simulations for GBR 830, a first-in-class humanized monoclonal antibody inhibiting OX40, to support clinical development in patients with moderate to severe atopic dermatitis

Abstract

GBR 830 is a monoclonal antibody against OX40, a costimulatory receptor present on activated T cells that are responsible for effector and memory immune responses. The safety and tolerability of single and repeated administration of GBR 830 has been demonstrated in phase 1 studies with healthy subjects and a phase 2a proof-of-concept study with patients who had moderate to severe atopic dermatitis (AD). To support pharmacokinetic (PK)-based dose selection for clinical development, a population PK model was developed using data from these completed studies (phase 1, PoC), with a total of 120 subjects contributing 1960 observations. Data were modeled employing NONMEM 7.3 using a first-order conditional estimation with interaction method. Intravenous (IV) and subcutaneous (SC) serum profiles were integrated into a 2-compartment model with linear clearance. Covariates (body weight, anti-drug antibody [ADA] status, disease [AD], age, sex, and race) were evaluated graphically before selecting for formal testing. Model parameters included systemic clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volumes, first order absorption from SC injection compartment (KA) and associated between-subject variability (BSV). Body weight was found to be the most important covariate influencing PK, followed by ADA. Final population parameter estimates were derived and model goodness-of-fit was assessed. The predictability was confirmed by prospective simulations of repeat IV infusions. Due to lack of rodent cross-reactivity for GBR 830, or any available surrogate antibody, dose regimen selection for an ongoing phase 2b study (NCT03568162) relied upon PK simulations to achieve a Ctrough that matched human whole-blood receptor occupancy.