Translational population target binding model for the anti-FcRn fragment antibody efgartigimod

Abstract

Efgartigimod is a human IgG1 antibody Fc-fragment that lowers IgG levels through blockade of the neonatal Fc receptor (FcRn) and is being evaluated for the treatment of patients with severe autoimmune diseases mediated by pathogenic IgG autoantibodies. Engineered for increased FcRn affinity at both acidic and physiological pH, efgartigimod can outcompete endogenous IgG binding, preventing FcRn-mediated recycling of IgGs and resulting in increased lysosomal degradation. A population pharmacokinetic-pharmacodynamic (PKPD) model including FcRn binding was developed based on data from two healthy volunteer studies after single and repeated administration of efgartigimod. This model was able to simultaneously describe the serum efgartigimod and total IgG profiles across dose groups, using drug-induced FcRn receptor occupancy as driver of total IgG suppression. The model was expanded to describe the PKPD of efgartigimod in cynomolgus monkeys, rabbits, rats and mice. Most species differences were explainable by including the species-specific in vitro affinity for FcRn binding at pH 7.4 and by allometric scaling of the physiological parameters. In vitro-in vivo scaling proved crucial for translation success: the drug effect was over/underpredicted in rabbits/mice when ignoring the lower/higher binding affinity of efgartigimod for these species versus human, respectively. Given the successful model prediction of the PK and total IgG dynamics across species, it was concluded that the PKPD of efgartigimod can be characterized by target binding. From the model, it is suggested that the initial fast decrease of measurable unbound efgartigimod following dosing is the result of combined clearance of free drug and high affinity target binding, while the relatively slow terminal PK phase reflects release of bound drug from the receptor. High affinity target binding protects the drug from elimination and results in a sustained PD effect characterized by an increase in the IgG degradation rate constant with increasing target receptor occupancy.