Sharvari Bhagwat, PhD: No relevant disclosure to display
Introduction: IgG is the most abundant immunoglobulin and the most prevalent autoantibody isotype. In autoimmune diseases such as Myasthenia Gravis (MG), pathogenic autoantibodies, including IgG, bind endogenous self-proteins and impair functionality or cause toxicity. FcRn inhibitors efficiently and profoundly reduce serum IgG levels in clinical settings. Reduced serum IgG levels strongly correlate with reduced pathogenic autoantibodies and disease improvement1. However, IgG-based FcRn inhibitors drive accelerated clearance of self.
INBRX-140 is engineered as a highly selective FcRn inhibitor that exploits albumin binding for FcRn-mediated recycling to reduce dosing frequency and improve patient outcomes.
Objectives: The pharmacokinetics (PK) of INBRX-140 and the relationship between INBRX-140 dosing and serum IgG levels in cynomolgus monkeys were explored. Simulations were conducted to predict steady-state exposures in humans and determine the appropriate dosing regimens that would enable target IgG depletion over the dosing period.
Methods: The PK of INBRX-140 in cynomolgus monkeys and corresponding IgG levels were characterized following single or multiple (two doses given three weeks apart) doses of 0.2, 2, 20, 40, 70, or 100 mg/kg via IV infusion or subcutaneous injection. Compartmental modeling of serum INBRX-140 PK and IgG data was performed. The PK-PD model parameters were translated appropriately to obtain human PK-PD parameter estimates. Standard allometric scaling protocols and literature-based calibrations were used to obtain a range of human PK parameters.
The human parameter estimates were used to simulate steady-state IgG levels at various doses and regimens to estimate a suitable dose that would maintain adequate IgG depletion when administered monthly.
Results: INBRX-140 PK increased with dose across the dose range of 0.2 to 100 mg/kg following IV infusion of INBRX-140. The concentration-time profiles indicated target-mediated drug disposition (TMDD). A 2-compartment PK model with linear and target-mediated clearance was used to describe the data. The simultaneous fitting of PK and IgG data adequately described IgG levels.
Concentration-time profiles of INBRX-140 and IgG were simulated at various doses using the range of estimated human parameters.
Conclusions: The prolonged systemic half-life of INBRX-140 enables dosing on a once-every-four-week schedule while reducing IgG levels. Simulated IgG profiles were used to identify doses and regimens required to achieve target IgG depletion.
Citations: [1] Patel DD, Bussel JB. Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention. J Allergy Clin Immunol. 2020 Sep;146(3):467-478. doi: 10.1016/j.jaci.2020.07.015. PMID: 32896307.
