ABSTRACT
Background. ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods. The QSP model was fit inNONMEMVersion 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE;N=659, IM) and treatment (STAMP;N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/ pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results. The QSP model provided an excellent fit to serum ADI concentrationtime data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion. This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants.
ABSTRACT
Background. ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential and an extended half-life. ADG20 is administered intramuscularly (IM). A QSP/PBPK model was constructed to support dose selection for a Phase 2/3 trial of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Methods. A QSP/PBPK model was used to simulate receptor occupancy (RO) and drug exposure in the upper airway (nasopharyngeal/oropharyngeal epithelial lining fluid [ELF] compartment). RO was linked to an existing viral dynamic model to enable the prediction of the natural time course of viral load and the effect of ADG20 on viral clearance and infectivity rate. RO was calculated using: 1) in vitro ADG20-SARS-CoV-2 binding kinetics (association rate constant (kon) of 1.52E+06 M-1•s1 and dissociation rate constant (koff) of 2.81E-04 s-1 from a Biacore assay;2) time course of ADG20 concentrations in ELF;and 3) time course of viral load following ADG20 administration. Molar SARS-CoV-2 viral binding site capacity was calculated assuming 40 spike proteins per virion, 3 binding sites per spike, and an initial viral load of log 107 copies/mL for all patients. The QSP/PBPK model and a 2018 CDC reference body weight distribution (45-150 kg) were used to simulate 1000 concentration-time profiles for a range of candidate ADG20 regimens. ADG20 regimens were evaluated against 2 criteria: 1) ability to attain near complete ( >90%), and durable (28-day) SARS-CoV-2 RO in the ELF;and 2) ability to maintain ELF ADG20 concentrations relative to a concentration (0.5 mg/L) associated with 100% viral growth suppression in an in vitro post-infection assay. Results. A single 300 mg IM ADG20 dose met the dose selection criteria in terms of RO (Figure A) and viral growth suppression (Figure B). Conclusion. These data support the evaluation of an ADG20 300 mg IM dose for the treatment of mild to moderate COVID-19. ADG20 is forecasted to attain near complete ( >90%) SARS-CoV-2 RO in the ELF and maintain ELF ADG20 concentrations above that associated with 100% viral growth suppression in vitro.