(S-091) Use of the Animal Rule to Develop JST-010 for Pre-Exposure Prophylaxis Against Infection by Yersinia pestis

Jessica Roberts – Allucent, LLC; Nathaniel Rill – Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases; Christopher Klimko – Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases; Sergei Biryukov – Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases; Christopher Cote – Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases (USAMRIID); John Atkinson – Atkinson Toxicology Consulting; Kelly Byrnes-Blake – Northwest PK Solutions, LLC; Dennis Miller – Just Evotec, Inc

Objectives: JST-010 is a humanized monoclonal antibody being developed as a medical countermeasure for pre-exposure prophylaxis against infection by Yersinia pestis that results in pneumonic plague. This analysis aimed to develop population pharmacokinetic (popPK) and time-to-event (TTE) models using preclinical data to inform the healthy volunteer pharmacokinetic (PK) dosing paradigm following the animal rule.

Methods: The PK of JST-010 was evaluated in normal (not exposed to Y. pestis) mice via intraperitoneal injection and rats and African Green Monkeys (AGM) via intramuscular injection. PK samples were terminal in mice, staggered sampling in rats, and rich sampling in AGMs. Pharmacology studies were performed in mice exposed to aerosolized Y. pestis for 21-28 days. Monolix was used to develop popPK models in mice, rats, and AGMs to characterize the PK of JST-010. Parametric TTE models (Monolix) were used to characterize survival in mice. JST-010 exposures associated with mouse survival were used to inform human equivalent exposures. First-in-human (FIH) doses were selected based on the no observed adverse effect levels (NOAEL) in rats and AGMs using body surface area and mg/kg approaches. Safety margins for a 60 kg individual were calculated using rat and AGM NOAEL exposures. Simulations were performed (Simulx) to evaluate flat-based dosing or mg/kg dosing paradigms to support the FIH dose selection for the clinical study.

Results: PopPK models in mice indicated a 1-compartment distribution and linear clearance following administration of JST-010. PopPK models in rats and AGMs demonstrated a first-order absorption followed by a 1-compartment (rats) or 2-compartment distribution (AGMs, due to neonatal Fc receptor recycling) and linear clearance. TTE models and subsequent simulations in mice indicated a 125-µg dose was sufficient for survival when administered 18 hours before Y. pestis exposure. This was confirmed by subsequent pharmacology experiments. A higher dose of 200 µg dose was also tested. Human matched exposures based on AGM extrapolation suggested a dose of 23 mg (matching area under the curve [AUC] for 200 µg in mouse) to 248 mg (matching maximal concentration (Cmax) for a 200 µg in mouse) would likely be required for survival. FIH dose projections suggested doses of 70 mg, 140 mg, and 280 mg in healthy adults would be safe based on safety margin calculations for Cmax (ranged from 15- to 4-fold) and AUC (ranged from 9- to 2-fold). Flat based dosing demonstrated similar exposure predictions to mg/kg dosing in 60-80 kg adults.

Conclusions: The proposed FIH doses of 70 mg, 140 mg, and 280 mg for the healthy volunteer study provide an adequate safety margin based on NOAEL exposures in rats and AGM. Human simulations indicate that flat based dosing (70 mg, 140 mg, and 280 mg) and mg/kg dosing (1 mg/kg, 2 mg/kg, and 4 mg/kg) will produce similar exposures without clinically meaningful differences in 60-80 kg individuals, supporting flat based dosing for the FIH clinical study. Furthermore, this dose range is likely to cover exposures required to achieve protection from Y. pestis based on mouse pharmacology studies. AGM survival studies are planned for animal rule extrapolation.

Citations: not applicable

Keywords: Animal Rule, Population Pharmacokinetics, Time-to-Event