1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models

Abstract

BackgroundExebacase (CF-301) is a novel lysin with rapid bacteriolytic and anti-biofilm activity against S. aureus, pronounced synergy with antibiotics and low propensity for resistance. Exebacase has undergone Phase 1–2 trials. This work was to develop pharmacokinetic (PK) model in animal and determine the relationship between exebacase exposure and efficacy in animals.MethodsPK data in 592 animals (4 species) included in population PK model. A range of linear and nonlinear mammillary models with allometric scaling fitted to the PK data using NONMEM and the most parsimonious model was selected by improvement in objective function value (P < 0.01). To evaluate efficacy, 349 animals with 177 mice (neutropenic thigh infection) and 172 rabbits (aortic valve infective endocarditis were treated with exebacase in addition to suboptimal doses of daptomycin (DAP). Full PK profiles were simulated for individual animals. Fifty-nine dosing regimens of exebacase in mice (0–90 mg/kg) and 18 regimens in rabbits (0–1.4 mg/kg) with q24h, q12h and q8h frequencies. Relationship between AUC/MIC, Cmax/MIC, T> MIC, and log-CFU was examined using a range of functions by comparing residual standard error (RSE).Results3-compartment model with allometric scaling best described the PK data and was validated by bootstrap and Goodness of Fit. Maximum drop in log10CFU/g in target tissues was at AUC/MIC< 0.2 for exebacase when added to DAP that was associated with CF reduction of -5 logs in rabbits (Figure (a)) with similar magnitudes in cardiac vegetations, kidney and spleen, and -4 logs in mice (Figure (b)). Treatment with DAP alone had log10CFU reduction of -1 in mice; and -2 in rabbits. AUC/MIC was an appropriate predictor of CFU reductions.ConclusionPK model adequately described the data for 4 animal species. Exebacase addition to DAP has a synergistic effect on efficacy measured by CFU reductions in target tissues in the animal models. Results support previously presented determinations of AUC/MIC as predictor of efficacy. Maximum reductions in CFU in rabbits and mice were observed at AUC/MIC ratios <0.2. These results further indicate that rabbit is the most appropriate efficacy model with MICs and antibacterial activity reflective of previously reported observations in human serum. Disclosures All authors: No reported disclosures.

Synergistic Activity of Exebacase (CF-301) in Addition to Daptomycin against Staphylococcus aureus in a Neutropenic Murine Thigh Infection Model

“…1. Overall, varying the exebacase dosing frequency had no impact on efficacy, as shown in Table 2, consistent with AUC/MIC being the pharmacodynamic driver of exebacase efficacy (12). The results of our in vivo study support reports demonstrating exebacase synergistic activity (13)(14)(15).…”