Use Of Computed Tomography (Ct) Scan To Assess Efficacy Of Mitigators Of Radiation-Induced Lung Injury (Rili): A Rhesus Macaque Whole-Thoracic Lung Irradiation (Wtli) Model

Screening medical countermeasures (MCM) against radiation injury requires identification of suitable early end-points. Using AEOL 10150, a catalytic anti-oxidant agent with known effects as a mitigator of RILI, we evaluated the utility of CT scan as a screening tool for assessing drug effect. Nonhuman primates (NHP, male, rhesus macaque) were exposed to an approximate LD 70/180d WTLI on D0 (6MV photons, 10.74 Gy to midplane @ 0.80 Gy/min). AEOL 1050 (5mg/kg) was administered SC, daily, D1-60. Longitudinal, non-contrast enhanced chest CT scans were obtained at baseline and D30-180 at 30±5 day intervals. Based on clinical signs of radiation toxicity, all animals (saline control = 20, AEOL 10150 test article = 20) received medical management including dexamethasone over the 180-d in-life phase. A proprietary treatment planning system was used to estimate RILI using two quantitative methods. A fixed cut-off (FCO) method identified areas of pneumonitis/fibrosis (PF) based on CT Hounsfield units (HU) range ≥ -200. An individualized cut-off (ICO) method was used to segment total lung volume (TLV) into low-density (LD), mid-density (MD) and high-density (HD) regions using two HU cut-offs (baseline scan’s mean TLV HU + 1 SD and HU = 0). AEOL 10150 improved post-WTLI 180-day survival from 25% to 50% (p = 0.042). Non-sedated breathing rate between the two cohorts was not different while sedated SpO2 was marginally lower in the control cohort from D60-D180. Mean PF volume was higher in the AEOL 10150 cohort relative to control at D30 (5.5 vs 2.4 cc) but lower at D90 (8.4 vs 13 cc), D120 (8 vs 18 cc) and D180 (11.7 vs 13 cc) suggesting a delayed effect. When evaluating segmental sub-volumes in the control cohort, mean LD HU showed predominantly an acute (D30) rise while mean MD HU showed a gradual delayed increase (D60-120), likely representing changes of acute and delayed RILI. The mean MD HU of AEOL 10150 cohort was lower than the control cohort at D90-120 but without impact on the acute changes in mean LD HU. Significant deaths in the control cohort and the potential impact of dexamethasone support preclude a robust statistical analysis. This comprehensive analysis of CT parameters in NHP exposed to LD70/180 WTLI notes distinct trends of RILI in the different sub-volumes of lung. Differential response between control and test cohorts using a known mitigator, AEOL 10150, validates the utility of CT scan as a MCM screening tool. D120 CT scan showed maximal differential impact of AEOL 10150 response and may provide an opportunity for quicker and more economical conduct of screening studies for testing mitigators of RILI. Support provided by Aeolus Pharmaceuticals, Inc. under Biomedical Advanced Research and Development Authority (BARDA) contract HHSO100201100007C.