The primary endpoints in these studies were survival and blood oxygen saturation. Secondary endpoints included clinical scores, blood gas and histopathology for cast formations. AEOL 10150 or PBS was given to rats one hour after sulfur mustard vapor exposure and repeated every 4 or 8 hours. Forty-eight hours after exposure, lung edema was assessed by changes in the bronchoalveolar lavage (BAL) protein levels. At euthanasia, 48 hours after exposure, AEOL 10150 significantly improved (p < 0.0001) pulse oximetry, and AEOL 10150 treated rats had improved blood oxygenation throughout the study period. AEOL 10150 reduced clinical scoring of respiratory quality and activity by more than 60% at the time of euthanasia (p < 0.005), and improved clinical scores were seen throughout the study period. Treatment with AEOL 10150 also restored blood gas parameters to near normal levels, including: pO2 (p < 0.001), pCO2 (p < 0.0016) and pH (p < 0.0006). Finally, AEOL 10150 treatment reduced airway cast formation by 50% at 24 hours (p < 0.017).
In prior studies AEOL 10150 reduced lung edema (p < 0.05), decreased SM-induced increases in macrophages (p < 0.05) and epithelial cells in BAL fluid (p < 0.05). In all three measurements AEOL 10150 provided approximately 100 percent protection -- with levels approximating that of the control animals in the study. These results indicate that AEOL 10150 significantly improves survival and attenuates lung injury from mustard gas exposure and may provide an effective countermeasure against mustard gas-induced lung injury.
"This study confirms AEOL 10150's potential as an effective countermeasure for mustard gas exposure. Given the dramatic improvements in survival and reductions in lung damage that we have seen in this and former studies, Aeolus plans to meet with the FDA to discuss the design of a pivotal study in rats, and an appropriate second species to satisfy the requirements for approval under the animal rule," stated John L. McManus, President and Chief Executive Officer of Aeolus Pharmaceuticals, Inc. "We are also grateful to NIH CounterACT for their support of this program, and to Dr. Day and Dr. Carl White, who have provided great leadership to this program."
CounterACT Center of Excellence
In 2011, the NIH, through its Countermeasures Against Chemical Threats Research Network (CounterACT) awarded a five-year, $12.7 million grant to Carl White, MD and Brian Day, PhD of the University of Colorado Anschutz Medical Campus and National Jewish Health, both in Denver, Colorado. The grant was awarded to continue the development of AEOL 10150 as a medical countermeasure (MCM) against mustard gas exposure (lung and skin) and chlorine gas exposure (lung). Also included in the grant is support of research looking at tissue plasminogen activator (TPA) and Silabilin as MCMs against sulfur mustard gas exposure.
Potential for AEOL 10150 as a Countermeasure Against Chemical Threats
AEOL 10150 has shown significant protective effects against radiation, mustard gas, chlorine gas, phosgene gas and nerve agents in animal models. A compound with the potential to protect against multiple threats would be of significant benefit in both the military and civilian efforts to protect citizens against potential threats. The United States Food and Drug Administration (FDA) has a special "Animal Rule" under which compounds may be approved for use against chemical and nuclear threats on the strength of animal efficacy studies, which allows the potential for an accelerated approval path versus conventional pharmaceutical applications.
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