PARS inhibitor therapy for smoke inhalation

DESCRIPTION (provided by applicant): Smoke inhalation is a major co-morbid factor in thermal injury. Therapy of smoke inhalation is supportive -there are no specific countermeasures to protect the lung from injury. We report the discovery that a nuclear cell death mechanism, mediated by poly (ADP-ribose) polymerase (PARP), accounts for the acute lung injury and inflammation in a classic ovine smoke inhalation and burn injury model. In Phase I, we tested our novel ultrapotent PARP inhibitor, INO-1001, and observed a dramatic reduction in lung injury: INO-1001 markedly increased the PaO2/FiO2 (PF) ratio and decreased neutrophil infiltration, wet-to-dry ratio, and lung lymph flow. In sheep challenged with smoke inhalation and Pseudomonal pneumonia, INO-1001 significantly increased the PF ratio and decreased peak airway pressure and pulmonary shunt fraction. The central objective of this Phase 2 SBIR is to establish the pathogenetic role of PARP activation in clinical smoke inhalation injury. We will utilize a prospective, randomized, double-blinded study of PARP inhibition in 200 patients admitted with acute smoke inhalation. Enrollment will include patients with all of the following characteristics: 1) thermal injury 20% BSA, 3) evidence of smoke inhalation (as evidenced by a majority of the following criteria: carboxyhemoglobin measured or back extrapolated > 40 % at the scene of trauma, carbonaceous sputum, an early decrease in PF ratio, blood tinged endotracheal secretions, or blackened bronchi by bronchoscopic exam), and 4) clinical judgment by the patient's physician that there is a high probability that the duration of mechanical ventilation will exceed 7 days. The clinical study will be conducted in 14 U.S. institutions with demonstrated clinical and research leadership in critical care of smoke inhalation injury. Administration of INO-1001 will be initiated prior to the onset of severe respiratory failure and continued for 5 days, the critical period of smoke inhalation induced pulmonary inflammation and respiratory insufficiency. Three primary clinical endpoints will be evaluated: 1) PF ratio, 2) duration of mechanical ventilation, and 3) dynamic pulmonary compliance, and an additional secondary endpoint, mortality, will be followed. The proposed clinical trial is expected to provide the foundation for FDA orphan drug approval of INO-1001 for treatment of acute smoke inhalation injury.