ARF6 Inhibitors for Treatment of Acute Lung Injury

项目总结

PROJECT SUMMARY Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result from a common pathogenic process: pulmonary injury or infection triggers an overwhelming inflammatory response (“cytokine storm”) that results in increased endothelial and epithelial permeability and efflux of inflammatory cells, protein, and water from the vascular system into the alveolar space. The further release of inflammatory agents from damaged lung tissue often triggers systemic inflammatory response syndrome (SIRS) and end organ failure, the main cause of death in ALI/ARDS. ALI and ARDS are precipitated by diverse etiologies including aspiration, inhalation injury, bacterial and viral pneumonias, trauma, burn injury, blood transfusion, sepsis, and other factors. In fact, biologic and chemical warfare agents are often selected for their ability to cause the devastating effects of ALI/ARDS. The incidence of ALI is estimated to be approximately 79 cases per 100,000 person-years. Improvements in outcome have come about over the past decade due to improved strategies of mechanical ventilation and advances in general supportive measures. Unfortunately, even today, the treatment for those afflicted remains largely supportive with a mortality rate of approximately 40%. Navigen’s objective is to develop a small molecule ARF6 inhibitor as a treatment for ALI/ARDS. In Phase I, we presented ARF6 as a target for treatment of ALI/ARDS, and we shared data establishing the potential therapeutic value of inhibiting ARF6 to treat ALI/ARDS. The specific aims of our Phase I application were to identify a number of ARF6 inhibitors with required potency and solubility, to characterize the pharmacokinetic (PK) properties of a small number of these compounds, and to obtain convincing in vivo proof-of-concept efficacy in a mouse model of LPS-induced ALI, exploring both dose-response relationships and time-of-treatment effects. We accomplished these goals and identified five compounds of interest. Since submitting our Phase II application in January, 2016, we have made significant progress and have identified a lead candidate, NAV-5093, to carry forward into Phase II. NAV-5093 is a water-soluble lysine prodrug (dihydrochloride salt) of NAV-4424, itself one of the leading 5 candidates identified in Phase I. NAV-5093 has the advantage of high water solubility, making it amenable to formulation for intravenous (IV) administration in the hospital setting for treatment of ALI/ARDS. NAV-5093 is cleaved rapidly to release parent NAV-4424 in vivo, and is effective in the mouse model of LPS- induced ALI as well as in Acinetobacter baumannii (AB)-induced pneumonia in neutropenic mice. Over the next two years in Phase II, we propose to accomplish the following: (1) demonstrate efficacy of NAV-5093 in two rat models of ALI using accepted outcome measures, (2) characterize the in vitro ADME and in vivo PK properties of NAV-5093, (3) conduct initial toxicity studies of NAV-5093 in rats, (4) manufacture NAV-5093 and optimize an aqueous formulation of NAV-5093 for IV administration, and (5) hold a pre-IND meeting with the FDA.