Novel Therapeutic Antibody Targeting of Extracellular NAMPT in Ventilator-Induced Lung Injury (VILI)

Mortality rates in intensive care units (ICUs) are unacceptably high and are directly related to the duration of mechanical ventilation that is required to support patients with respiratory failure. For example, acute respiratory distress syndrome (ARDS) is a vexing acute inflammatory lung disease requiring mechanical ventilatory support as the result of severe hypoxemia and respiratory failure. The estimated 200,000 ARDS cases/yr (U.S.) exhibit a mortality rate of 30-40% with ventilator-induced lung injury (VILI), a potent stimulus for lung inflammation and release of multiple inflammatory cytokines (known as cytokine storm), a significant contributor to ARDS severity and mortality. VILI may also ensue in mechanically ventilated patients with respiratory failure in intensive care units (ICUs) even when ARDS is not present. As no clinical therapeutic intervention in the ICU has significantly addressed VILI, there remains a serious unmet need for effective preventive therapies for VILI. Aqualung Therapeutics scientists have identified nicotinamide phosphoribosyltransferase (NAMPT) as a novel upstream therapeutic target in the development of VILI, and have developed human monoclonal antibodies (Fabs or fragment antigen-binding) designed to neutralize circulating extracellular NAMPT (or eNAMPT). Given the lack of approved VILI therapies, ALT seeks to improve ICU outcomes by developing the human monoclonal Fab, eNamptor™, as an innovative strategy to reduce or eliminate VILI, targeting circulating eNAMPT. eNamptor™ will be given prophylactically at the time of intubation in critically ill ICU patients receiving mechanical ventilation, a marked advantage compared with prior ICU strategies. We expect that eNamptor™ will reduce or eliminate VILI incidence and severity, reduce the number of days ICU patients require mechanical ventilation, reduce healthcare costs, and improve ICU survival. With this background, the goal of this STTR Phase I/II Fast Track application is to evaluate NAMPT-neutralizing pegylated and non-pegylated human monoclonal eNamptor™ Fab candidates for efficacy in attenuating eNAMPT-induced NFkB in vitro signaling and preclinical murine VILI in vivo models (STTR Phase I). In addition, we will conduct pharmacokinetic/pharmacodynamic and toxicology studies with lead eNamptor™ Fab candidates in rat and canine models (STTR Phase II). This STTR Phase I/II Fast Track application represents a collaboration between a biotech startup company (Aqualung Therapeutics Corporation), an academic entity (University of Arizona) and a private company (Gennova Biopharmaceutical Ltd.). Together, we will address a serious and important unmet need by validating eNamptor™ as a viable VILI therapeutic approach. We anticipate these efforts will lead to submission of a IND application to the FDA to promote eNamptor™ as a therapeutic strategy for VILI in man.PUBLIC HEALTH RELEVANCE: Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disease (estimated 200,000 cases per year in the United States) with an unacceptable high mortality rate of 30-40%. Mechanical ventilation directly contributes to de novo lung injury in ARDS patients as well as in mechanically ventilated ICU patients with respiratory failure (estimated 700,000 U.S. cases/yr) due to a condition known as ventilator-induced lung injury (VILI). Despite recent advances in care of the critically ill, there remains a need for therapeutic options to address the extremely harmful consequences of VILI. This Fast Track Phase I/II STTR seeks to utilize a novel therapeutic strategy targeting extracellular NAMPT to reduce VILI morbidity and mortality.