Novel therapeutic approach for severe ARDS with a potent pharmacologic allosteric hemoglobin modifier

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Acute respiratory distress syndrome (ARDS) is a life-threatening condition featuring acute onset of non- cardiogenic respiratory failure and hypoxemia. Consequently, patients with ARDS have severe hypoxemia due to a significant impairment of gas exchange, and the goal of supportive therapy is to prevent critical tissue hypoxia, which can cause acute cardiac arrest and death or have long-term neurologic consequences for survivors. ARDS affects almost 200,000 individuals annually in the US, leading to >3.5 million hospital days and nearly 75,000 deaths. Despite developments in our understanding of protective ventilation strategies and modern advanced life support techniques, such as extracorporeal membrane oxygenation (ECMO), mortality associated with ARDS remains unacceptably high and has not improved appreciably in two decades. Indeed, the mainstay of supportive therapy in the ICU includes improving arterial oxygen (O2) saturation by introducing supplemental O2 and supporting respiration with mechanical ventilation, but there are limits to the capacity of such measures to benefit patients. In fact, exposure to a high fraction of O2 may actually increase risk for mortality in critically ill patients. Similarly, excessive distention from mechanical ventilation can exacerbate acute lung injury, although the goal of protective lung ventilation is simply to offer mechanical support without inducing harm. Hence, maximal therapy with supplemental O2 and mechanical ventilation is often not sufficient to sustain life until the lungs recover. We propose a novel, paradigm shifting therapeutic strategy using a small molecule drug to enhance supportive care measures and potentially limit the morbidity and mortality of ARDS. Our therapeutic candidate, VZHE-039.glycine salt, a water-soluble synthetic analog of the natural aromatic aldehyde vanillin, is a highly potent allosteric modifier of hemoglobin (Hb) that demonstrated its ability to rapidly and potently increase the capacity of Hb to bind and transport O2 when administered intravenously to pigs. The aromatic aldehyde constituent of VZHE-039 forms reversible Schiff-base interactions with N-terminal valine amines in the α-cleft of Hb to allosterically modify Hb by stabilizing its high O2-affinity state. The result is a rapid, pharmacologic shift in Hb O2 affinity, which can increase the margin of safety to prevent acute desaturation and limit the need for more invasive mechanical ventilation or additional supplemental O2. This novel approach also has the potential to delay or even prevent the need for emergent salvage with ECMO. Our goal is to provide definitive evidence of the potential of this approach by assessing its efficacy in a LPS endotoxin model of severe ARDS in pigs. Following promising results in our Phase I study demonstrating highly reproducible and dose-dependent pharmacodynamics achieving shifts in hemoglobin oxygen affinity, a definitive efficacy study in a high fidelity large animal model would support advancement into a human clinical trial.