Novel therapeutic approach for severe ARDS with a potent pharmacologic allosteric hemoglobin modifier - 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, TD-7, a synthetic analog of the natural aromatic aldehyde vanillin, is a highly potent, short acting
allosteric modifier of hemoglobin (Hb) that increases the capacity of Hb to bind and transport O2 by stabilizing its
quaternary structure in a high O2-affinity state. This pharmacologic effect can improve the margin of safety by
increasing O2 saturation at critical PO2 levels and prevent acute desaturation events without requiring more
invasive mechanical ventilation or additional supplemental O2. This intervention also has the potential to delay
or even prevent the need for emergent ECMO. Importantly, preliminary evidence for this approach demonstrates
that improvements in arterial O2 saturation with high Hb O2 affinity do not compromise tissue O2 unloading and,
instead, effectively reduce tissue hypoxia during an ARDS insult. While preliminary studies establish aromatic
aldehyde-containing compounds, such as TD-7, as a promising clinical approach to ARDS, our ultimate goal is
to provide definitive evidence of efficacy in a high fidelity porcine ARDS model to support advancement of this
drug candidate to human clinical trials. This will be achieved in a step-wise approach: first, with the optimization
of intravenous formulation and delivery of TD-7 to achieve targeted in vivo pharmacodynamic effects (‘dose-
finding’) in mini-pigs in Phase I, and subsequently, with the performance of a definitive efficacy study to assess
oxygenation and prevention of tissue hypoxia in a porcine ARDS model in Phase II.
