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Principal Investigator: David Richard Light
Organization: ILLEXCOR THERAPEUTICS, LLC
Fiscal Year: 2024
Award: $807,795
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <4-hydroxy-3-methoxybenzaldehyde><ARDS><Acute><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Acute respiratory failure><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Affinity><Airway failure><Aldehydes><American><Amines><Aminoacetic Acid><Animal Model><Animal Models and Related Studies><Animals><Asystole><Binding><Blood gas><Body Tissues><Bolus><Bolus Infusion><Bronchoscopes><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cardiac Arrest><Cardiac Death><Cessation of life><Clinical><Clinical Trials><Continuous Infusion><Critical Care><Critical Illness><Critically Ill><Da Nang Lung><Death><Death Rate><Development><Dissociation><Dose><Drugs><Endotoxins><Event><Exposure to><Extracorporeal Membrane Oxygenation><Family suidae><Gases><Glycine><Goals><Heart><Heart Arrest><Hemoglobin><Histopathology><Hour><Human><Hydrogen Oxide><Hypoxemia><Hypoxia><Hypoxic><IV Infusion><IV bolus><Impairment><Individual><Infusion><Infusion procedures><Injury><Intravenous Bolus><Intravenous infusion procedures><Kidney><Kidney Urinary System><L-Valine><Laboratories><Left><Length of Stay><Life><Liver><Lobe><Lung><Lung Respiratory System><Lung damage><Maintenance><Measures><Mechanical ventilation><Mechanics><Medical><Medication><Modeling><Modern Man><Modernization><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><N-terminal><NH2-terminal><Natural Compound><Neurologic><Neurological><Number of Days in Hospital><O element><O2 element><Organ failure><Outcome><Oxygen><Oxygen Deficiency><Parents><Partial Pressure><Patients><Pharmaceutical Preparations><Pharmacodynamics><Phase><Phase I Study><Pigs><Pimonidazole><Placebo Control><Protocol><Protocols documentation><Randomized><Refractory><Reproducibility><Respiration><Respiratory Failure><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Safety><Schiff Bases><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severities><Shock Lung><Sodium Chloride><Staining method><Stains><Stiff lung><Suidae><Supportive Therapy><Supportive care><Survivors><Swine><Techniques><Therapeutic><Tissue Fixation><Tissues><Titrations><Validation><Valine><Water><Whole Blood><amine><analog><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cost><death risk><developmental><drug/agent><efficacy study><hemodynamics><hepatic body system><hepatic organ system><hospital days><hospital length of stay><hospital stay><hypoxemic><improved><in vivo><indexing><infusions><injuries><innovate><innovation><innovative><intravenous administration><intravenous infusion><lobes><lung injury><lung lobe><mechanic><mechanical><mechanical respiratory assist><mechanically ventilated><model of animal><mortality><mortality rate><mortality ratio><mortality risk><naturally occurring compound><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oxygen transport><parent><pharmacologic><phase 1 study><placebo controlled><porcine><prevent><preventing><primary outcome><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><randomisation><randomization><randomly assigned><renal><respiratory><respiratory mechanism><salt><scale up><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><small molecule><suid><tertiary care><therapeutic candidate><validations><vanillaldehyde><vanillin><ventilation><wet lung>