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

使用有效的药理变构血红蛋白调节剂治疗严重急性呼吸窘迫综合征的新方法

基本信息

批准号：
10697249
负责人：
David Richard Light
金额：
$ 74.56万
依托单位：
ILLEXCOR THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10697249
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Acute respiratory failure Affect Affinity Aldehydes American Amines Animal Model Animals Binding Blood gas Bolus Infusion Bronchoscopes COVID-19 pandemic Cardiac Death Cessation of life Clinical Clinical Trials Continuous Infusion Critical Care Critical Illness Development Dissociation Dose Endotoxins Event Exposure to Extracorporeal Membrane Oxygenation Family suidae Gases Glycine Goals Heart Heart Arrest Hemoglobin Histopathology Hour Human Hypoxemia Hypoxia Impairment Individual Infusion procedures Injury Intravenous Bolus Intravenous infusion procedures Kidney Laboratories Left Length of Stay Life Liver Lobe Lung Maintenance Measures Mechanical ventilation Mechanics Medical Modeling Modernization Monitor Morbidity - disease rate N-terminal Natural Compound Neurologic Organ failure Outcome Oxygen Parents Partial Pressure Patients Pharmaceutical Preparations Pharmacodynamics Phase Pimonidazole Placebo Control Protocols documentation Randomized Refractory Reproducibility Respiration Respiratory Failure Safety Schiff Bases Severities Sodium Chloride Stains Supportive care Survivors Techniques Therapeutic Tissue Fixation Tissues Titrations Validation Valine Water Whole Blood analog cost efficacy study hemodynamics improved in vivo indexing innovation intravenous administration lung injury lung lobe mortality mortality risk novel novel strategies novel therapeutic intervention novel therapeutics oxygen transport pharmacologic phase 1 study prevent primary outcome respiratory scale up small molecule tertiary care therapeutic candidate vanillin ventilation

项目摘要

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.

急性呼吸窘迫综合征（ARDS）是一种威胁生命的疾病心源性呼吸衰竭和低氧血症。因此，ARD患者患有严重的低氧血症气体交换的重大损害，支持治疗的目的是防止关键组织缺氧，可能导致急性心脏骤停和死亡或对幸存者。在美国，ARDS每年影响近20万人，导致350万医院的日子和近75,000人死亡。尽管我们对保护性通风策略和现代的了解有所发展先进的生命支持技术，例如体外膜氧合（ECMO），死亡率相关 ARDS仍然无法接受，并且在二十年中没有得到更多的欣赏。的确，主要是中流台 ICU支持疗法的支持包括提高动脉氧（O2）的满意度 O2并通过机械通气支持呼吸，但是这种措施的能力有限使患者受益。实际上，暴露于高度的O2实际上可能会增加重病死亡率的风险患者。同样，与机械通气的距离超过距离可能会加剧急性肺损伤，尽管保护性肺通风的目的只是提供机械支撑而不会引起损害。因此，在肺恢复。我们提出了一种使用小分子药物的新型范式转移疗法策略增强支持性护理措施，并可能限制ARDS的发病率和死亡率。我们的疗法候选人，VZHE-039.-甘氨酸盐，一种天然芳族醛香草蛋白的水溶性合成类似物血红蛋白（HB）的高潜在变构修饰剂，证明了其快速和潜在增加的能力当静脉注射到猪时，Hb结合和运输O2的能力。芳香醛 VZHE-039的组成形成了与N末端阀胺的可逆Schiff碱相互作用 HB通过稳定其高O2亲和力来改变HB。结果是快速的药理转移 HB O2亲和力，这可以增加安全余地以防止急性宗教并限制更多的需求侵入性机械通气或其他补充O2。这种新颖的方法也有可能延迟甚至阻止ECMO紧急打捞的需求。我们的目标是提供明确的证据通过评估其在猪中严重ARDS的LPS内毒素模型中评估其有效性，这种方法的潜力。在我们的第一阶段的研究中，以下承诺结果证明了高度繁殖和剂量依赖性药学动力学实现了血红蛋白氧亲和力的转变，这是一项高保真度的确定性研究大型动物模型将支持进入人类临床试验。