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

• 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
• 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

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）是一种以非呼吸道感染急性发作为特征的危及生命的疾病。 心源性呼吸衰竭和低氧血症。因此，患有ARDS的患者由于 严重损害气体交换，支持治疗的目标是防止关键组织 缺氧，这可能导致急性心脏骤停和死亡，或有长期的神经系统后果， 幸存者在美国，ARDS每年影响近20万人，导致> 350万住院日， 近七万五千人死亡尽管我们对保护性通风策略和现代通风技术的理解有所发展， 先进的生命支持技术，如体外膜氧合（ECMO），死亡率相关 ARDS的发病率仍然高得令人无法接受，并且在二十年内没有明显改善。的确， ICU中的支持治疗包括通过补充氧气来改善动脉血氧饱和度 氧气和支持呼吸机械通气，但有限制的能力，这些措施 造福患者。事实上，暴露于高比例的O2实际上可能会增加危重患者的死亡风险。 患者类似地，机械通气引起的过度膨胀可加重急性肺损伤，尽管 保护性肺通气的目的仅仅是提供机械支持而不引起伤害。因此，我们认为， 补充O2和机械通气的最大治疗通常不足以维持生命， 肺部恢复。我们提出了一种新的，范式转移的治疗策略，使用小分子药物， 加强支持性护理措施，并可能限制ARDS的发病率和死亡率。我们的治疗 甘氨酸盐，天然芳香醛香草醛的水溶性合成类似物， 一种高效的血红蛋白（Hb）变构修饰剂，证明其能够快速有效地增加 当静脉注射给猪时，Hb结合和转运O2的能力。芳族醛 VZHE-039的一种组分与α-裂缝中的N-末端缬氨酸胺形成可逆的席夫碱相互作用， Hb通过稳定其高O2-亲和力状态来变构修饰Hb。结果是一种快速的，药理学的转变， Hb O2亲和力，可增加安全范围，以防止急性去饱和，并限制对更多的 有创机械通气或额外补充O2。这种新颖的方法也有可能 延迟甚至阻止使用ECMO进行紧急抢救的需要。我们的目标是提供确凿的证据 通过评估其在猪严重ARDS的LPS内毒素模型中的有效性来评估这种方法的潜力。 在我们的I期研究中获得了令人鼓舞的结果，证明了高度可重复性和剂量依赖性， 实现血红蛋白氧亲和力变化的药效学，一项高保真的确定性疗效研究 大型动物模型将支持人类临床试验的进展。