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）是一种危及生命的疾病，其特征是急性发作的非呼吸窘迫综合征。心源性呼吸衰竭和低氧血症检查，ARDS患者因出现严重低氧血症。气体交换的显着损害，支持治疗的目标是防止关键组织缺氧，可能导致急性心脏骤停和死亡，或对患者产生长期的神经系统后果在美国，ARDS 每年影响近 20 万人，导致住院日数超过 350 万天。尽管我们对保护性通气策略和现代技术的理解不断进步，仍有近 75,000 人死亡。先进的生命支持技术，例如体外膜肺氧合（ECMO）、死亡率相关 ARDS 的发病率仍然高得令人无法接受，而且二十年来并未明显改善，这已成为中流砥柱。 ICU 中支持治疗的主要内容包括通过引入补充疗法来改善动脉氧 (O2) 饱和度 O2 并通过机械通气支持呼吸，但此类措施的能力有限事实上，接触高浓度的氧气实际上可能会增加危重病人的死亡风险。同样，机械通气造成的过度膨胀会加剧急性肺损伤，尽管如此。保护性肺通气的目标只是提供机械支持而不造成伤害。补充氧气和机械通气的最大治疗通常不足以维持生命，直到我们提出了一种新颖的、范式转变的治疗策略，使用小分子药物来恢复。加强支持性护理措施并可能限制 ARDS 的发病率和死亡率。候选者，VZHE-039.甘氨酸盐，天然芳香醛香草醛的水溶性合成类似物，是一种高效的血红蛋白 (Hb) 变构调节剂，已证明其能够快速有效地增加血红蛋白静脉注射给猪时 Hb 结合和转运 O2 的能力。 VZHE-039 的成分与 α-裂隙中的 N 端缬氨酸胺形成可逆席夫碱相互作用 Hb 通过稳定 Hb 的高 O2 亲和力状态来变构修饰 Hb，其结果是快速的药理学转变。 Hb O2 亲和力，可以增加安全边际以防止急性去饱和并限制更多的需求有创机械通气或额外补充氧气这种新颖的方法也有潜力。延迟甚至避免使用 ECMO 进行紧急抢救的需要，我们的目标是提供明确的证据。通过评估该方法在猪严重 ARDS 的 LPS 内毒素模型中的功效，了解该方法的潜力。我们的第一阶段研究取得了令人鼓舞的结果，证明了高度可重复性和剂量依赖性药效学实现血红蛋白氧亲和力的改变，高保真度的明确疗效研究大型动物模型将支持进入人体临床试验。