Low Dose Oral Carbon Monoxide Therapeutic for Virus-Induced Lung Injury

低剂量口服一氧化碳治疗病毒引起的肺损伤

• 批准号: 10682510
• 负责人: Edward Gomperts
• 金额: $ 29.99万
• 依托单位: HILLHURST BIOPHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682510
• 关键词: 2019-nCoV; Accidents; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Animal Model; Animals; Antiviral Agents; Award; Binding; Biological Availability; COVID-19; COVID-19 impact; COVID-19 patient; COVID-19 treatment; Canis familiaris; Carbon Monoxide; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Clinical Research; Clinical Trials; Data; Development; Dexamethasone; Dose; Economics; Experimental Animal Model; Experimental Models; Formulation; Gases; Goals; Hemoglobin; Hemoglobin concentration result; Human; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Inhalation; Inhalation Exposure; Injury; Innate Immune Response; Intensive Care; Intensive Care Units; Kinetics; Laboratories; Life; Liquid substance; Literature; Lung; Lung diseases; Lung infections; Mesocricetus auratus; Methods; Modality; Modeling; Morbidity - disease rate; Mus; Oral; Pathology; Patients; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; Pulmonary Inflammation; Rattus; Research; Research Personnel; Research Support; Respiratory physiology; Risk; SARS-CoV-2 infection; Safety; Seasons; Secure; Sickle Cell Anemia; Small Business Innovation Research Grant; Taxes; Testing; Therapeutic; Therapeutic Uses; Time; Tissue Model; Toxic effect; Toxicology; Translations; Treatment Efficacy; United States; Vaccination; Viral; Viral Load result; Viral Respiratory Tract Infection; Virus; Virus Diseases; Writing; antiviral drug development; clinically relevant; experience; healthy volunteer; hospital care; human subject; immunoregulation; improved; improved outcome; in vivo; innovation; lung injury; mortality; novel; novel strategies; novel therapeutics; pandemic disease; phase 2 study; pre-Investigational New Drug meeting; pre-clinical; preclinical efficacy; preclinical study; prevent; research clinical testing; therapeutic development; therapeutically effective; treatment strategy; viral pandemic

PROJECT SUMMARY There is an urgent need for the development of new approaches to treat patients suffering from pulmonary injury from viral infections, as demonstrated by the severe impact of COVID-19, which is a global pandemic that, at the time of writing, is estimated have impacted approximately 50 million people in the United States, leading to morbidity, substantial hospital and intensive care utilization, and mortality. In multiple preclinical studies, we and others have defined the therapeutic potential of low dose exogenous carbon monoxide (CO) in acute lung injury, including in virus-induced pulmonary injury, by reducing inflammation and promoting viral clearance. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies, and the safety and tolerability of CO has been demonstrated in 23 successful Phase 1 and 2 clinical studies, including in patients with pulmonary conditions such as ARDS and COPD. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options in COVID patients due to, for iCO, the risk of accidental inhalation exposure from the presence of compressed CO gas cylinders and imprecise dosing, especially in COVID-19 patients that have limited and variable respiratory function, and, for CORMs, problematic release kinetics and toxicological concerns with carrier molecules. The objective of the proposed project is to investigate HBI-002, a novel oral low dose CO drug product that enables the use of low dose CO in viral infections associated with acute pulmonary injury, such as COVID-19. HBI-002 is an oral liquid drug product containing CO. An IND is in place for HBI-002, with a Phase 1 clinical trial in healthy volunteers planned in 2022. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of viral acute lung injury as has been shown with other forms of CO and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in acute lung injury and our and others findings in virus-induced lung injury, our central hypothesis that will be tested in this project is: HBI-002 modulates the immune response to regulate inflammation and improve viral clearance in experimental models of virally induced lung injury sufficiently to warrant a Phase 2 clinical trial.

项目总结 迫切需要开发新的方法来治疗肺损伤患者。 防止病毒感染，新冠肺炎的严重影响就证明了这一点，这是一种全球大流行，在 在写这篇文章的时候，估计已经影响了美国大约5000万人，导致 发病率、大量医院和重症监护使用率以及死亡率。在多项临床前研究中，我们和 其他人定义了低剂量外源性一氧化碳(CO)在急性肺损伤中的治疗潜力， 包括在病毒引起的肺损伤中，通过减少炎症和促进病毒清除。 到目前为止，吸入CO气体(ICO)和结合到载体分子(球茎)上的CO一直是选择的方式 在大多数动物和所有临床研究中，CO的安全性和耐受性都已得到证实 在23项成功的1期和2期临床研究中，包括患有ARDS等肺部疾病的患者 和慢性阻塞性肺病。然而，ICO和球茎预计不会在药学上被接受和可行 对于ICO来说，COVID患者由于意外吸入暴露于 存在压缩的CO气瓶和剂量不准确，特别是在患有 有限和可变的呼吸功能，对于球茎来说，有问题的释放动力学和毒理学 对载体分子的担忧。该项目的目标是研究一种新型口服液HBI-002。 剂量一氧化碳药物产品，使低剂量一氧化碳能够用于与急性肺病相关的病毒感染 受伤，如新冠肺炎。 HBI-002是一种含CO的口服液。针对HBI-002的IND已经到位，并进行了一期临床试验 在计划于2022年进行的健康志愿者中。开发的下一步是证明HBI-002是有效的 在临床相关的病毒性急性肺损伤动物模型中，与其他形式的CO和TO一样 更好地理解行动的潜在机制(S)。基于CO在急性肺病中的大量文献 损伤以及OUR和其他在病毒诱导的肺损伤中的发现，我们的中心假设将在这里得到验证 项目是：HBI-002调节免疫反应以调节炎症和改善病毒清除 在病毒诱导的肺损伤的实验模型中，足以保证进行第二阶段临床试验。