Preclinical development of an immunomodulatory agent capable of mitigating SARS-CoV-2 virus related hypercytokinemia

能够减轻 SARS-CoV-2 病毒相关高细胞因子血症的免疫调节剂的临床前开发

基本信息

批准号：
10155839
负责人：
JODI K CRAIGO
金额：
$ 100万
依托单位：
CYTOAGENTS, INC.
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：
2021-03-06 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155839
关键词：
2019-nCoV Acute Lung Injury Adult Respiratory Distress Syndrome Adverse event African African Green Monkey Animals Antiviral Agents Antiviral Therapy COVID-19 COVID-19 outbreak COVID-19 treatment Caring Cessation of life China Clinic Clinical Coronavirus Country Development Disease Disease Outbreaks Dose Drug Kinetics Economic Burden Epitopes Evaluation Functional disorder Funding Health Healthcare Healthcare Systems Hospitalization Human Immune response Immunomodulators Individual Infection Inflammatory Response Influenza Intensive Care Investigational Drugs Investigational New Drug Application Knowledge Lead Length of Stay Lower Respiratory Tract Infection Lung Measurable Measures Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modality Modeling Mucositis Mus National Institute of Allergy and Infectious Disease Natural Immunity Oral Oseltamivir Outcome Oxygen Pathogenicity Patients Phase II Clinical Trials Pneumonia Pulmonary Edema Pulmonary Pathology Reaction Time Recovery Reporting Respiratory Mucosa Risk SARS coronavirus SARS-CoV-2 infection Safety Schedule Security Severe Acute Respiratory Syndrome Severities Severity of illness Signal Pathway Societies Structure of parenchyma of lung Testing Therapeutic Time Toxicology Treatment Protocols United States National Institutes of Health Urbanization Vaccines Viral Viral Load result Virus Virus Diseases Weight World Health World Health Organization adaptive immunity associated symptom base chemokine clinical practice cytokine cytokine release syndrome drug development efficacy evaluation healthy volunteer influenzavirus macrophage mortality mouse model nonhuman primate novel novel coronavirus novel virus pandemic disease phase 1 study preclinical development preclinical study public health emergency respiratory response stem treatment duration viral resistance

项目摘要

Abstract CytoAgents is developing GP1681 (beraprost-314d) to regulate the uncontrolled inflammatory response that can result from viral infections. This inflammatory response is associated with increased disease severity, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and death. The emergence of novel viruses with pandemic potential poses a major threat to world health and security. In particular, the emergence of novel coronaviruses (CoVs) of animal origin in recent decades indicates that these viruses will continue to cross species boundaries and cause outbreaks in humans. The current outbreak of SARS-CoV-2, a highly pathogenic CoV that causes lower respiratory tract infections and severe pneumonia, represents a severe public health emergency and has been declared a global pandemic by the World Health Organization. SARS-CoV-2 has so far infected nearly 3M individuals in 185 countries, resulting in over 200K deaths, with the greatest number of confirmed cases in the U.S. While most individuals with COVID-19 report only mild illness, about 14% develop severe disease requiring hospitalization and oxygen support, and 5% require intensive care. This has resulted in a significant burden on healthcare systems in several countries, as well as a massive economic burden globally. Studies have revealed that the severity of viral disease and negative health outcomes are often associated with an overstimulated cytokine response, rather than the viral load per se. Overactivation of the inflammatory response results in the uncontrolled release of proinflammatory cytokines, known as hypercytokinemia, which contributes to the destruction of lung tissue, and in severe cases, leads to ARDS, multiorgan dysfunction, and death. GP1681 moderates hypercytokinemia and may reduce the duration and severity of many viral diseases, including COVID-19. Evaluation in mouse models has shown notable efficacy of GP1681 in the treatment of influenza. Knowledge of the mechanism of action of GP1681 suggests that it may be equally effective in treating COVID-19. CytoAgents has submitted an Investigational New Drug (IND) Application to the FDA for an influenza indication and received approval to proceed with a Phase 1 study. Additional NIH (NIAID)-funded preclinical studies are also underway in influenza models. To assess the potential of GP1681 for use against COVID-19, the aims of this project are 1) IND-enabling toxicology studies expanding the initial toxicology screens, as longer treatment may be needed given the typical COVID-19 disease course; 2) Pharmacokinetic (PK) analysis in a non-human primate (NHP) model; and 3) Assessment of the efficacy of delayed GP1681 treatment in an NHP model of COVID-19, as therapy in the clinic is typically initiated at some time after viral infection. The outcomes of this project will prepare CytoAgents for an IND application for the use of GP1681 in the treatment of COVID-19.

抽象的细胞代理正在开发GP1681（Beraprost-314d），以调节可以控制的炎症反应病毒感染引起。这种炎症反应与疾病严重程度增加有关受伤（ALI），急性呼吸窘迫综合征（ARDS）和死亡。新颖病毒的出现与大流行潜力对世界卫生和安全构成了重大威胁。特别是新颖的出现近几十年来，动物起源的冠状病毒（COV）表明这些病毒将继续越过物种边界并引起人类爆发。 SARS-COV-2的当前爆发是一种高度致病的引起下呼吸道感染和严重肺炎的COV代表严重的公共卫生紧急情况并已被世界卫生组织宣布为全球大流行。 SARS-COV-2这样在185个国家中感染了近300万个人，导致超过200万人死亡，数量最多在美国确认的案件，而大多数患有COVID-19的人仅报告轻度疾病，但大约有14％的人发展需要住院和氧气支持的严重疾病，5％需要重症监护。这导致了在几个国家的医疗保健系统上的重大负担以及巨大的经济负担全球。研究表明，病毒疾病和健康结果的严重程度通常是与过度刺激的细胞因子反应相关，而不是病毒载量本身。过度活化炎症反应导致促炎细胞因子的不受控制释放，称为高胞浆血症有助于肺组织的破坏，在严重的情况下，导致ARDS，多器官功能障碍和死亡。 GP1681调节高环境血症，可能会减少持续时间和许多病毒疾病的严重程度，包括COVID-19。鼠标模型中的评估显示出明显的功效 GP1681在流感治疗中。了解GP1681的作用机理的知识表明它可能同样有效地治疗Covid-19。细胞者提交了一种调查新药（IND）向FDA申请以进行流感指示，并获得了1阶段研究的批准。在流感模型中，其他NIH（NIAID）资助的临床前研究也正在进行中。评估潜力 gp1681用于与COVID-19的使用，该项目的目的是1）扩大的毒理学研究鉴于典型的COVID-19疾病病程，可能需要更长的治疗，因为最初的毒理学筛查可能需要更长的治疗。 2）非人类灵长类动力学（NHP）模型中的药代动力学（PK）分析； 3）评估的功效在诊所的NHP模型中，延迟的GP1681治疗通常在某些诊所开始病毒感染后的时间。该项目的结果将为IND申请的细胞代理准备使用 GP1681在Covid-19的治疗中。