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 CytoAgents 正在开发 GP1681（beraprost-314d）来调节失控的炎症反应，该反应可以由病毒感染引起。这种炎症反应与疾病严重程度、急性肺损伤的增加有关。损伤（ALI）、急性呼吸窘迫综合征（ARDS）和死亡。新型病毒的出现大流行的可能性对世界健康和安全构成重大威胁。尤其是小说的出现近几十年来动物源性冠状病毒（CoV）的出现表明这些病毒将继续交叉传播物种边界并导致人类爆发。当前爆发的 SARS-CoV-2（一种高致病性病毒）引起下呼吸道感染和严重肺炎的冠状病毒代表着严重的公共卫生问题并已被世界卫生组织宣布为全球大流行病。 SARS-CoV-2 具有如此目前已感染 185 个国家的近 300 万人，导致超过 20 万人死亡，其中死亡人数最多美国确诊病例虽然大多数 COVID-19 患者仅报告病情较轻，但约 14% 的患者病情较轻病情严重需要住院治疗和吸氧，5%需要重症监护。这导致了给一些国家的医疗保健系统带来沉重负担以及巨大的经济负担全球。研究表明，病毒性疾病的严重程度和负面健康结果往往是与过度刺激的细胞因子反应有关，而不是病毒载量本身。过度激活炎症反应导致促炎细胞因子不受控制的释放，称为高细胞因子血症会导致肺组织破坏，严重时会导致 ARDS，多器官功能障碍，甚至死亡。 GP1681 可缓解高细胞因子血症，并可能缩短持续时间和许多病毒性疾病的严重程度，包括 COVID-19。小鼠模型的评估显示出显着的功效 GP1681治疗流感。对 GP1681 作用机制的了解表明，它可能在治疗 COVID-19 方面同样有效。 CytoAgents 已提交研究性新药 (IND) 向 FDA 申请流感适应症并获得批准进行第一阶段研究。美国国立卫生研究院 (NIAID) 资助的其他流感模型临床前研究也在进行中。评估潜力 GP1681 用于对抗 COVID-19，该项目的目标是 1) 扩大支持 IND 的毒理学研究初始毒理学筛查，因为考虑到典型的 COVID-19 病程，可能需要更长的治疗时间； 2）非人灵长类（NHP）模型中的药代动力学（PK）分析； 3) 功效评估在 COVID-19 的 NHP 模型中延迟了 GP1681 治疗，因为临床治疗通常在某些时间开始病毒感染后的时间。该项目的成果将为 CytoAgents 的 IND 申请做好准备，以供使用 GP1681 在治疗 COVID-19 中的作用。