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

• 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
• 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

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.

摘要 CytoAgents正在开发GP 1681（贝前列素-314d），以调节不受控制的炎症反应， 是由病毒感染引起的这种炎症反应与疾病严重程度的增加、急性肺损伤、急性呼吸道疾病和慢性阻塞性肺疾病有关。 急性呼吸窘迫综合征（ARDS）和死亡。新型病毒的出现， 大流行病的可能性对世界卫生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）的研究表明，这些病毒将继续交叉 物种界限并在人类中引起爆发。目前爆发的SARS-CoV-2是一种高致病性 冠状病毒引起下呼吸道感染和严重肺炎，代表着严重的公共卫生问题， 紧急情况，并已被世界卫生组织宣布为全球大流行病。SARS-CoV-2是 迄今感染了185个国家的近300万人，导致20多万人死亡，其中死亡人数最多的是 虽然大多数COVID-19患者只报告轻度疾病，但约14%的人发展为 需要住院和氧气支持的严重疾病，5%需要重症监护。这导致 这给一些国家的医疗保健系统带来了沉重的负担， 在全球研究表明，病毒性疾病的严重程度和负面的健康结果往往是 与过度刺激的细胞因子反应相关，而不是病毒载量本身。过度激活 炎症反应导致促炎细胞因子的不受控制的释放， 高细胞因子血症，其导致肺组织的破坏，并且在严重的情况下，导致ARDS， 多器官功能障碍和死亡GP 1681可调节高细胞因子血症，并可减少持续时间和 包括COVID-19在内的许多病毒性疾病的严重程度。在小鼠模型中的评价显示出显著的功效， GP 1681治疗流感对GP 1681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1期研究。 NIH（NIAID）资助的其他临床前研究也在流感模型中进行。评估潜在 GP 1681用于对抗COVID-19，该项目的目的是1）IND使毒理学研究扩大 初步毒理学筛查，因为考虑到典型的COVID-19病程，可能需要更长的治疗时间; 2)在非人灵长类动物（NHP）模型中的药代动力学（PK）分析;和3）评估 在COVID-19的NHP模型中延迟GP 1681治疗，因为临床治疗通常在一些时间开始， 病毒感染后的时间。本项目的成果将为IND申请准备CytoAgents， GP 1681在治疗COVID-19中的应用。