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

摘要 CytoAgents正在开发GP1681(beraprost-314d)来调节不受控制的炎症反应，从而可以 由病毒感染所致。这种炎症反应与疾病严重程度的增加、急性肺 损伤(ALI)、急性呼吸窘迫综合征(ARDS)和死亡。随着新病毒的出现， 大流行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 近几十年来动物来源的冠状病毒(CoV)表明，这些病毒将继续交叉 物种界限，并在人类中引起疫情。目前暴发的SARS-CoV-2是一种高致病性病毒 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 这是一种紧急情况，已被世界卫生组织宣布为全球大流行。SARS-CoV-2有这样的情况 远距离感染185个国家的近300万人，导致超过20万人死亡，其中最多的是 美国确诊病例虽然大多数新冠肺炎携带者只报告患有轻微疾病，但约14%的人患上 严重疾病需要住院和氧气支持，5%需要重症监护。这导致了 给几个国家的医疗保健系统造成了巨大的负担，以及巨大的经济负担 全球范围内。研究表明，病毒性疾病的严重性和负面健康后果往往 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的不受控制的释放，称为 高细胞分裂素血症会破坏肺组织，严重时会导致急性呼吸窘迫综合征， 多器官功能障碍和死亡。GP1681可缓解高细胞分裂素血症，并可能缩短持续时间和 许多病毒性疾病的严重性，包括新冠肺炎。在小鼠模型中的评估显示出显著的疗效 GP1681在治疗流感中的作用。对GP1681作用机制的了解表明，它可能 在治疗新冠肺炎方面同样有效。CytoAgents已提交研究用新药(IND) 向FDA申请流感适应症，并获得批准继续进行第一阶段研究。 其他由美国国立卫生研究院(NIAID)资助的流感模型临床前研究也在进行中。来评估潜在的 用于对抗新冠肺炎的GP1681，该项目的目标是1)扩大印度的毒理学研究 最初的毒理学筛选，因为考虑到典型的新冠肺炎病程，可能需要更长的治疗时间； 2)非人灵长类动物(NHP)模型的药代动力学(PK)分析；以及3)疗效评估 新冠肺炎的NHP模型中的延迟GP1681治疗，因为临床上的治疗通常是在某些 病毒感染后的时间。该项目的成果将为IND应用程序准备CytoAgents以供使用 GP1681在新冠肺炎治疗中的应用。

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.