Preclinical development of an immunomodulatory agent capable of mitigating influenza related hypercytokinemia

摘要 流感是一种严重的、可能危及生命的病毒性疾病，其特点是周期性的全球暴发。 夺走了数十万人的生命。在2017-2018年期间，流感造成近8万人死亡 仅在美国，就导致2300万人次就医和100万人次住院。流感给我们带来的负担 据估计，美国每年的医疗保健费用为112亿美元，其中直接医疗成本为32亿美元。接种疫苗 方案可以减少流感病例的数量，但多个毒株的存在和不断出现 新疫苗的出现使消除疾病或确保疫苗储备提供保护变得不可能 以防止下一次大流行。流感的症状--从流鼻水和喉咙痛开始的一种谱系 急性呼吸窘迫和多器官功能障碍--是正常运作的免疫系统的“副作用”。 患上严重流感的患者会出现过度活跃和持续的免疫反应，这是由 在称为细胞因子风暴的过程中释放细胞信号分子。病毒载量作为一种 流感结局的预测因素和几项研究记录了患者对抗病毒药物的不良反应。 此外，被批准用于流感的抗病毒药物中有三分之一对某些病毒株无效，这种病毒株是一种流感株。 可对任何抗病毒药物产生抗药性，有时在暴发疫情中发现抗药性水平很高 菌株。 CytoAgents正在开发一种治疗严重流感的小分子药物。我们的平台技术 使用一种经过充分研究的化合物，GP1681，在多个临床试验中被发现是安全和耐受性良好的 研究；但该化合物以前从未被研究过作为治疗流感的药物。值得注意的是，在动物身上 用小鼠感染H5N1流感的模型实验，我们的初步数据表明，GP1681 将存活率从15%提高到60%，同时还包括抗病毒药物的联合治疗导致 100%的存活率。 我们的Lead的1a期临床试验已经获得批准，但美国食品和药物管理局 政府已经推荐了一些额外的开发活动和非临床评估研究。 因此，我们在这个直接到第二阶段的项目中的具体目标是：目标1：体外分析GP1681‘S对血管内皮细胞生长的影响 流感病毒复制，与人前列腺素受体结合，以及与EP4激动剂竞争。目标2： 多发性骨髓瘤外周血单个核细胞释放20种细胞因子的体外分析 个人和不同的种族背景。目的3：体内评价GP1681对小鼠流感的疗效 挑战模型，包括GP1681的剂量反应、延迟治疗的疗效、GP1681的影响 抗病毒耐药和多毒株流感，以及GP1681与现有的 抗病毒药物。这些研究将伴随着初步的临床试验，以评估我们的铅的安全性和有效性 化合物及其最终的商业部署，流感是新药应用的第一个适应症 (保密协议)。最终，使用GP1681的治疗有可能使任何流感样疾病(ILI)患者受益。

Abstract Influenza is a serious and potentially life-threatening viral disease characterized by periodic global outbreaks that claim hundreds of thousands of lives. During the 2017-2018 season, influenza caused nearly 80,000 deaths in the U.S., alone, leading to 23 million medical visits and 1 million hospitalizations. The burden of influenza on American healthcare is estimated at $11.2 billion annually, with $3.2 billion in direct medical costs. Vaccination programs can reduce the number of flu cases, but the existence of multiple strains and the continual emergence of new ones make it impossible to eliminate the disease or ensure that vaccine stockpiles will offer protection from the next pandemic. The symptoms of influenza – a spectrum that runs from a runny nose and sore throat to acute respiratory distress and multi-organ dysfunction – are “side effects” of a functioning immune system. Patients that develop severe influenza suffer from an overactive and sustained immune response initiated by the release of cell signaling molecules in a process referred to as a cytokine storm. Viral load is of little use as a predictor of influenza outcomes and several studies have recorded poor patient responses to antiviral drugs. Further, a third of the antivirals approved for influenza are ineffective for certain virus strains, an influenza strain can develop resistance to any antiviral, and resistance is sometimes found at significant levels in outbreak strains. CytoAgents is developing a small molecule pharmaceutical to treat severe influenza. Our platform technology employs a well-studied compound, GP1681, that was found to be safe and well-tolerated in multiple clinical studies; but the compound had NOT been previously investigated as an influenza therapeutic. Notably, in animal model experiments using mice infected with influenza H5N1, our preliminary data demonstrated that GP1681 increased survival from 15% to 60%, while a combination treatment that also included an antiviral resulted in 100% survival. The initiation of Phase 1a clinical trials of our lead has been approved, however, the U.S. Food and Drug Administration has recommended some additional development activities and nonclinical evaluation studies. Thus, our specific aims in this Direct to Phase II project are: Aim 1: In vitro analyses of GP1681's effects on influenza virus replication, binding to human prostanoid receptors, and competition with EP4 agonists. Aim 2: Ex vivo analysis of release of 20 cytokines from peripheral blood mononuclear cells derived from multiple individuals and different racial backgrounds. Aim 3: In vivo assessment of GP1681 efficacy in mouse influenza challenge models, including dose response of GP1681, efficacy of delayed GP1681 treatment, effects of GP1681 against antiviral-resistant and multiple strains of influenza, and synergistic activity of GP1681 with existing antivirals. These studies will accompany initial clinical trials to evaluate the safety and efficacy of our lead compound and its eventual commercial deployment, with influenza as a first indication for a New Drug Application (NDA). Ultimately, treatment with GP1681 has the potential to benefit patients with any influenza-like-illness (ILI).