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

能够减轻流感相关高细胞因子血症的免疫调节剂的临床前开发

• 批准号: 10161744
• 负责人: JODI K CRAIGO
• 金额: $ 81.35万
• 依托单位: CYTOAGENTS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161744
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Agonist; American; Animal Model; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Appearance; Asia; Binding; Caring; Cessation of life; Chronic; Clinical Research; Clinical Trials; Data; Development; Diagnosis; Disease; Disease Outbreaks; Disease Outcome; Dose; EP4 receptor; Economic Burden; Ensure; Epithelial; Epoprostenol; Esthesia; Evaluation; Evaluation Studies; Functional disorder; Healthcare; Healthcare Systems; Hospitalization; Hour; Human; Immune response; Immunization Programs; Immunomodulators; In Vitro; Individual; Infection; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza Therapeutic; Innate Immune Response; Intermittent Claudication; Investigational Drugs; Isomerism; Lead; Length of Stay; Life; Link; Lung; Mediating; Medical; Medical Care Costs; Modeling; Mus; Natural Immunity; Nose; Oral; Oseltamivir; Outcome; Pain; Patients; Periodicity; Peripheral; Peripheral Blood Mononuclear Cell; Peripheral Vascular Diseases; Pharmacologic Substance; Phase; Phase Ia Clinical Trial; Platelet aggregation; Play; Process; Prostaglandins; Prostaglandins I; Recovery; Research; Resistance development; Respiration Disorders; Role; Running; Safety; Seasonal Variations; Seasons; Severities; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Societies; Sodium; Sore Throat; Stereoisomer; Structure of parenchyma of lung; Symptoms; Synthetic Prostaglandins; Technology; Therapeutic; Time; Tissues; Ulcer; United States; United States Food and Drug Administration; Vaccines; Vasodilator Agents; Viral Load result; Virus; Virus Diseases; Virus Replication; Visit; WFDC2 gene; adaptive immunity; artery occlusion; clinical practice; combat; cost; cytokine; cytokine release syndrome; experimental study; flu; health economics; immune system function; immunopathology; improved; in vivo; influenza infection; influenza virus strain; influenzavirus; mortality; novel strategies; novel therapeutics; pandemic disease; patient response; preclinical development; prevent; pulmonary arterial hypertension; receptor; respiratory; response; side effect; small molecule; treatment effect; vaccination strategy; viral resistance

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).

抽象的 流感是一种严重且潜在的威胁生命的病毒疾病，其特征是定期全球暴发 这夺走了数十万生命。在2017-2018赛季，影响力造成近80,000人死亡 仅在美国，就会导致2300万次医疗访问和100万个住院治疗。影响的影响 美国医疗保健估计每年为112亿美元，直接医疗费用为32亿美元。疫苗接种 程序可以减少流感病例的数量，但存在多种菌株和持续出现 新的使无法消除疾病或确保疫苗储存将提供保护 从下一个大流行。影响的症状 - 从流鼻涕和喉咙痛的频谱 对于急性呼吸窘迫和多器官功能障碍 - 是功能性免疫系统的“副作用”。 受到由过度活跃和持续的免疫反应产生严重影响者的患者 在称为细胞因子风暴的过程中释放细胞信号分子。病毒负荷几乎没有用作 影响力结果的预测指标和几项研究记录了患者对抗病毒药物的反应不佳。 此外，三分之一的抗病毒药批准用于影响某些病毒菌株无效，这是一种影响 可以产生对任何抗病毒的抵抗力，有时会在爆发中发现抗性 菌株。 细胞代理正在开发一种小分子药物来治疗严重影响。我们的平台技术 员工是一个良好的化合物GP1681，发现在多个临床中很安全且耐受性良好 研究；但是该化合物以前尚未作为影响力治疗。值得注意的是，在动物中 使用Intelltza H5N1感染的小鼠的模型实验，我们的初步数据表明GP1681 将生存率从15％提高到60％，而联合治疗也包括抗病毒药导致 100％生存。 但是，我们铅的1A期临床试验的主动性已获得批准，但是美国食品和药物 管理已推荐一些其他开发活动和非临床评估研究。 这是我们直接对II阶段项目的具体目标是：目标1：对GP1681对GP1681的影响的体外分析 流感病毒复制，与人前列腺素受体结合以及与EP4激动剂的竞争。目标2： 离体分析来自多个的多个外周血单核细胞的20种细胞因子释放 个人和不同的种族背景。 AIM 3：GP1681小鼠影响力效率的体内评估 挑战模型，包括GP1681的剂量反应，延迟GP1681治疗的有效性，GP1681的影响 反对抗病毒抗性和多种影响力菌株，以及GP1681的协同活性 抗病毒药。这些研究将适应初步的临床试验，以评估我们的铅的安全性和效率 化合物及其最终的商业部署，ractractza是新药申请的第一个指示 （NDA）。最终，使用GP1681的治疗有可能使患者受益于任何影响力的患者（ILI）。