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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

基本信息

批准号：
10010120
负责人：
JODI K CRAIGO
金额：
$ 84.83万
依托单位：
CYTOAGENTS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-08 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010120
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 Epithelium Epoprostenol Esthesia Evaluation Evaluation Studies Functional disorder Healthcare Healthcare Systems Hospitalization Hour Human Immune response 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 Vaccination 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 improved in vivo influenzavirus mortality novel strategies novel therapeutics pandemic disease patient response preclinical development prevent programs pulmonary arterial hypertension receptor respiratory response side effect small molecule treatment effect vaccination strategy viral resistance

项目摘要

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).

摘要流感是一种严重的、可能威胁生命的病毒性疾病，其特征是周期性的全球性爆发夺去了数十万人的生命在2017-2018赛季期间，流感造成近8万人死亡在美国，仅这一项就导致了2 300万人次就医和100万人次住院。流感给人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，其中直接医疗费用为32亿美元。疫苗接种计划可以减少流感病例的数量，但多种菌株的存在和不断出现，新疫苗的出现使得消灭这种疾病或确保疫苗储备提供保护成为不可能下一次大流行的威胁流感的症状--从流鼻涕到喉咙痛急性呼吸窘迫和多器官功能障碍-是免疫系统功能正常的“副作用”。发生严重流感的患者遭受由流感病毒引起的过度活跃和持续的免疫应答。在称为细胞因子风暴的过程中释放细胞信号分子。病毒载量作为一种预测流感的结果和几项研究记录了病人对抗病毒药物的反应差。此外，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，可以对任何抗病毒药物产生耐药性，有时在爆发中发现显著水平的耐药性，菌株 CytoAgents正在开发一种治疗严重流感的小分子药物。我们的平台技术采用了一种经过充分研究的化合物GP 1681，在多种临床试验中发现该化合物安全且耐受性良好。研究;但该化合物以前没有被研究作为流感治疗。特别是，在动物使用感染H5 N1流感病毒的小鼠进行的模型实验，我们的初步数据表明，GP 1681 存活率从15%提高到60%，而包括抗病毒药物的联合治疗导致百分之百存活我们的铅的1a期临床试验已经获得批准，但是，美国食品和药物管理局（FDA）管理部门建议开展一些额外的开发活动和非临床评价研究。因此，我们在这个直接进入II期项目中的具体目标是：流感病毒复制、与人前列腺素受体的结合以及与EP 4激动剂的竞争。目标二：来自多种来源的外周血单个核细胞的20种细胞因子释放的离体分析不同的种族和不同的背景。目的3：GP 1681在小鼠流感中的功效的体内评估激发模型，包括GP 1681的剂量反应、延迟GP 1681治疗的功效、GP 1681的作用 GP 1681对抗抗病毒抗性和多种流感病毒株的协同活性，以及GP 1681与现有的抗病毒药这些研究将伴随初步临床试验，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，流感作为新药申请的第一个适应症（NDA）。最终，GP 1681治疗有可能使任何流感样疾病（ILI）患者受益。