Development of the New Synthetic Triterpenoid CDDO-2P-Im for Chemoprevention of the ARDS of COVID-19

开发新型合成三萜类化合物 CDDO-2P-Im 用于化学预防 COVID-19 ARDS

• 批准号: 10202843
• 负责人: Michael B Sporn
• 金额: $ 24.98万
• 依托单位: TRITERPENOID THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202843
• 关键词: 2019-nCoV; Address; Admission activity; Adult Respiratory Distress Syndrome; Antibiotics; Automobile Driving; Binding; Biological Assay; Biomedical Research; Blood Vessels; CCL2 gene; COVID-19; Cell Culture Techniques; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Cytokine Gene; Cytokine Network Pathway; DNA Polymerase II; Data; Development; Diabetes Mellitus; Disease; Edema; Elderly; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Failure; Future; Gene Expression; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hour; Human; Immune; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza A Virus, H1N1 Subtype; Influenza A virus; Interleukin-6; Intervention; Investigation; K-18 conjugate; Laboratories; Liquid substance; Lung; Lung Lavage Fluid; Macrophage Activation; Macrophage activation syndrome; Membrane; Middle East Respiratory Syndrome Coronavirus; Oral; Organ; Oryctolagus cuniculus; Outpatients; Pathogenicity; Patients; Peptides; Pharmaceutical Preparations; Pharmacology and Toxicology; Play; Population; Production; RNA; Reader; Regimen; Research; Research Institute; Respiratory Failure; Risk; Rivers; SARS coronavirus; Severities; Smoking; Stains; Syndrome; TNF gene; Testing; Texas; Therapeutic; Transgenic Mice; Tumor-infiltrating immune cells; Up-Regulation; Viral; Virus Diseases; Virus Replication; Zoonoses; chemokine; clinical development; comorbidity; cytokine; cytokine release syndrome; disorder risk; effective therapy; efficacy study; enzyme linked immunospot assay; first responder; high risk population; in vitro Model; in vivo; industry partner; innovation; interstitial; lead optimization; lung injury; macrophage; microbial; monocyte; mortality; mouse model; novel therapeutics; oleanane; polyclonal antibody; preclinical development; prevent; recruit; remdesivir; research clinical testing; respiratory; small molecule; ventilation

PROJECT ABSTRACT COVID-19 infection is associated with substantial mortality in patients with clinical co-morbidities, including smoking, advanced age and diabetes mellitus. In these patients, COVID-19 infection leads to a hyperinflammatory state producing vascular leak, interstitial edema, hyaline membrane formation and ARDS. COVID-19 patients requiring ICU admission have high circulating levels of IL-6, GM-CSF, MCP and MIP1 (CCL2) cytokines compared to those with uncomplicated illnesses. This hyper-inflammation syndrome, (aka “cytokine storm”) is a prodromal feature of ARDS and multi-organ failure. Bronchoalveolar fluids (BALF) from patients with severe COVID-19 are enriched in CCL2, one of the most potent chemokines driving the recruitment of monocytes into the lung. Of note, cytokine storm is also associated with extensive lung damage in SARS-CoV and MERS- CoV infections, suggesting that innate hyper-inflammation is common to respiratory zoonoses. There is no effective treatment currently available that may be deployed as an intervention to either prevent or ameliorate the cytokine storm of COVID-19. To address this need, our research team is actively engaged in the preclinical development of an optimized lead agent (CDDO-2P-Im, or ‘2P-Im’), a highly potent synthetic triterpenoid that is the most advanced among a class of small molecules recognized as effective modifiers of the host inflammatory response. Our data show that 2P-Im broadly inhibits expression of cytokine networks and pathways underlying hyper-inflammation. In particular, 2P-Im and its related derivatives are potent suppressors of macrophage activation, suppressing the production of MIP1 (CCL2) by human macrophages at picomolar concentrations. 2P- Im is an innovative new drug, with a mechanism of action not shared by any other drug currently under investigation for in use in treating COVID-19. We envision 2P-Im will be provided to patients as an oral agent deployed to prevent macrophage activation syndrome and disrupt progression to the ARDS of COVID-19 disease in high-risk populations. 2P-Im also has potential for use in the outpatient setting as a chemopreventive regimen to reduce risk in first responders, residents living in group settings, and other high-risk groups exposed to COVID-19. Preliminary data demonstrate potent cytoprotective effects in assays of efficacy against Influenza virus A H1N1 and Influenza virus A H3N2. Through partnership between Triterpenoid Therapeutics (TTX) and the Texas Biomedical Research Institute, we will pursue full-scale, IND-enabling efficacy studies in established mouse models of COVID-19. Specifically, we will define the capacity of 2P-Im to prevent the cytopathic effects of SARS-CoV-2 in established, validated in vitro models of COVID-19 (Aim 1); and demonstrate the in vivo efficacy of 2P-Im against SARS-CoV-2 induced inflammation and capacity to promote survival in the established K18-hACE2 mouse model of COVID-19 (Aim 2). The proposed plan will lead to approval of an IND that will allow for future clinical trials of 2P-Im in patients with COVID-19, which is the ultimate goal of this project.

项目摘要 COVID-19感染与临床合并症患者的大量死亡率有关，包括 吸烟，高龄和糖尿病。在这些患者中，Covid-19感染导致 产生血管泄漏，间质水肿，透明膜形成和ARDS的高炎性状态。 需要ICU入院的COVID-19患者具有高循环水平的IL-6，GM-CSF，MCP和MIP1（CCL2） 与患有简单疾病的细胞因子相比。这种超炎症综合征（又称“ Cytokin” Storm”）是ARDS和多器官衰竭的前瞻性特征。 严重的Covid-19富含CCL2，这是驱动单核细胞募集的最有效的趋化因子之一 值得注意的是，细胞因子风暴还与SARS-COV和MERS-的广泛肺损伤有关 COV感染，这表明先天性超炎是呼吸自我的常见。没有 当前可用的有效治疗方法可以作为预防或改善的干预措施部署 Covid-19的细胞因子风暴。为了满足这一需求，我们的研究团队积极参与临床前 开发优化的铅剂（CDDO-2P-IM或“ 2p-im”），这是一种高潜在的合成三萜类化合物 在一类小分子中，最先进的是宿主炎症的有效修饰剂 回复。我们的数据表明，2P-IM广泛抑制细胞因子网络和途径的表达 超炎。特别是，2p-im及其相关的衍生物是巨噬细胞的潜在补充 激活，以皮摩尔浓度在人类巨噬细胞中抑制MIP1（CCL2）的产生。 2p- IM是一种创新的新药，具有目前没有其他药物的行动机制 用于治疗Covid-19的研究。我们设想2p-im将作为口服代理提供给患者 部署以防止巨噬细胞激活综合征和破坏COVID-19的ARDS的进展 高危人群中的疾病。 2p-im还具有在门诊环境中作为化学预防的潜力 降低急救人员风险的方案，居住在小组环境中的居民以及其他高风险团体 到19号。初步数据表明在针对流感的效率测定中潜在的细胞保护作用 病毒A H1N1和流感病毒A H3N2。通过三萜治疗学（TTX）和 德克萨斯生物医学研究所，我们将在已建立的全面，富有效率的研究中进行全面的效率研究 cOVID-129的小鼠模型，特别是，我们将定义2p-im的能力防止细胞病变作用 在既定的，经过验证的covid-19的体外模型中的SARS-COV-2（AIM 1）；并演示体内 2P-IM对SARS-COV-2诱导的注射和促进已建立生存的能力的效率 COVID-19的K18-HACE2小鼠模型（AIM 2）。拟议的计划将导致IND的批准，该计划将允许 对于2P-IM的未来临床试验，在Covid-19患者中，这是该项目的最终目标。