Evaluation of Optimized Lead Candidates for Encephalitic Alphaviruses in Animal Models

在动物模型中评估脑炎甲病毒的优化先导候选物

• 批准号: 10116266
• 负责人: Colleen B Jonsson
• 金额: $ 256.58万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116266
• 关键词: Address; Aerosols; Alphavirus; Alphavirus Infections; Americas; Animal Model; Animals; Antiviral Agents; Back; Biodistribution; Biological Markers; Cardiovascular system; Collaborations; Data; Development; Development Plans; Diagnosis; Disease; Disease Outbreaks; Dose; Drug Kinetics; Drug resistance; Eastern Equine Encephalitis Virus; Endemic Diseases; Epidemic; Evaluation; Human; Infection; Interruption; Lead; Macaca fascicularis; Maximum Tolerated Dose; Measures; Methods; Modeling; Mus; Pharmacotherapy; Population; Process; Public Health; Rattus; Readiness; Regimen; Reporting; Research; Research Project Grants; Route; Safety; Series; Technology; Testing; Therapeutic; Toxic effect; Toxicokinetics; Vaccination; Vaccines; Venezuelan; Venezuelan Equine Encephalitis Virus; Virus; Western Equine Encephalitis Virus; acute toxicity; efficacy evaluation; efficacy study; lead candidate; lead optimization; meetings; mouse model; multidisciplinary; nonhuman primate; pharmacokinetics and pharmacodynamics; prevent; product development; programs; prophylactic; prototype; relating to nervous system; respiratory; response; safety study; small molecule; subcutaneous

Program Abstract- Project 2 Currently, there are no licensed human vaccines or antivirals for treating or preventing any encephalitic alphavirus infection. Because epidemics of alphaviruses are sporadic and unpredictable, and endemic disease is common (estimated 10,000 cases annually in the Americas) but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we propose a first of its kind small molecule with prophylactic and therapeutic potential that could be relevant for use both in natural epidemics of V/E/WEEV as well as a deliberate release scenario. In summary, a successful effort will result in a new class of antiviral drugs for treatment of encephalitic alphaviruses; Venezuelan (VEEV), Eastern (EEEV) and Western equine encephalitis viruses (WEEV). Research Project 2 within the U19 Center of Excellence for Encephalitic Alphavirus Therapeutics program will lead, support and manage testing of optimized lead molecules in animal models for safety, toxicity, pharmacokinetics and efficacy. The proposed multidisciplinary efforts are focused on accomplishing studies (Aims 1 and 2) that together with Research Project 1 and 3 will inform selection of the best leads for Technology Readiness Level 5 studies (medicalcountermeasures.gov) mid-way through the program (i.e. Aims 3 and 4). Aim 1 will assess lead optimized molecules for broad spectrum efficacy, PK and dose range finding studies in mouse models and preliminary safety in rat in years 1-3. Aim 2 will assess four lead optimized molecules for therapeutic window, dosing, delay of treatment to define dosing regimen and potential indications for treatment in lethal mouse models of V/E/WEEV in years 1-3. Aim 3 will evaluate lead candidate molecules with favorable criteria in nonGLP and GLP rat and non-human primate (NHP) safety, PK and toxicokinetic studies in collaboration with BASi, a commercial research organization. The pivotal efficacy studies in Aim 4 will evaluate the efficacy of the best lead quinazolinone in two animal species, mouse and cynomolgus monkeys, using dosing regimens defined in the preceding 3-4 years. The Center has two planned meetings with the FDA, one informal meeting mid-way through the program and one formal meeting prior to the efficacy studies in NHP in Aim 4. These studies will contribute to the reports to be readied by our consultants at Leidos.

项目摘要-项目2 目前，没有获得许可的人类疫苗或抗病毒药物可用于治疗或预防任何脑炎 甲病毒感染。因为甲病毒的流行是零星的、不可预测的，并且是地方病 很常见（美洲每年估计有 10,000 例），但很少被诊断出来，很难识别所有 需要接种疫苗的人群；因此，需要一种有效的暴露后处理方法来中断 持续爆发。为了满足这一公共卫生需求，我们提出了第一种小分子 预防和治疗潜力可能与 V/E/WEEV 自然流行病的使用相关 以及故意的释放场景。总之，成功的努力将产生一类新的抗病毒药物 用于治疗脑炎甲病毒；委内瑞拉马 (VEEV)、东部马 (EEEV) 和西部马 脑炎病毒（WEEV）。 U19 脑炎甲病毒卓越中心研究项目 2 治疗计划将领导、支持和管理动物模型中优化先导分子的测试 安全性、毒性、药代动力学和功效。拟议的多学科努力重点是 完成研究（目标 1 和 2），与研究项目 1 和 3 一起为选择 技术准备度 5 级研究 (medicalcountermeasures.gov) 的最佳线索 计划（即目标 3 和 4）。目标 1 将评估先导优化分子的广谱功效、PK 和 小鼠模型中的剂量范围探索研究以及大鼠 1-3 年内的初步安全性。目标 2 将评估四个 针对治疗窗、剂量、治疗延迟进行优化的分子，以定义给药方案和 1-3 年 V/E/WEEV 致死小鼠模型治疗的潜在适应症。目标 3 将评估领先优势 在非GLP和GLP大鼠和非人类灵长类动物（NHP）安全性、PK方面具有良好标准的候选分子 与商业研究组织 BASi 合作进行毒代动力学研究。关键功效 目标 4 中的研究将评估最佳铅喹唑啉酮对两种动物物种（小鼠和小鼠）的功效。 食蟹猴，使用之前 3-4 年定义的给药方案。该中心计划有两个 与 FDA 的会议、计划中途的一次非正式会议以及计划实施前的一次正式会议 目标 4 中 NHP 的功效研究。这些研究将有助于我们的顾问准备的报告 莱多斯。