Development of BIO 300 for mitigation and/or treatment of radiation pneumonitis and fibrosis

开发用于缓解和/或治疗放射性肺炎和纤维化的 BIO 300

基本信息

批准号：
10401463
负责人：
Isabel Lauren Jackson
金额：
$ 37.43万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2020-06-16 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10401463
关键词：
Acute Address Advanced Development Agreement Anatomy Animal Model Animals Area BCL2L1 gene Biological Process Blinded Blood specimen Bone Marrow C57L/J Mouse Cancer Patient Cell Aging Cell Death Cell Survival Cells Clinical Clinical Data Collaborations Combined Modality Therapy Competitive Binding Complex DNA Damage DNA Repair Data Development Disease Progression Dose Drug Exposure Drug Kinetics Enzyme-Linked Immunosorbent Assay Estrogen Receptor beta Evaluation Exposure to Fibrosis Goals Hour Human In Vitro Individual Inflammation Inflammatory Response Intramuscular Intramuscular Injections Knowledge Life Lung Mediating Medical Imaging Methods Modeling Morbidity - disease rate Mus NF-kappa B Natural History Nuclear Accidents Oral Oral Administration Outcome Outcome Measure Oxidative Stress Pathogenesis Patients Peripheral Blood Mononuclear Cell Pharmacology Plasma Play Protac Publishing Pulmonary Inflammation Radiation Accidents Radiation Dose Unit Radiation Injuries Radiation Pneumonitis Radiation Sicknesses Radiation Syndromes Radiation Toxicity Radiation exposure Radiation induced damage Radiation therapy Randomized Readiness Recovery of Function Regimen Regulatory Pathway Research Rodent Role Safety Signal Transduction Statistical Data Interpretation Structure of parenchyma of lung Supportive care Suspensions Syndrome Systems Biology Technology Testing Therapeutic Tissues Treatment Efficacy United States Food and Drug Administration Whole-Body Irradiation animal efficacy animal rule base candidate marker design efficacy study experience experimental study functional outcomes good laboratory practice improved indexing injury recovery lung injury medical countermeasure member model design mouse model nonhuman primate novel pharmacodynamic biomarker pharmacometrics pneumonitis and fibrosis radiation countermeasure senescence standard of care survival outcome tissue biomarkers transcriptome sequencing

项目摘要

Project Summary/Abstract – Project 4 Radiation Pneumonitis/Fibrosis There is a critical, unmet need to develop medical countermeasures (MCM) for the mitigation of the delayed effects of acute radiation exposure (DEARE), namely radiation pneumonitis/fibrosis, in victims successfully treated for acute radiation sickness following a radiological or nuclear incident. The overall objective of project 4 is to complete activities necessary to bring BIO 300 (“BIO 300”) nanosuspension (Humanetics Corporation, Edina, MN) towards approval under the U.S. Food and Drug Administration (FDA) Animal Rule regulatory pathway for the indication to increase survival in individuals acutely exposed to pulmonary-toxic doses of radiation [e.g. delayed effects of acute radiation-exposure (DEARE)-lung]. Our published data indicates BIO 300 (400 mg/kg, QD, oral gavage) confers a significant improvement in survival from DEARE-lung when treatment is started 24 hours after exposure to life-threatening doses of radiation and continued for six weeks (5). Further, clinical data demonstrate an excellent safety profile when BIO 300 is administered as a daily oral regimen (500 - 1500 mg) over a minimum duration of six weeks. Project 4 is highly interactive with the other Projects and Cores within the INTERACT Consortium. Studies in Aim 1 are designed to optimize the BIO 300 dosing regimen to maximize the likelihood of survival from DEARE- lung. Higher drug exposure has been observed in murine and non-human primate models when BIO 300 is administered by intramuscular (IM) injection versus oral administration. Therefore, IM administration may further improve the therapeutic benefit of BIO 300 on 220-day survival and mitigation of lung damage beyond that observed with oral dosing. Specific Aim 2 will be conducted in collaboration with Core B-Multispecies Efficacy and Pharmacometric Modeling. Experiments in this aim are designed to identify and validate plasma-based pharmacodynamic (PD) biomarkers associated with BIO 300 mediated ERb activation and downstream effects on cellular senescence in rodents and NHP. A systems biology approach incorporating pharmacometric modeling will be utilized, and will incorporate known BIO 300-mediated effects on PD biomarkers in cancer patients undergoing clinical radiation therapy to relate the proposed mechanism of action of BIO 300 in animal models to the presumed mechanism in humans. The role of cellular senescence in DEARE-lung is further explored in Aim 3 through the testing of senolytic agents alone or in combination with BIO 300. Further, Aim 3 will address knowledge gaps relevant to the pathophysiological mechanisms underlying ARS evolving towards DEARE and testing of novel senolytic agents (BCL-xL-P) through strong collaborations with Projects 1, 2, and 3. Power calculations and statistical analysis for Project 4 will be performed by the biostatistician in Core A - Administrative Core. The proposed Aims are only achievable through a cooperative research agreement, as proposed by the INTERACT Consortium, whose members bring together expertise in every major area required to probe the complex biological processes orchestrating radiation damage in lung tissue and discover new biomarkers for tissue injury and recovery.

项目摘要/摘要 – 项目 4 放射性肺炎/纤维化制定医疗对策 (MCM) 来缓解这种情况是一个至关重要的、尚未得到满足的需求。急性辐射暴露（DEARE）对受害者的延迟影响，即放射性肺炎/纤维化成功治疗放射性或核事故后的急性放射病总体目标。项目 4 的目的是完成将 BIO 300（“BIO 300”）纳米悬浮液（Humanetics Corporation（明尼苏达州埃迪纳）即将获得美国食品和药物管理局 (FDA) 动物规则的批准提高急性暴露于肺毒性剂量的个体的生存率的调节途径辐射的影响[例如急性辐射暴露（DEARE）-肺的延迟影响]。 300（400 mg/kg，QD，口服强饲）可显着改善 DEARE-lung 的存活率接受危及生命的辐射剂量后 24 小时开始治疗，并持续六周 (5) 此外，临床数据表明，每日口服 BIO 300 具有出色的安全性。治疗方案（500 - 1500 mg）至少持续六周。项目 4 与 INTERACT 联盟研究中的其他项目和核心具有高度互动性。目标 1 旨在优化 BIO 300 给药方案，以最大限度地提高 DEARE- 患者的生存可能性当 BIO 300 存在时，在小鼠和非人类灵长类动物模型中观察到较高的药物暴露。与口服给药相比，肌肉注射（IM）给药因此，IM 给药可能会进一步发展。提高 BIO 300 对 220 天生存率的治疗效果并减轻肺损伤具体目标 2 将与 Core B-Multispecies Efficacy 合作进行。该目的的实验旨在识别和验证基于血浆的药物。与 BIO 300 介导的 ERb 激活和下游效应相关的药效 (PD) 生物标志物啮齿类动物和 NHP 细胞衰老的研究，一种结合药理学的系统生物学方法。将利用模型，并将结合已知的 BIO 300 介导的对癌症 PD 生物标志物的影响接受临床放射治疗的患者将 BIO 300 在动物中的作用机制联系起来人类推测的机制模型进一步证实了细胞衰老在 DEARE-lung 中的作用。通过单独测试 senolytic 药物或与 BIO 300 结合使用，在目标 3 中进行了探索。此外，目标 3 将解决与 ARS 发展的病理生理机制相关的知识空白 DEARE 和通过与项目 1、2 和项目的强有力合作测试新型 senolytic 药物 (BCL-xL-P) 3. 项目 4 的功效计算和统计分析将由核心 A 的生物统计学家进行 - 行政核心。拟议的目标只能通过合作研究协议来实现，因为由 INTERACT 联盟提出，其成员汇集了所需的每个主要领域的专业知识探索肺组织辐射损伤的复杂生物过程并发现新的组织损伤和恢复的生物标志物。