TGx-DDI (DDT-BMQ-000008) ring trial: a cross-site validation study of an in vitro transcriptomic biomarker for genotoxicity testing

TGx-DDI (DDT-BMQ-000008) 环试验：用于遗传毒性测试的体外转录组生物标志物的跨站点验证研究

• 批准号: 10409881
• 负责人: Saddef Haq
• 金额: $ 25万
• 依托单位: HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2023-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409881
• 关键词: TGx; DDI; DDT; BMQ; 000008

1 Project Abstract/Summary 2 Genotoxicity testing is a crucial component of preclinical safety evaluation for drugs and 3 chemicals. The development of biomarkers that can enhance efficiency and translational 4 relevance during the drug development process is critical to both FDA and NIH’s public health 5 mission. We have developed the TGx-DDI transcriptomic biomarker, which meets critical drug 6 development needs by providing an efficient, reproducible approach to assessing whether a drug 7 causes DNA damage that is relevant to the development of cancer in vivo. The interpretation of 8 positive in vitro genotoxicity findings in new drug testing is a major challenge to industry and 9 regulatory agencies. These tests have high sensitivity, but low specificity, leading to high rates of 10 irrelevant positive findings. Irrelevant positive results can trigger expensive, time-consuming 11 follow-up tests with uncertain outcomes that involve animal usage and can result in the exclusion 12 of potentially useful drug candidates from further development. TGx-DDI is a novel, transcriptomic 13 biomarker measuring changes in the expression of 64 genes in human cells culture following 14 exposure to test agents relative to solvent controls. In combination with a publicly accessible web 15 tool available via the National Toxicology Program, this approach provides important evidence to 16 classify whether a tested compound is or is not DNA-damage inducing (DDI) with high specificity 17 for in vivo genotoxicity. The TGx-DDI biomarker is under evaluation to complement in vitro positive 18 chromosome damage tests as part of the FDA’s 21st Century Cures mandated Drug Development 19 Tools (DDT) Qualification Process. In support of this evaluation, this application seeks funding to 20 execute a multi-site ring trial to evaluate the reproducibility of the TGx-DDI biomarker method 21 under comparable conditions at multiple laboratories. A total of 17 blinded compounds will be 22 tested at four different laboratory sites using common standard operating procedures, a common 23 cell line, and a common transcriptomic platform (NanoString). The study will be deemed a 24 successful demonstration of cross-laboratory performance if each laboratory successfully 25 executes the defined protocols and arrives at the same, correct call (DDI or non-DDI) for each of 26 the compounds. The results of this study will be incorporated into the final data package to be 27 submitted to the FDA DDT qualification program and will hopefully lead to the official qualification 28 of the TGx-DDI biomarker. Once qualified, this marker will provide critical weight of evidence to 29 support the current genotoxicity testing battery and will thus enhance the accuracy and efficiency 30 of drug development. This represents a major step towards modernizing our approach to risk 31 assessment by using new tools and analytical pipelines like the ones described here.

1项目摘要/摘要 2遗传毒性测试是药物临床前安全性评价的重要组成部分 3种化学物质。可提高效率和转化率的生物标记物的开发 4药物开发过程中的相关性对FDA和NIH的公共健康都至关重要 5.任务。我们已经开发出满足关键药物的TGX-DDI转录生物标记物 6通过提供一种高效、可重复的方法来评估一种药物是否 7会导致DNA损伤，这与体内癌症的发展有关。释义--解读 8新药测试中的体外遗传毒性阳性结果是对工业和 9个监管机构。这些检测具有很高的敏感性，但特异性较低，导致高发病率。 10个不相关的阳性发现。无关紧要的积极结果可能会引发昂贵、耗时的 11次后续试验，结果不确定，涉及动物使用，可能导致排除 12个来自进一步开发的潜在有用的候选药物。TGX-DDI是一种新颖的、转录的 13个生物标志物检测基因在人细胞培养中的表达变化 14与溶剂对照相比，暴露于测试剂。与公众可访问的网络相结合 15通过国家毒理学计划提供的工具，这种方法提供了重要的证据 16对被测化合物是否具有高度特异性的DNA损伤诱导(DDI)进行分类 17为体内遗传毒性。TGX-DDI生物标志物正在评估为补体体外阳性 作为FDA 21世纪治疗强制药物开发的一部分，18项染色体损伤测试 19工具(滴滴涕)鉴定流程。为了支持这项评估，本申请寻求资金，以 20进行多部位环试验以评估TGX-DDI生物标记物方法的重复性 21在多个实验室的可比条件下。共有17种失明化合物将被 22在四个不同的实验室地点使用共同的标准操作程序进行测试，共同的 23细胞株，以及一个共同的转录平台(纳米串)。这项研究将被视为 24如果每个实验室都成功，则成功演示跨实验室性能 25执行定义的协议，并为每个协议提供相同、正确的调用(DDI或非DDI 26化合物。这项研究的结果将被纳入最终的数据包中， 27提交给FDA滴滴涕资格认证计划，有望获得官方资格 TGX-DDI生物标志物中的28个。一旦合格，这一标记物将为 29支持目前的遗传毒性测试电池，从而提高准确性和效率 30%的药物开发。这是我们实现风险管理方法现代化的重要一步。 31使用此处所述的新工具和分析管道进行评估。