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/概要 2遗传毒性试验是药物临床前安全性评价的重要组成部分， 3化学品生物标志物的发展，可以提高效率和翻译 4药物开发过程中的相关性对FDA和NIH的公共健康至关重要 5.使命。我们已经开发了TGx-DDI转录组生物标志物，其符合关键药物 通过提供一种有效的、可重复的方法来评估药物是否 7引起与体内癌症发展相关的DNA损伤。的解释 在新药测试中发现8个阳性体外遗传毒性结果是对行业的重大挑战， 9个监管机构。这些测试灵敏度高，但特异性低，导致高患病率 10个不相关的阳性结果。不相关的积极结果可能会引发昂贵，耗时的 11项涉及动物使用并可能导致排除的结局不确定的随访试验 12个潜在有用的候选药物从进一步发展。TGx-DDI是一种新的转录组学 13种生物标志物测量人类细胞培养物中64种基因表达的变化， 14相对于溶剂对照暴露于测试试剂。与可公开访问的Web相结合 15工具可通过国家毒理学计划，这种方法提供了重要的证据， 16以高特异性分类测试化合物是否是DNA损伤诱导（DDI）的 17例为体内遗传毒性。正在评价TGx-DDI生物标志物，以补充体外阳性 18项染色体损伤试验作为FDA 21世纪世纪治愈授权药物开发的一部分 19工具（滴滴涕）资格鉴定程序。为了支持这项评估，本申请寻求资金， 20执行多位点环试验以评估TGx-DDI生物标志物方法的再现性 21在多个实验室的可比条件下。总共将有17种设盲化合物 在四个不同的实验室地点使用共同的标准操作程序对22个进行了测试， 23细胞系，和一个共同的转录组学平台（NanoString）。该研究将被视为 24个实验室成功演示跨实验室性能，如果每个实验室成功 25执行所定义的协议，并对每个协议达到相同的正确调用（DDI或非DDI）。 26篇化合物本研究的结果将纳入最终数据包， 27提交给FDA滴滴涕资格认证计划，并有望导致官方资格 28的TGx-DDI生物标志物。一旦合格，该标记将提供关键的证据权重， 29支持目前的遗传毒性测试组合，从而提高准确性和效率 30药物开发这代表着我们在风险管理方法现代化方面迈出的重要一步 31评估通过使用新的工具和分析管道，如这里所描述的。