Validation and qualification of an ex vivo human cardiac tissue-based assay for the assessment of the potential cardiotoxicity of pharmaceutical compounds

项目总结 药物引起的心脏毒性和不良事件仍然是这两个行业以及 监管者。早期识别药物发现和开发过程中的这些潜在责任的现行战略 开发过程包括体外分析、动物模型和广泛的基于心电的 心脏复极研究是在第二阶段临床试验期间在受试者身上进行的。这些是后者 这些研究被称为“彻底的Qt”研究(TQt)，因为它们专门关注与药物有关的研究。 QT间期的变化--心脏复极和诱发心律失常的生物标志物 活动。虽然这些策略在识别潜在危险的前心律失常方面做出了贡献 分子，这一点也变得越来越明显，这种方法可以进行重大改进。最近， FDA药品评价和管理中心心血管和肾脏产品部门的领导 研究促进了许多旨在征集小说开发和验证的倡议 评估新药心脏安全性的实验模型。正如监管机构明确表示的那样，目标是 “到2015年7月，用一种或多种临床前化验取代TQT临床研究”(诺曼博士 斯托克布里奇，中国证监会-HESI-FDA会议，2013年7月24日，马里兰州银泉)。物种差异造成 所有以动物模型为基础的方法都有不可逾越的局限性。此外，较新的战略依赖于 在心肌细胞上，人工来源的干细胞或iPS细胞并不能忠实地复制所有生理上的 这是天然成人心肌细胞的特征，并不能模拟衰老和并存的影响。 AnaBios最近开发了一种新型的基于体外人体心脏的药物安全性评价平台，该平台 目前正在FDA接受正式的Biomarker资格认证。技术依赖于利用率 用于进行体外心脏活动测量的实验室中存活的人类供体心脏 确定新药致心律失常的潜力。此方法最初在第一阶段得到验证 使用一组以盲法测试的5种参考化合物。我们证明了这个人类前男友的能力- 正确区分促心律失常药物和非促心律失常药物的体内试验。这一新方法 提供人类临床心脏研究的近亲，但避免了与药物暴露相关的风险 临床中的人体试验，以及临床研究带来的高昂成本和延长的时间线。这个 目前的第二阶段提案将充分利用我们的体外人体心脏方法，通过进一步验证和 精炼致心律失常模型，并通过将平台推进到商业化准备阶段 将允许提供大量的药物安全评估服务。通过为研究人员提供相关的 以人为本的安全数据，我们预计这一二期项目产生的服务将改变心脏 药物安全评估。

PROJECT SUMMARY Drug-induced cardiac toxicity and adverse events remain a major challenge for both industry as well as regulators. The current strategies for early identification of these potential liabilities in the drug discovery and development process involves a combination of in vitro assays, animal models and an extensive ECG-based cardiac repolarization study which is conducted on human subjects during Phase 2 clinical trial. These latter studies are known as “Thorough QT” studies (TQT) since they have specifically focused on drug-related changes in the QT interval, a biomarker for cardiac repolarization and the induction of pro-arrhythmic cardiac activity. While these strategies have contributed in the identification of potentially dangerous pro-arrhythmic molecules, it is also becoming apparent that this approach is amenable to significant improvements. Recently, the leadership at the Division of Cardiovascular and Renal Products of the FDA Center for Drug Evaluation and Research has facilitated a number of initiatives aimed at soliciting the development and validation of novel experimental models for assessing cardiac safety of new drugs. As explicitly stated by the regulators, the goal is “to replace the TQT clinical studies with one or more pre-clinical assays, by July 2015” (Dr. Norman Stockbridge, CSRC-HESI-FDA Meeting, July 24, 2013, Silver Spring, MD). Species differences create insurmountable limitations for all approached based on animal models. In addition, newer strategies relying on cardiomyocytes artificially derived from stem cells or iPS cells do not faithfully replicate all the physiological features of native adult human cardiomyocytes and do not model the effects of aging and comorbidities. AnaBios has recently developed a novel ex-vivo human heart-based drug safety evaluation platform, which is currently undergoing formal Biomarker Qualification at the FDA. The technology relies upon the utilization of viable human donor hearts in the laboratory for conducting ex-vivo measurements of cardiac action potentials to determine the arrhythmogenicity of new drugs. This approach was initially validated in Phase I using a set of 5 reference compounds tested in blinded fashion. We demonstrated the ability of this human ex- vivo assay to correctly discriminate pro-arrhythmic from non-pro-arrhythmic drugs. This new approach provides the next of kin to a human clinical cardiac study, but avoids the risks related to drug exposure in humans in the clinic, as well as the high costs and extended timelines which come with the clinical studies. The present Phase II proposal will fully leverage our ex-vivo human heart methods by further validating and refining the arrhythmogenicity model and by advancing the platform to a commercialization-ready stage that will permit service of a large number of drug safety evaluations. By providing researchers with the relevant human based safety data, we anticipate the services resulting from this Phase II project will transform cardiac drug safety assessment.