Validation and qualification of an ex vivo human cardiac tissue-based assay for t

基于离体人体心脏组织测定的验证和鉴定

• 批准号: 8715622
• 负责人: Andrea Ghetti
• 金额: $ 20.07万
• 依托单位: ANABIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-24 至 2015-12-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715622
• 关键词: 8 year old; Action Potentials; Address; Adverse event; Area; Arrhythmia; Biological Assay; Biological Markers; Cardiac; Cardiotoxicity; Cardiovascular system; Clinical; Clinical Research; Clinical Trials; Data; Development; Dose; Drug Evaluation; Drug Exposure; Drug Industry; Early identification; Electrocardiogram; Evaluation; Evaluation Research; Experimental Models; Exposure to; Goals; Heart; Human; In Vitro; Incidence; Industry; Kidney; Laboratories; Leadership; Letters; Measurement; Measures; Methodology; Noise; Organ Donor; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preclinical Drug Development; Process; Risk; Safety; Services; Signal Transduction; Silver; System; Technology; Testing; TimeLine; Tissue Sample; Tissues; Validation; base; clinically relevant; commercialization; cost; cost effective; drug development; drug discovery; exposed human population; human subject; human tissue; improved; in vivo; man; meetings; novel; pre-clinical; public health relevance; response; screening

DESCRIPTION (provided by applicant): Drug-induced cardiac toxicity and adverse events remains 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 and in vivo assays, followed by an extensive ECG-based cardiac repolarization study which is conducted on human subjects during Phase II. 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 undoubtedly contributed in the early identification of potentially dangerous pro-arrhythmic molecules, it is also becoming apparent that this approach, now over 8 years old, is amenable to significant improvements. Recently, both leaders in the pharmaceutical industry as well as regulators from the FDA, have expressed concerns related to: a) The costs associated with the current approach, in particular the TQT studies; b) The prolonged timelines involved in TQT studies; c) The false positive rate due to the utilization of biomarkers (like QT prolongation) that do not completely correlate with the occurrence of arrhythmias; d) The risks involved in exposing patients to high doses of drugs still in development, as required by the TQT studies. Based on these concerns, 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 and, in particular, their pro-arrhythmic potential. 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). AnaBios has recently developed a novel 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 function. This approach will be utilized to test human cardiac responses to novel drug in a pre-clinical assay, providing the next best kin to a human clinical cardiac study, but avoidin the risks related to drug exposure in man, the high costs and extended timelines which come with the clinical studies. The present proposal focuses on the validation of this ex-vivo heart platform in order to demonstrate its feasibility, robustness and overall value in predicting human clinical responses.

描述（由申请人提供）：药物引起的心脏毒性和不良事件仍然是行业和监管机构面临的主要挑战。目前在药物发现和开发过程中早期识别这些潜在缺陷的策略涉及体外和体内测定的结合，然后在第二阶段对人类受试者进行广泛的基于心电图的心脏复极研究。 后面的这些研究被称为“彻底 QT”研究 (TQT)，因为它们特别关注 QT 间期的药物相关变化，QT 间期是心脏复极的生物标志物和诱发促心律失常的心脏活动。虽然这些策略无疑有助于早期识别潜在危险的促心律失常分子，但也越来越明显的是，这种已有 8 年多历史的方法值得重大改进。最近，制药行业的领导者以及 FDA 的监管机构都表达了对以下方面的担忧： a) 与当前方法相关的成本，特别是 TQT 研究； b) TQT 研究涉及的时间较长； c) 由于使用与心律失常的发生不完全相关的生物标志物（如 QT 延长）而导致的假阳性率； d) 根据 TQT 研究的要求，使患者接触仍在开发中的高剂量药物所涉及的风险。基于这些担忧，FDA 药物评价和研究中心心血管和肾脏产品部门的领导层推动了一系列举措，旨在开发和验证用于评估新药心脏安全性的新型实验模型，特别是它们的促心律失常潜力。正如监管机构明确指出的，目标是“ 到 2015 年 7 月，用一种或多种临床前检测取代 TQT 临床研究”（Norman Stockbridge 博士，CSRC-HESI-FDA 会议，2013 年 7 月 24 日，马里兰州银泉）。AnaBios 最近开发了一种新型人类心脏基于药物安全性的评估平台，目前正在 FDA 进行正式的生物标志物认证，该技术依赖于在实验室中利用活的人类捐赠心脏进行离体测量。这种方法将用于在临床前测定中测试人类心脏对新药物的反应，为人类临床心脏研究提供下一个最佳的亲属，但避免与人类药物暴露相关的风险和高成本。以及临床研究带来的延长的时间表。目前的提案重点是验证该离体心脏平台，以证明其在预测人类临床反应方面的可行性、稳健性和整体价值。

项目成果

Human ex-vivo action potential model for pro-arrhythmia risk assessment.

用于心律失常风险评估的人类离体动作电位模型。

• 发表时间: 2016
• 影响因子: 1.9
• 作者: Page, Guy;Ratchada, Phachareeya;Miron, Yannick;Steiner, Guido;Ghetti, Andre;Miller, Paul E;Reynolds, Jack A;Wang, Ken;Greiter;Polonchuk, Liudmila;Traebert, Martin;Gintant, Gary A;Abi
• 通讯作者: Abi