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.
The identification of cardiotoxic drugs in advance of adverse events in humans remains an area of major challenge for pharmaceutical companies and Federal regulators. The present proposal aims at developing a predictive, robust and cost-effective laboratory methodology based on human cardiac tissue from organ donors. It is expected that the technology outcome of this project will significantly improve the ability to identify potentially dangerous molecules and therefore reduce or eliminate human exposure to such agents