SBIR-STTR Award

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 'toreplace 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.

Thesaurus Terms:
8 Year Old;Action Potentials;Address;Adverse Event;Area;Arrhythmia;Base;Biological Assay;Biological Markers;Cardiac;Cardiotoxicity;Cardiovascular System;Clinical;Clinical Research;Clinical Trials;Clinically Relevant;Commercialization;Cost;Cost Effective;Data;Development;Dose;Drug Development;Drug Discovery;Drug Evaluation;Drug Exposure;Drug Industry;Early Identification;Electrocardiogram;Evaluation;Evaluation Research;Experimental Models;Exposed Human Population;Exposure To;Goals;Heart;Human;Human Subject;Human Tissue;Improved;In Vitro;In Vivo;Incidence;Industry;Kidney;Laboratories;Leadership;Letters;Man;Measurement;Measures;Meetings;Methodology;Noise;Novel;Organ Donor;Outcome;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Pre-Clinical;Preclinical Drug Development;Process;Public Health Relevance;Response;Risk;Safety;Screening;Services;Signal Transduction;Silver;System;Technology;Testing;Timeline;Tissue Sample;Tissues;Validation;

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.

Public Health Relevance Statement:
PROJECT NARRATIVE 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 new drugs and therefore reduce or eliminate human exposure to such agents.

NIH Spending Category:
Cardiovascular; Heart Disease

Project Terms:
Action Potentials; Adult; Adverse event; age effect; Algorithms; Animal Model; Animals; Area; Arrhythmia; base; Biochemical; Biological Assay; Biological Markers; Blinded; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular system; Cells; Clinic; Clinical; Clinical Research; commercialization; Comorbidity; cost; cost effective; Data; data acquisition; Development; Dimethyl Sulfoxide; drug development; drug discovery; Drug Evaluation; Drug Exposure; drug testing; Drug usage; Early identification; Electrocardiogram; Electrodes; Evaluation; Evaluation Research; Exhibits; Experimental Models; exposed human population; Exposure to; Goals; Heart; Human; human subject; improved; In Vitro; in vitro Assay; Incidence; induced pluripotent stem cell; Industry; Kidney; Laboratories; Leadership; Measurement; meetings; Methodology; Methods; Modeling; molecular carrier; novel; novel strategies; novel therapeutics; Organ Donor; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; Phase II Clinical Trials; Physiological; pre-clinical; Pre-Clinical Model; Preparation; Process; Property; Publishing; Recovery; research clinical testing; Research Personnel; Risk; Risk Assessment; Safety; Sampling; scale up; Sensitivity and Specificity; Services; Silver; Small Business Innovation Research Grant; species difference; Staging; Stem cells; System; Technology; Testing; Time; TimeLine; tissue processing; Tissues; Toxic effect; Validation; Ventricular