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MAIN CONFERENCE

4:00-6:00pm Conference Pre-Registration 

MONDAY, MAY 12

7:30am–6:00pm Registration Open 

7:30am Morning Coffee 

8:20 Chairperson’s Remarks 
Peter Siegl, Ph.D., Independent Consultant (formerly at Merck & Co.)

8:25 Developing and Using an Integrated Risk Assessment for Managing Drug Candidates in Early Development
Peter Siegl, Ph.D., Independent Consultant 
Safety of drugs has received a great deal of public attention recently. Of particular note are drugs removed from the market because post-marketing safety data indicating that they are associated with the cardiac arrhythmia, Torsade de Pointes, and mortality. We can learn from these experiences to strike an effective balance between patient safety and availability of new drugs that truly benefit human health. This presentation will focus on the use of integrated risk assessments where combination of assays and information are employed to more effectively perform risk to benefit assessments for new drug candidates.

8:55 Pre-Clinical Cardiac Toxicity: Testing Compounds Beyond hERG
Gary Gintant, Ph.D., Senior Group Leader, Department of Integrative Pharmacology, Abbott Laboratories
It is well recognized that delayed repolarization accompanying hERG block is linked to potential arrhythmia, including Torsades-de-Pointes. However, this effect represents a narrow perspective in regards to ensuring cardiac safety. The multiple ion channels contributing to different electrophysiologic phenotypes of the heart represent multiple potential off-target effects that can modify impulse initiation (chronotropic effects), conduction (dromotropic effects), or contractility (inotropic effects). In addition, drugs may also affect cardiac contractility by actions unrelated to sarcolemmal ion channels. This presentation will present recent cases of pharmacologic cardiac toxicity and discuss approaches to detect and avoid such effects in the future.

9:25 Leveraging Early Liability and Drug Safety Assessment by Integration of Innovative Screening Automation and Novel Bioassay Technology 
Mary Ellen Cvijic, Ph.D., Senior Research Investigator, Lead Evaluation-Applied Biotechnology, 
Bristol-Myers Squibb Co.
Liability and drug safety assessment is the key to advance high quality drug candidates to the clinic. Case studies will be presented to illustrate the rationale and impact of our strategy on lead selection before advancing candidates into in vivo proof-of-concept studies. By employing this strategy, we demonstrate that this approach can significantly shorten timelines for lead optimization and influence chemical synthesis by providing complete in vitro data packages earlier in the discovery process. The criteria for selection of bioassay technology to assess compound liabilities will be recommended based on the lessons we learned. Future technology needs and process improvements for monitoring cardiotoxicity and off-target liabilities will also be discussed. 

9:55    Technology Watch  Automated Cardiac Ion Channel Safety Screening Assays to Detect Use- and Voltage-Dependent Modulation of Drug Affinity John P. Imredy, Ph.D., Research Fellow, Cellular Safety Investigations Safety Assessment, Merck Research Laboratories Inhibition of cardiac Na2+ or Ca2+ currents (INa or ICa L) can lead to undesirable electrocardiographic effects in vivo.  Evaluation of INa and ICa,L block may involve determination of use- or voltage-dependent changes in the affinity of block.  Optimization and validation of automated ion channel assays require tailoring assay protocols and current recording conditions to the possibilities offered by the new technology.  This presentation will highlight specific challenges encountered during the implementation of use- and voltage-dependent inhibition assays in automated ion channel cardiac safety screening.

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10:10 Networking Coffee Break 

10:40 Cardiomyocytes Derived from Human Embryonic Stem Cells – Novel Opportunities for Drug Safety Assessment 
Peter Sartipy, Ph.D., Senior Scientist and Project Manager, Cellartis AB
Human embryonic stem cells can be differentiated into spontaneously contracting cardiomyocytes in vitro. Molecular and functional characterization has demonstrated that the differentiated cells share similarities with their adult counterparts. For example, they express many of the important ion-channels, such as the hERG channel, and their functionality can be assayed using specific inhibitors in combination with electrophysiological evaluation. The availability of human stem cell derived cardiomyocytes allows the design and development of innovative assay systems to address relevant cardiac safety pharmacology parameters.

11:10 Assessing Cardiac Safety in Clinical Trials: Imaging Strategies
Pamela S. Douglas M.D., MACC, FASE , Professor of Research in Cardiovascular Diseases, Director, Cardiovascular Imaging Center, Duke Clinical Research Institute 
While cardiac toxicity should ideally be detected in preclinical testing, surveillance for cardiac safety is a critical component of clinical trials for all drugs. Cardiac toxicity can take many forms including electrophysiologic, myocardial, vascular, and inflammatory each of which has different manifestations and natural history, and each requires different algorithms for surveillance. Using cancer therapies as a model, approaches to toxicity detection using biomarkers and imaging strategies will be discussed.

11:40 A Panel of Cardiac Ion Channels for Cardiac Risk Assessment
Arthur M. Brown, M.D., Ph.D., Chairman and CEO, ChanTest, Inc., Adjunct Professor, Case Western Reserve University
A cardiac channel panel consisting of the nine most important cardiac ion channels has been validated with automated and manual patch clamp, pharmacology, cDNA sequence and Western blot. The Cardiac Channel Panel™ identifies not only drugs with HERG risk. More complicated effects are also identified. One drug was negative for HERG block, positive for APD and QT prolongation, positive in the channel panel and potentially proarrhythmic. Another drug was positive for HERG block, negative for APD/QT prolongation, positive for sodium and calcium channel block in the Channel Panel™ and potentially antiarrhythmic. Screening a panel of cardiac ion channels provides a mechanistic explanation for drug effects on cardiac excitability.

12:10   Multiplexed Assays on the MesoScale Discovery Platform to Assess Rat Critical Target Organ Toxicities Warren Glaab, Ph.D., Associate Director, Systems Toxicology, Safety Assessment, Merck Research Laboratories

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1:25 Session Break 

1:40 Chairperson’s Remarks 
Thomas Force, M.D., Professor of Medicine and Clinical Director of the Center for Translational Medicine, Thomas Jefferson University 

1:45 Understanding Cardiotoxicity of Tyrosine Kinase Inhibitors: From Clinical Outcomes to Mechanisms of Cardiotoxicity (Part I) 
Ming Hui Chen, M.D., M.M.Sc., FACC, Assistant Professor of Medicine, Harvard Medical School Brigham and Women’s Hospital and Children’s Hospital Boston
In this two-part talk by Drs. Chen and Force, we will illustrate the importance of interdisciplinary collaboration and a translational approach to defining cardiotoxicity of new anti-cancer therapies. Specifically, we will focus on the translational work done with sunitinib (Lancet) and imatinib (Nature Medicine), along with the clinical and imaging approaches used with early clinical detection of unexpected cardiotoxicity and start to define concepts and mechanisms which may underlie the cardiotoxicity. We will also summarize what is known about cardiotoxicity of other TKIs, focusing on basic mechanism through which interruption of specific signaling pathways leads to cardiomyocyte dysfunction and/or death. 

2:15 Understanding Cardiotoxicity of Tyrosine Kinase Inhibitors: From Clinical Outcomes to Mechanisms of Cardiotoxicity (Part II) 
Thomas Force, M.D., Professor of Medicine and Clinical Director of the Center for Translational Medicine, Thomas Jefferson University 

 

2:45 Technology Watch   Pre-Clinical Assessment of Cardiac Functionality: Relevance of ES-Cell Derived Systems in Drug Development and Toxicology Heribert Bohlen, PD, Ph.D., Med., CEO, Axiogenesis AG Well-defined pure cardiomyocytes derived from mouse ES cells can be used in functional studies and toxicology assays to provide valuable insight into the clinical behavior of a compound in development. Clinical modeling analyses using these cells – either healthy or diseased-state – in pre-clinical development, will provide knowledge on inclusion and/or exclusion criteria for early phase clinical studies and help to reduce costs and the overall time to Phase III.

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3:00 Grand Opening Refreshment Break in the Exhibit Hall 

3:40 Re-engineering of Imatinib to Decrease Cardiac Risk: Translational Ideas in Drug Discovery
Ariel Fernandez, Ph. D., Chair in Engineering and Professor of Bioengineering, Rice University, Texas
Molecular targeting is central to drug-based cancer therapy, but remains challenging because drugs often lack specificity, which may cause toxic side effects. I shall survey a translational bottom-up strategy to curb side effects and focus primarily on kinases. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a portion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. We created a modified version of imatinib and our findings identify the re-engineered imatinib as an agent to treat GISTs with curbed side effects. 

4:10 Evaluation of Cardiotoxicity of Novel Molecular Therapies
Roger J. Hajjar, M.D., Professor of Medicine, Director, Cardiovascular Research Center, Mount Sinai School of Medicine, New York
Even though the main focus of cardiac toxicity has been the electrophysiological effects, especially those that produce QT prolongation, the indirect effects can also target the myofilaments, the mitochondria, and intracellular transporters. One such example is the cancer therapeutic agent, imatinib mesylate, which has mitochondrial effects in cultured cardiomyocytes. Supporting this, electron micrographs of both cardiac biopsies from individuals with imatinib-induced heart failure and the hearts of mice treated with imatinib showed mitochondrial abnormalities. Therefore, evaluation of various agents needs to take into account cardiac toxicity at the level of the membrane, cytoplasm, sarcoplasmic reticulum, mitochondria, and myofilaments.

4:40 Translating Pharmacogenomics to Personalized Medicine: Optimizing Drug Safety in Clinical Studies to Prevent Cardiotoxicity 
Amalia M. Issa, Ph.D., MPH, Associate Professor, University of Houston and Director, Program in Personalized Medicine and Targeted Therapeutics 
Drug-induced forms of cardiotoxicity, such as long-QT syndrome (LQTS) and torsades des pointes are well documented problems that have been demonstrated to be largely due to genetic polymorphisms in drug metabolizing enzymes. Pharmacogenomics research is increasingly directed at developing genomic diagnostics and tests with predictive ability for ADRs. We have evaluated the potential for pharmacogenomics to determine ADRs in phase III clinical trials and in post-marketing studies, with a particular focus on the development of tools to identify risk of drug-induced cardiotoxicity ADRs.

5:10 Happy Hour in the Exhibit Hall 

6:10 End of Day 

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