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Recommended Short Courses*

Monday, June 14
9:00 am – 12:00 pm
(SC3) Translating Safety Biomarkers from the Lab to the Clinic
(SC4) Use of Stem Cells for Safety Screening 

2:00 pm - 5:00 pm
(SC6) Addressing Safety Concerns for Biological Drugs
(SC8) Mechanistic Insights into Cardiotoxicity

Wednesday, June 16 (Dinner will be served.)
6:00 pm - 9:00 pm
(SC9) Mechanistic Insights into Hepatotoxicity
 

*Separate Registration Required.



TUESDAY, JUNE, 15


7:15 am Registration and Morning Coffee


Translating Pre-Clinical Predictions To Clinical Safety

8:15 Chairperson's Opening Remarks

Gary Gintant, Ph.D., Senior Group Leader, Department of Integrative Pharmacology, Global Pharmaceutical Research & Development, Abbott Laboratories

8:25 Preclinical Cardiac Safety: Moving Ahead of hERG

Gary Gintant, Ph.D., Senior Group Leader, Department of Integrative Pharmacology, Global Pharmaceutical Research & Development, Abbott Laboratories

This presentation will discuss newer data related to the utility of various assays in the pre-clinical assessment of cardiac safety. Specific topics will include a) novel and evolving preclinical models, and b) how to link contingency tables, likelihood ratios and PK/PD modeling with the ICH S7B integrated risk assessment to guide the efficient design of early clinical studies.

8:55 To be announced

9:25 In vitro-In vivo Correlation of Cardiotoxicity for a Small Molecule Inhibitor

Amy Kim, Ph.D., Senior Scientist/Toxicologist, Department of Safety Assessment, Genentech, Inc.

QTc prolongation continues to be a potential cardiovascular toxicity risk for small molecule development. For a small molecule inhibitor, we describe in vitro to in vivo correlation of hERG inhibition and QT prolongation including ex-vivo (Langendorff guinea pig assay) and in vivo models (guinea pig and cynomolgus monkey), which enabled us to build a robust dataset demonstrating potential for cardiac liability for this molecule. Subsequently, the data generated from the in vitro to in vivo correlation was used to improve the structure-activity relationship of backup compounds for cardiovascular toxicity.

9:55 Networking Coffee Break


Novel in vitro Approaches For Assessing Cardiac Liabilities

10:25 Enriched Human Cardiomyocytes from Embryonic Stem Cells for Drug Discovery and Safety Pharmacology

William Sun, Ph.D., Group Leader, Stem Cell Technology, Experimental Therapeutics Centre, A*STAR

Using a trangenic approach, we can generate a pure population of cardiomyocytes from human embryonic stem cells. The enriched cardiomyocytes contract spontaneously in culture and express markers of primary cardiomyocytes. Extracellular recordings from these cells using microelectrode array enable evaluation of compounds for drug-induced QT prolongation. Functional human cardiomyocytes from stem cells are thus useful for drug discovery and predictive toxicology.

10:55 High Content Cardiotoxicity Profiling with Engineered Heart Tissues: Mitochondrial Toxicity and Genomic Influences

Tetsuro Wakatsuki, Ph.D., Assistant Professor, Physiology, Biotechnology and Bioengineering Center, Medical College of Wisconsin

Our objective is to recapitulate genome-based cardiotoxicity in engineered heart tissues (EHTs) fabricated from various inbred rat strains that show different susceptibilities to cardiovascular diseases. The cell-matrix solution contracted around the scaffold to form a miniaturized sheet (4X4mm) of EHT and their contractility, mitochondrial membrane potential, respiration, ATP synthesis, and reactive oxygen spices (ROS) production are monitored in high-throughput to assess the physiological states of myocytes in EHTs. Effects of genomic influence that alter cardiotoxicity of small molecules will be discussed.

11:25 Evolution of in vitro Strategies for Cardiotoxicity Assessment

Adam W. Hendricson, Ph.D., Research Investigator, Lead Evaluation and Ion Channels, Bristol-Myers Squibb Co.

Early and accurate assessment of cardiovascular ion channel toxicity is fundamental to preclinical research. For maximum impact, an in vitro assay triage must provide meaningful throughput and clear connectivity with in vivo measurements. Evolving technologies and perspectives are changing the landscape of in vitro CV safety. The current presentation will detail advances in functional in vitro assay approaches to CV safety, including automated electrophysiology.

Sponsored by
Elsevier
11:55 Luncheon Presentation I
Using Data Sources, Organization, and Longitudinal Views of Preclinical, Clinical and Post-Market Observations to Better Inform Drug Development Candidates Assessments
Philip MacLaughlin, Senior Product Manager, Elsevier
There is increasing emphasis on assessing drug candidates for prioritization and decision support throughout the drug discovery and development process. The safety, efficacy and delivery properties of the candidate must be assessed using the best comparative data within regulatory and business contexts.  Particularly rich sources of information in context are FDA Approval Packages, but they are not indexed or searchable; locating the relevant data can be impossible. This workshop will focus on work that we have done to these and other related relevant sources to make them accessible, so that a wide range of questions can be answered in a timely way to support better-informed drug development pipeline decisions.

    Sponsored by

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12:25 pm Luncheon Presentation II
Development of  Multiplexed Biomarker Assays for Toxicity
Pankaj Oberoi, Ph.D., Director, Qualified Kit Development, Director, Scientific Services, Meso Scale Discovery
Fingerprints of the protein expression in different tissue and samples can be used for drug efficacy, toxicology, and target selection. Multiplexing has the advantage of rapidly measuring levels of multiple analytes from a limited sample volume, which is critical for preclinical and clinical studies where samples are precious and often limited. Development of multiplexed assays, however, poses several challenges that we have overcome using the Meso Scale Discovery platform. One major hurdle to multiplexing is that proteins are present over 9 logs of concentrations (pg/ml to mg/ml) and the concentration of any given protein can vary by over 1000 fold for different conditions. Another challenge is that the sample matrixes and weak binding interactions with matrix proteins can interfere differentially with proteins. Naturally occurring binding partners can obscure the apparent concentration of a protein. Choosing the appropriate sets of assay diluents can solve these problems for some assays and create problems for others. Specificity of antibodies plays a major role in the ability to multiplex biomarkers. Multiplexing can be used to help understand the complex interaction of proteins that may be missed when measuring one protein at a time. We were able to overcome many of these challenges in developing a panel of preclinical toxicology markers where the protein levels can vary by several 100 fold when tissue specific injury occurs. We will present the assay development of cardiac muscle, skeletal muscle, and kidney injury markers. These lessons and development techniques can be applied broadly to developing multiplexed assays for secreted proteins as well as intracellular signaling markers.

 


Drug-Class Associated Cardiotoxicity

1:25 Chairperson's Remarks

Thomas Force, M.D., Professor, Medicine; Clinical Director, Center for Translational Medicine, Thomas Jefferson University

1:35 Understanding Cardiotoxicity of Tyrosine Kinase Inhibitors: From Clinical Outcomes to Mechanisms of Cardiotoxicity

Thomas Force, M.D., Professor, Medicine; Clinical Director, Center for Translational Medicine, Thomas Jefferson University

QTc prolongation continues to be a potential cardiovascular toxicity risk for small molecule development. For a small molecule inhibitor, we describe in vitro to in vivo correlation of hERG inhibition and QT prolongation including ex-vivo (Langendorff guinea pig assay) and in vivo models (guinea pig and cynomolgus monkey), which enabled us to build a robust dataset demonstrating potential for cardiac liability for this molecule. Subsequently, the data generated from the in vitro to in vivo correlation was used to improve the structure-activity relationship of backup compounds for cardiovascular toxicity.

2:05 Biologicals and Cardiac Toxicity Risk: Relating Toxicity to Mechanism of Action 

Noël Dybdal, Ph.D., D.V.M., Associate Director, Principal Scientist, Safety Assessment, Genentech, Inc.

Biological therapeutics in general and monoclonal antibodies specifically are highly targeted in their activity, risk of off-target toxicity is low. Adverse cardiovascular effects associated with these drugs to date result from on-target pharmacology and relate to their mechanism of action. Species specificity of biologics presents challenges that limit the extent to which cardiotoxicity risk can be assessed preclinically. The process and results of ongoing investigations into the mechanism of trastuzumab-associated cardiotoxicity will be presented and discussed as a case study.

2:35 PANEL DISCUSSION: How Well Can We Correlate In Vitro and In Vivo Models to Predict Cardiotoxicity?

Moderator: Thomas Force, M.D., Professor of Medicine and Clinical Director of the Center for Translational Medicine, Thomas Jefferson University

 

Sponsored by
QUINTILES_NEW
3:05 New Regulatory Landscapes for the Prospective Exclusion of Unacceptable Cardiovascular Risk: FDA and EMA Documents addressing the Development of New Antidiabetic Drugs for Type 2 Diabetes Mellitus
J. Rick Turner, Ph.D., Senior Scientific Director, Cardiac Safety Services, Quintiles
The US Food and Drug Administration’s December 2008 Guidance for Industry entitled Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes made assessment of cardiovascular safety a critical focus during the development of new antidiabetic therapies for Type 2 diabetes mellitus.  In January 2010, the European Medicines Agency released a draft document entitled Guideline on Clinical Investigation of Medicinal Products in the Treatment of Diabetes Mellitus.  This presentation provides a brief historical perspective on the evolution of these documents, and compares and contrasts the guidance provided by these two regulatory agencies on cardiovascular risk assessment.
Learning Objectives
Understand the evolution of regulatory guidance in this area.
Understand the details of the guidance provided by each regulatory agency.
Become aware of the similarities and differences between the two documents.
Consider how similar approaches may be used in other therapeutic areas.


3:35 Grand Opening Refreshment Break in the Exhibit Hall

PLENARY KEYNOTE PANEL

4:15 Shifting Sands of Pharmaceutical Discovery

Panelists:

Cris Waller Chris L. Waller, Ph.D., Senior Director, HealthCare Informatics, Medical Business Technology, Pfizer, Inc.







Gary PeltzGary Peltz, M.D., Ph.D., Professor, Anesthesia, Stanford University







Marvin BayneMarvin Bayne, Ph.D., Vice President, Head, Discovery Technologies, Merck & Co.







Thomas BocanThomas Bocan, Ph.D., Senior Director, Head, Pre-clinical BioImaging Center, Pfizer Global R&D,, Pfizer, Inc.







Peggy Guzzie-PeckPeggy Guzzie-Peck, Ph.D., DABT, Vice President, Head, Toxicology, Pathology & LAM, Johnson & Johnson, Pharma R&D






Key questions to be addressed:

  • How does academic research impact pharma drug discovery?
  • How does the creation of cross-pharma pre-competitive collaborations impact drug discovery, spanning chemistry, biology, and knowledge management?
  • Adoption of new technologies, such as, molecular Imaging: Can it help drug discovery and how quickly?
  • How effectively and efficiently can we collaborate to develop safer drugs?

5:45 Happy Hour in the Exhibit Hall

6:45 End of Day


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SPONSORSHIPS & EXHIBITS

The exhibit hall has sold out the past four years, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2015, contact:

Joseph Vacca
Associate Director, Business Development
781-972-5431
jvacca@healthtech.com 

 

 

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