Institute for Scientific Exchange, Inc. Presents:

 

ETS-2006 6th International Conference on Early Toxicity Screening   June 22-23, 2006 The Edgewater Hotel, Seattle, WA, USA

Featuring experts from the following institutions: The ADMET Group LLC; Arena Pharmaceuticals; AstraZeneca; Biotrin International; CeeTox, Inc.; Charles River Laboratories Preclinical Sciences; CZ Technologies, LLC; HemoGenix, Inc.; Hoffmann-La Roche Inc.; Institute for In Vitro Sciences, Inc.; Invitrogen Corporation; Merck Research Laboratories; Multi Channel Systems MCS GmbH; NIEHS; Novartis Institutes for Biomedical Research; Promega Corp.; Seattle Genetics, Inc.; Unilever R&D; University of Washington

 

PARTICIPATING EXHIBITORS:

  REGISTER

      Seattle, Washington State, USA

 

 

Thursday, June 22, 2006

 

  REGISTER

 

 

8:00 AM – 9:00 AM – REGISTRATION

 

8:00 AM – 5:00 PM – EXHIBITS

 

8:45 AM – 8:55 AM – Exhibitor Presentation – Advion BioServices

 

8:55 AM – 9:00 AM – Welcoming Remarks

 

9:00 AM – 9:30 AM

The Use of Primary Human Cells in Early Toxicology Screening for Prediction of Livertoxicity and Hematopoietic Liabilities (Claudia McGinnis, Maria Eckert, Novartis Institutes for Biomedical Research; Cambridge MA) Side effects such as livertoxicity and bone marrow suppression cause serious limitations in the development of new drugs. Early toxicology screening characterizes early drug candidates for potential liabilities and supports the lead optimization process towards a cleaner compound profile. Two cell-based, high-throughput luminescence assays for the detection of liver- and bone marrow toxicity were developed using primary human cells, cryopreserved human hepatocytes and fresh human bone marrow. In vitro toxic effects of test compounds were tested in a microplate format and cell viability determined by quantitation of cellular ATP. Data will be presented on the validation of these assays with a set of marketed drugs and Novartis compounds. The assays are implemented as a global, routine service for lead finding and optimization phases.

9:30 AM – 10:00 AM

In Silico Models for the Prediction of Dose‑Dependent Human Hepatotoxicity (Ailan Cheng, CZ Technologies, LLC.  State College, PA) This talk will present a new, fully‑general in silico model which is able to predict the occurrence of dose‑dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non‑toxic and provides a confidence level to indicate which predictions are most likely to be correct.  Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

 

10:00 AM – 10:30 AM

A Microarray-based Approach to Understanding Drug Bioactivation in Rodent Liver (Greg Slatter and Wei Tang, Rosetta Inpharmatics LLC (A subsidiary of Merck & Co., Inc.) Seattle, WA, and Drug Metabolism Research, Merck Research Laboratories, Rahway NJ) Gene expression profiling using DNA microarrays has the potential to improve how the pharmaceutical industry relates preclinical hepatic effects to underlying factors such as drug concentration, reactive metabolite formation, and oxidative stress. Dose-related effects on compound-specific transcriptional fingerprints can be correlated with diverse biological phenotypes to define differences within structurally- or pharmacologically-related compounds. As such, the biological sequelae and underpinnings of chemical exposure can be elucidated earlier in development and in greater detail than ever before.

 

10:30 AM – 10:50 AM – BREAK

 

10:50 AM – 11:20 AM

QT Prolongation: A Roche Perspective on Predictive Assays (Heather Guthrie, Hoffmann-La Roche Inc.; Nutley, NJ) The prediction of clinical QT prolongation through preclinical assays has been under debate due to the lack of correlation in identifying drug candidates producing adverse cardiovascular events in human. Although QT prolongation has been associated with IKr block, hERG inhibition has been considered a weak biomarker in detecting proarrhythmic risk. More sensitive assays are required to elucidate events which lead to QT prolongation, such as triangulation, reverse-use dependence, dispersion of repolarization, beat-to-beat instability, etc. In compliance with the ICH S7B guidelines (Oct. 19, 2005), Roche has implemented the Langendorff isolated heart assay to be used in used in conjunction with the hERG assay and non-rodent radiotelemetry model as a core battery cardiovascular derisking strategy.

 

11:20 AM – 11:50 AM

 New Cell Models & Assays in Cardiac Safety Profiling (Thomas Meyer, Multi Channel Systems MCS GmbH; Sartipy, Peter  Cellartis SA; Guenther, Elke  Natural and Medical Sciences Institute at the Tuebingen University; Reutlingen, GERMANY) The early screening for cardiotoxic side effects of new medical entities currently requires to compromise between data quality and throughput. Whereas the gold standard is patch clamp of primary ventricular cardiomyocytes of suitable species, HTS suitable assays use cell lines stably expressing the hERG channels for electrophysiological and non-electrophysiological assays. The limitations of these assays have been discussed extensively previously. With the combination of the QT-Screen system (Multi Channel Systems, Reutlingen, Germany)with cardiomyocyte aggregations differentiated from human embryonic stem cells (Cellartis SA, Gothenburg, Sweden), a novel assay is going to overcome the species limitation and provide a functional electrophysiological readout. First results do look promising; however a thorough evaluation regarding the
 development status of the cells, ion channel expression pattern and reproducibility is still required.

 

11:50 AM – 1:15 PM – LUNCH

 

1:15 PM – 1:25 PM – Exhibitor Presentation –  XenoTech LLC

 

1:30 PM – 2:00 PM

Predictive In Vitro Hemotoxicology and the Concept of “In Vitro Comparative Toxicity, Cross-Platform Technology (Ivan N. Rich, HemoGenix, Inc.; Colorado Springs, CO) The HALO Predictive Hemotoxicology Platform (PHP), which can detect and measure up to 14 lympho-hematopoietic cells populations from 5 species simultaneously, has been described at previous ETS meetings. The HALO Platform is now joined by 2 new in vitro toxicity platforms, LUMENESC and STEMTox. LUMENESC detects toxicity on mesenchymal stem cells and their differentiating elements while STEMTox detects toxicity in proliferating cells from numerous other organs and tissues. The same luminescence detection system is common to all 3 platforms, but together can be used to compare toxicity in over 50 different cell types derived from 14 different human cell systems.

 

2:00 PM – 2:30 PM

Medium Throughput Automated In Vitro and Ex Vivo Assays for Frontloading Bone Marrow Toxicity Screening (François Pognan, AstraZeneca, Global Safety Assessment,  Cheshire UK) Bone marrow toxicity is a cause of late stage compound attrition in the pharmaceutical industry.  This is typically assessed during the pre-Candidate Drug phase. The objective of bone marrow early screening in the discovery phase is to identify chemistry-associated liabilities and to frontload risk assessment. To this end, a screening tiered approach has been developed that enables a large number of compounds to be evaluated around early 'Lead Optimisation' phase. Various cell lines representative of broad bone marrow lineages are used as pre-assessment of chemicals series (Tier 1). Then, a new and automated assay using primary bone marrow cells following a similar principle to the Colony Forming Unit (CFU) assay (Tier 2), is run to qualify and confirm tier 1 findings. This may also trigger in vivo study frontloading (Tier 3). This tiered approach allows weeding out early on compounds with chemistry-related bone marrow toxicity from the research project pipelines.

 

2:30 PM – 3:00 PM

Skeletal Muscle:  A Target for Toxicity by Marketed and Investigational Drugs (Russell Westwood, AstraZeneca R&D Alderley Park; Cheshire, UK) Skeletal muscle is not as homogeneous as it might first appear and each drug type can show a different temporal development and character of muscle fiber toxicity.  The changes seen by pathology may give an indication of mechanism allowing further tailored investigations.  The presentation although focusing on statin induced myopathy will contrast the findings with those from other drugs. 

 

3:00 PM – 3:20 PM – BREAK

 

 

3:20 PM – 3:30 PM – Exhibitor Presentation –  Simulation Plus, Inc.

 

3:30 PM – 4:00 PM

Microfluidic (Lab-on-a-chip) Screening Technologies (Albert Folch, University of Washington, Seattle, WA) Microtechnology offers the attractive possibility of modulating the microenvironment of single cells and, for the same price, obtain data at high throughput for a small cost.  Microfluidic or “Lab on a Chip” devices, in particular, promise to play a key role for several reasons: 1) the dimensions of microchannels can be comparable to or smaller than a single cell;  2) the unique physicochemical behavior of liquids confined to microenvironments enables new strategies for delivering compounds to cells on a subcellular level;  3) the devices consume small quantities of precious/hazardous reagents (thus reducing cost of operation/disposal);  and 4) they can be mass-produced in low-cost, portable units.  Not surprisingly, in recent years there has been an eruption of microfluidic implementations of a variety of traditional bioanalysis techniques. I will review the latest efforts of our laboratory in the development of cell-based microdevices for cell biology studies, such as neuromuscular synaptogenesis, axon guidance, and chemotaxis.

 

4:00 PM – 4:30 PM

Integrated Discrete Co-culture Technologies (Organ(s)-on-a-Chip) for Toxicity Screening (Albert P. Li, The ADMET Group LLC; Rockville, MD) A novel technology has been developed in our laboratory to allow the co-culturing of multiple cell types as physically-separated (discrete) cultures while being interconnected (integrated) by an overlying medium, a technology termed IDC –Integrated Discrete Co-culture.  Using this technology, the toxic potential of an agent towards multiple cell types can be evaluated under virtually identical conditions.  The IDC can be applied to evaluate the toxic potential of an agent towards multiple organs (Organs-on-a-Chip), or multiple cells of the same organ (Organ-on-a-chip).  Data of both applications will be shown to demonstrate the utility of this novel technology which has the potential to refine, replace, and reduce the use of animals in research.  The use of human cells in the IDC will allow the assessment of human toxicity either for multiple key cell types of a single organ (e.g. evaluation of pulmonary toxicity via the co-culturing of large airway epithelium, small airway epithelium, pulmonary microvascular endothelial cells), or multiple organs (e.g. hepatocytes (liver); kidney (proximal tubule epithelial cells; CNS (astrocytes); vascular endothelium (aorta endothelial cells; and lung (small airway epithelial cells).

 

4:30 PM – 5:00 PM

Development of an Early Toxicity Screening Cascade for the Assessment of the Activity of Antibody-Drug Conjugates (May Sutherland, Changpu Yu, Renee McCormick, Kerry Klussman, Julie McEarchern, Che Law, and Alan Wahl. Seattle Genetics, Inc., Seattle, WA) In order to minimize systemic toxicity and maximize tumor exposure, we have developed a strategy to deliver anti-cancer drugs directly to tumors by conjugating them to antibodies specific for tumor antigens. The potential toxic effects of these antibody-drug conjugates against normal tissues, however, cannot be wholly identified or predicted based upon the properties of attached drugs or the antibody itself. We therefore developed a series of in vitro assays representing known sensitive organs to evaluate the safety of our antibody-drug conjugates. The development of assays comprising primary cultures of human and nonhuman primate cells to assess safety of anti-body drug conjugates will be discussed.

 

5:00 PM – 5:10 PM – SHORT BREAK

 

5:10 PM – 5:40 PM

Histologically Defined Biomarkers in Drug Development (Martin Shaw, Biotrin International; Dublin, IRELAND) Using biomarkers with unique, histologically defined distributions leads to increased sensitivity, specificity and easier interpretation of results. This presentation will review their use in hepatotoxicity and nephrotoxicity testing and the discovery of new biomarkers by immunohistological screening – Histomics@. Data will be presented demonstrating how histologically defined biomarkers enable toxic compounds to be detected earlier and at lower doses.

 

5:40 PM – 6:15 PM:  Panel Discussion Session 1& 2

 

END OF DAY

Friday, June 23, 2006

 

 

8:00 AM – 9:00 AM – REGISTRATION

 

8:00 AM – 5:00 PM – EXHIBITS

 

8:50 AM – 9:00 AM – Exhibitor Presentation – Qualyst

 

9:00 AM – 9:30 AM

Improving Drug Candidate Selection by Incorporating In Vitro Toxicity Data into the Discovery Process (Jim McKim, CeeTox, Inc.; Kalamazoo, MI) Identifying potential adverse properties of new chemical entities early in the discovery process enhances the candidate selection process and increases the probability of success in preclinical and clinical safety studies.  This approach requires a robust array of cell-based screening paradigms that can be tiered in a way that enables researchers to fine tune the discovery funnel for choosing leads that have been optimized for both the desired attributes of a drug and for safety.  A systems biology approach combined with multiple endpoint analysis, dose-response, and in vivo validation can provide an excellent bridge between the in vitro screening environment and expected in vivo effects. This presentation will focus on a tiered approach to in vitro screening and demonstrate the in vivo predictive value of the data obtained.  

 

9:30 AM – 10:00 AM

Comparison of In Vitro Assays of Cellular Toxicity in the Human Hepatic Cell Line HepG2 (Silvia Miret, Unilever R&D; Vlaardingen, The NETHERLANDS) In this study we compared different in vitro assays for cytotoxicity in HepG2 cells. The assays evaluated included Alamar Blue for the measurement of mitochondrial activity, ATPlite and ViaLight Plus for the determination of cellular ATP, ToxiLight for cellular necrosis and Caspase-3 assay, Apo-ONE assay and Caspase-Glo for caspase-3/7 activity. It was concluded that the best way to evaluate the potential cytotoxicity of a compound is to employ a battery of assays that focus on different aspects of cell death. However, the use of ViaLight Plus, ToxiLight and Caspase-3 assay resulted in the most useful combination.

 

10:00 AM – 10:30 AM

Validation & Regulatory Acceptance of In Vitro Toxicity/Potency Assays ((Hans Raabe, Institute for In Vitro Sciences, Inc.; Gaithersburg, MD) This session will focus on the design and validation of in vitro bioassays intended for use in the regulated environment.  Bioassay are designed around four components; a specific cell or tissue, defined exposure conditions, characterized endpoint measures of the biological effect, and a predetermined relationship between the endpoint values and the effect being predicted (potency or toxicity). The assay’s predictive capacity is dependent on maintaining consistency in these parameters from assay validation through its routine use for regulatory submissions.

 

10:30 AM – 10:50 AM – BREAK

 

10:50 AM – 11:20 AM: Panel Discussion Session 3

 

 

11:20 AM –11:30 AM – Exhibitor Presentation – SOLVO Biotechnology

 

11:30 AM – 12:00 PM

Bioluminescent Approaches For In Vitro ADME/Tox (James J. Cali, Promega Corp.; Madison, WI) Bioluminescent assays offer significant advantages for configuring sensitive, simple to perform assays with ADME/Tox applications. Cell-based assays will be described that examine test compounds for P450 induction at the enzyme level and for cytotoxicity. In vitro assays will also be described for measuring P450 and monoamine oxidase inhibition and the stimulation of P-glycoprotein (MDR1) ATPase activity by test compounds. Each system relies on the light generating reaction of firefly luciferase, correlating light output with target activity. This suite of homogeneous assay is sensitive, robust and convenient for small scale and high throughput applications.

 

12:00 PM – 12:30 PM

The Role of Early In Vivo Toxicity Screening in Drug Safety Evaluation (Jessica E. Sutherland, Charles River Laboratories Preclinical Services; Worcester, MA) A properly designed toxicity screening program (including in vivo studies) can be used to optimize lead compounds in attempt to identify which should move from discovery into development.  Early in vivo toxicity screening is also useful during pilot and dose range-finding studies or when formulation decisions are needed.  Selection of the proper animal model(s), sample size, route of administration, and toxicological endpoints is vital to the success of these early nonclinical assays.

 

12:30 PM – 2:00 PM – LUNCH BREAK

 

2:00 PM –2:10 PM – Exhibitor Presentation – CeeTox, Inc.

 

2:10 PM – 2:40 PM

Managing Oxidative Bioactivation in Drug Discovery (Wei Tang, Merck Research Laboratories, Rahway, NJ) The rate of success had steadily declined in all phases of the drug development process during recent years.  One of the underlying causes of attrition is safety-related issues, which, in some cases, may be attributed to the formation of reactive metabolites and subsequent covalent modification of proteins.  In this regard, compound 1 examined in our laboratory produced a high level of CB in human liver microsomal incubations.  The CB is likely due to the formation of an iminium ion resulting from P450-catalyzed oxidation of the piperidine moiety of compound 1.  A joint effort between Medicinal Chemistry and Drug metabolism eventually led to the identification of a pyrrolidine analogue 2 as a drug candidate.  Compound 2 not only maintained pharmacological potency and selectivity but also exhibited a lower propensity to CB.  It is hoped that practice of this type will reduce attrition rate in drug development, while the ultimate goal is to provide safer medicine to the public.

 

2:40 PM – 3:10 PM

Detection and Quantification of Neurotoxic Ab42 Aggregates (Mary Michael Brodey, BioSource Cytokines & Signaling; Invitrogen Corporation Camarillo, CA) Many neurodegenerative diseases can be characterized by fibrillar inclusions and soluble oligomeric protein aggregates. Soluble aggregates of beta amyloid are implicated as the etiological agent in Alzheimer’s disease. Using a highly sensitive, bead-based immunoassay developed for the Luminex^TM platform, we are able to quantify neurotoxic aggregates of beta amyloid 1-42 (Ab42). The toxicity of these aggregates is confirmed by monitoring cell metabolism with alamarBlue^TM and MTS, using PC-12 and SH-SY5Y cells. The use of multiplexed, bead-based immunoassays to monitor activation of signal transduction pathways and changes in cytokine production profiles will be discussed.

 

3:10 PM – 3:40 PM

Strategies to Eliminate Toxicity with Structural Modification Approaches in Drug Discovery (Weichao Chen, Arena Pharmaceuticals, San Diego, CA)  Toxicity of drug candidates is one of the major problems facing the pharmaceutical industry. Hepatotoxicity, cardiotoxicity and drug-drug interaction related toxicities are the three major reasons for the failure of drug candidates.   Early toxicity screening could weed out compounds with potential toxicity, and structure activity relationship for toxicity could be established with screening results. Structural modification approaches can be utilized to avoid potential toxicity of drug candidates.  Case studies including both successes and failures in drug discovery will be presented.

 

3:40 PM –3:50 PM – Exhibitor Presentation – BRI Biopharmaceutical Research Inc.

 

3:50 PM – 4:10PM –  BREAK

 

4:10 PM – 4:40 PM

A New Approach to Toxicity Testing at the NTP:  High Throughput Screening (Kristine L. Witt, NIEHS; Research Triangle Park, NC) Since mid-2005, NIEHS/NTP has formally participated in the NIH Molecular Libraries Initiative (MLI) by collaborating directly with the NIH Chemical Genomics Center to use high throughput screening (HTS) to test compounds for activity against defined targets.  This collaboration adds toxicity testing capabilities to MLI, and has allowed rapid implementation of NTP’s HTS program designed to screen large numbers of compounds for toxicity.  NTP will link HTS-produced toxicity data to data from classical in vivo toxicity tests, with the goal of identifying mechanisms of action requiring additional investigation, developing predictive models for biological response, and prioritizing substances for further toxicological evaluation.

 

4:40 PM – 5:10 PM: Panel Discussion Session 4

 

END OF CONFERENCE

 

 

POSTER PRESENTATIONS:

 

Poster Presentations are always encouraged.  Please submit your poster abstract for approval by the organizing board by May 30^th.  Poster size should be no larger than 3 feet high by 7 feet long.  Abstracts of posters will be included in the participant binder and in the ISE website.  There is no formal poster presentation scheduled.  All posters will remain displayed throughout the conference.  Please be prepared to display your poster during registration on Wednesday, June 21^st or before the first session begins on Thursday, June 22^nd.  Poster presenters will have ample time for discussion during breaks and the Panel discussions. Submit posters abstracts for approval to Nola Mahaney, VP, Operations; ISE, Inc.; 5707 Calverton Street, Suite 2C; Baltimore, MD 21228 or fax at (410) 869-9560 or email file attachment to nola@isciencex.com.  Approved poster presenters are responsible for completing a conference attendance registration form and payment of fee (visit www.isciencex.com/register.htm) and for the shipping of the poster itself.  Please contact Nola Mahaney for any questions or concerns.  Please refer to “Travel Information” for hotel address and shipping information.

 

PARTICIPATING EXHIBITORS:

CeeTox

 Hotel Information:

 

 

Travel Information:

Seattle’s only waterfront hotel. All the makings of a breathtaking vacation await you at The Edgewater. Nestled on Seattle’s waterfront at Pier 67, we’re surrounded by beauty: The majestic Olympic Mountains. The sparkling waters of Elliott Bay. And the velvety-pink sunsets of the Northwest sky. We’re in the heart of downtown, so you’ll be within walking distance to the city’s favorite sites. But you just might decide to relax right here, soaking up the view beside a river-rock fireplace.

 

Hotel Information:

The Edgewater Hotel, 2411 Alaskan Way, Pier 67
Seattle, Washington (WA) 98121 Hotel Direct (Tel) 206.728.7000 (Fax) 206.419.4119 Reservations 800.624.0670  www.edgewaterhotel.com

http://www.edgewaterhotel.com/default.aspx?pageid=reservation

Please ask for “DDI-2006” block for ISE, Inc.

 

 Early Registration Discount: (SAVE $$$ until April 3, 2006) 

 

Exhibitors:            US$2000.00 (ETS-2006) ________

                                US$2000.00(DDI-2006)   ________

                                US$3000.00 (both events) ______

 

Contact Nola Mahaney for Exhibitor or Sponsorship Opportunities at nola@isciencex.com, or phone (410) 869-9166); or visit www.isciencex.com/exhibitors

 

Academic/Government participants will receive a 50% discount. 

 

  REGISTER

PLEASE NOTE WHICH PROGRAM YOU WISH TO ATTEND IF REGISTERING FOR MULTIPLE PROGRAMS.

 

Event(s) (check all events registered)	Individual Course/Conference - $ (Check if only registering for one single event)	Special Combination Discounts:  Check one of the combinations if registering for more than one event Early Registration Discounts Available (see below)
Tutorial 1 06/19/2006	US $400.00 ______	Both Tutorials:  US$800.00  ________   1 Tutorial and 1 Conference: US $1700.00 _______
Tutorial 2 06/19/2006	US $400.00 ______	2 Tutorials and 1 Conference: US$2000.00   __________   Both Conferences: US $2500.00  __________
DDI-2006 06/20-06/21/2006	US $1500.00 ______	1 Course and 2 Conferences:  US$2700.00 ___________   All Four Events: US $2900.00  __________
ETS-2006 06/22-06/23/2006	US $1500.00 ______

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  REGISTER

 

Payment

Payment may be made by check or credit card.  Checks should be made in US $, payable to Institute for Scientific Exchange, Inc.  Mail to: ISE, Inc., 5707 Calverton Street, Suite 2C, Baltimore, MD 21228, USA

 

Cancellation Policy

All cancellations are subjected to a $250.00 cancellation fee. Longer than 30 days, 100% refund (less $250.00). Less than 30 days, no refund but registration may be transferred to another person.  All refund requests must be in writing.  All refunds will be issued after the meeting has occurred. No refunds requests will be accepted after May 19, 2006. Please submit cancellation and refund requests including transferring of registration to:

 

Fax:  410-869-9560

E-mail: nola@isciencex.com

Cancellation Deadline: May 19, 2006

 

Email to nola@isciencex.com or mail/fax completed form with remittance to: ISE, Inc. 5707 Calverton Street, Suite 2C, Baltimore, MD 21228, USA; FAX No:  (410) 869-9560.  Payment may be made by check in US$, payable to Institute for Scientific Exchange, Inc. or by credit card.

  REGISTER