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7:00am Registration (Open until 5:30pm)

8:20am Chairperson's Remarks
Judith K. Marquis, Ph.D., Group Vice President, Pharmacology &
Preclinical Development, Genzyme Corp.

8:30 Challenges of Doxercalciferol, a Prodrug of a Potent Vitamin D Hormone
Joyce Knutson, Ph.D., Senior Director of Research, Bone Care
International
Doxercalciferol is a potent compound (therapeutic dose in micrograms), that is inactive until metabolized in the liver to an active form (circulating concentration pg/mL) that is also an endogenous compound. Bioanalytical challenges were compounded by species differences in sensitivity and gender differences in metabolism. Anticipation and proactive actions to overcome these preclinical challenges resulted in the successful development of doxercalciferol for treating dialysis patients for secondary hyperparathyroidism.

9:00 Predicting the Undesirable Pharmacodynamic Effects of Small Molecules on Physiological Function: From the Brain to the Heart
Vivek Kadambi, Ph.D., Director of Drug Safety Evaluation, Millennium Pharmaceuticals, Inc.
This presentation will focus on two case studies which have shown a good correlation
between the effects observed in nonclincial studies and in humans. Case study 1 will focus on the CNS effects relating to sedation and somnolence. Case study 2 will focus on the electrophysiologic effects on the cardiac conduction system.

9:30 GMX1777 Case Study: Using Metabolomics to Determine the Mechanism of Action of an Anti-Cancer Compound
Anne Roulston Ph.D., Group Leader, Cancer Biology, Gemin X Biotechnologies Inc., Canada
GMX1777 is a soluble prodrug of the pharmacologically active compound GMX1778. Initiation of Phase I clinical trials began in patients with refractory solid tumors and lymphomas. We have since discovered that GMX1778 functions by inhibiting nicotinamide phosphoribosyl transferase (NAMPRT), an enzyme involved in nicotinamide adenine dinucleotide (oxidized) (NAD+) biosynthesis. The approach used to identify the key mechanism of action of GMX1778 and the new opportunities this information provides for the clinical development of GMX1777 will be discussed.

10:00 Technology Spotlight (Sponsorship Available)

10:15 Technology Spotlight (Sponsorship Available)

10:30 Poster Competition & Refreshment Break in the Exhibit Hall

11:30 Discovery and Development of AMD3100 as a Stem Cell Mobilizer
Ron T. MacFarland, Ph.D., Senior Director, Pharmacology and Toxicology, Anormed Pharmaceuticals
AMD3100 is a small molecule inhibitor of the chemokine receptor CXCR4 and blocks binding of its cognate ligand SDF-1. AMD3100 was originally discovered in an antiviral drug screening program, and its initial development directed towards use in the treatment of HIV infection. Transient increases in white blood cell counts observed in humans following AMD3100 administration, combined with an understanding of the role of the SDF-1/CXCR4 axis in blood cell homing and maturation in the bone marrow prompted investigation and subsequent development of AMD3100 for use as a stem cell mobilizing agent.

12:00pm The Importance of Integrating Disciplines to Increase the Probability of Successful Drug Development
Cindy Berman, Ph.D., Independent Consultant
Several examples will be presented of cross-species pharmacological responsiveness for small molecules that can be extended to selection of a clinical starting dose. Toxicity will be discussed as it relates to non-specific effects. Potential PK differences between normal and disease conditions (in vitro, animal, or human) will be compared, as well as the importance of understanding whether a drug receptor is up or down regulated in the disease condition. Potential "tox" differences between normals and patients will be described, emphasizing the importance of understanding the clinical population and testing for toxicity in an appropriate model.

1:45 Chairperson's Remarks
Carl L. Alden, Ph.D., Vice President, Preclinical Development & Drug Safety Evaluation, Millennium Pharmaceuticals, Inc.

1:50 Integration of Novel Technologies in Discovery and Early Development Toxicology
Eric A. G. Blomme, D.V.M., Ph.D., Diplomate A.C.V.P., Project Leader, Abbott Laboratories
Toxicity represents an important cause of failure in the late stages of discovery and preclinical development. Therefore, early identification of the toxic liabilities of experimental compounds represents one of the most promising alternatives to decrease overall R&D costs. In this presentation, we will review our current Discovery toxicology strategy that leverages several new methodologies in an effort to characterize the toxicologic profile of compounds at early stages. Using specific examples, we will illustrate how this approach can be successfully implemented in a discovery or preclinical organization.

2:20 A Lead Optimization and Early Development Toxicology Strategy Specific to Novel Oncology Targets
Carl L. Alden, Ph.D., Vice President, Preclinical Development & Drug Safety Evaluation, Millennium Pharmaceuticals, Inc.
Discovery stage and early nonclinical development toxicology studies in the oncology therapeutic area present unique challenges in predicting for success in the clinic, relative to adverse effects. The attrition rate in oncology development is over 90%, often because of toxicity. Frequently, what is termed failed efficacy is actually a consequence of lack of tumor specificity for the therapeutic target. The challenge to the discovery & early development stage toxicologist is amplified for novel targets in oncology. A strategy to avoid progressing molecules with chemical structure based adverse effects while refining the understanding of the tumor specificity and the PK/PD/toxicity relationships across species, specific to novel oncology therapeutic candidates, will be the focus of this presentation.

2:50 Predictive Value of in Vitro Safety Studies
Willi Suter, Ph.D., Unit Head, Genetic Toxicology and Safety Pharmacology, SP&A, Novartis Pharma AG
The predictivity of in vitro methods and their importance for decision-making in drug development is shown for four important areas of pharmaceutical safety evaluations, i.e. genetic toxicology, safety pharmacology, phototoxicity and organ toxicity. A comprehensive analysis of the predictivity of genetic toxicity tests for rodent carcinogenicity revealed a major problem with the specificity of the in vitro mammalian cell assays, which indicates the risk that efficacious drug candidates might have been dropped because of false positive in vitro results. Therefore, data from in vitro studies, including the recently introduced hERG channel inhibition test to predict QT interval prolongation and from the in vitro 3T3 NRU phototoxicity test to predict phototoxicity should be used with great care for decision-making. In vitro organ toxicity models provide important mechanistic information. The information obtained from in vitro models has significantly improved the safety of patients in clinical studies, since there is much more data available early in the development process.

3:20 Plenary Keynote

4:00 Ice Cream Refreshment Break in the Exhibit Hall with BEST OF SHOW AWARDS

4:45 Strategies for Early Toxicity Testing with Focus on Genotoxicity Evaluations
Michael J. Schlosser, Ph.D., D.A.B.T., President and Founder of Midwest BioResearch (MBR)
There is a wide array of new screening tools available to toxicologists, but the use of a particular screen must be decided carefully to optimize the success of a drug program. Although rapid throughput genetic toxicity screens that require minimal amounts of compound are available during lead optimization, their value for predicting regulatory outcome is dependent on the specific screen chosen. Screens that mimic the ICH genotoxicity testing battery are best at predicting IND success and will need to keep pace with possible changes in ICH guidelines to maintain predictive value. Regulatory-based genotoxicity screening technologies are also useful in supporting the safety of metabolites, impurities and degradation products when only minimal amounts of these materials are available. Several examples of regulatory-based genotoxicity screening strategies, including SAR techniques, will be presented.

5:15 Speaker to Be Determined

5:45 End of Day