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Tuesday, October 17

8:30 Chairperson’s Comments Marcel van Duin, Ph.D.
	8:40 The Use of Integrative Pharmacology in Drug Repositioning  Louis A. Tartaglia, Ph.D., Senior Vice President and General Manager, Drug Repositioning & Selection, Gene Logic Inc.  A set of technologies has been integrated to provide  the means of efficiently associating compounds with potential new therapeutic utilities. These technologies could be applied to chemical entities throughout the drug discovery and development process. This would be in stark contrast to the unsystematic and serendipitous observations that are classically relied upon to reveal alternative or new drug indications. The specific technologies to be used and early proof of concept experiments are outlined and discussed. This application of reverse-chemical genetics (i.e., Target -> Compound -> Disease -> Drug) in mammalian systems will more rapidly assign disease utility to the rapidly growing orphan chemical matter within the industry. These technologies will therefore reduce pipeline gaps within the pharmaceutical industry during this critical period when growth may become threatened by reduced (and increasingly costly) new product flow.
	9:10 Drug Repurposing: Why Now? Why Is It Important? How Do You Do It?  Christopher A. Lipinski, Ph.D., Scientific Advisor, Melior Discovery and Adjunct Senior Research Fellow, Exploratory Medicinal Sciences, Pfizer Global R&D Groton Labs Drug Repurposing is finding a new use for an old drug. Drivers for the importance of this approach are: 1) the shortage of high quality targets for oral drugs; 2) the unfavorable economics of drug discovery against poorly validated or unvalidated targets and 3) the ability to obtain US patent protection. A variety of complimentary approaches are possible for drug repurposing. The majority of new uses are related to the original drug mechanism. I will describe the experimental, in-vivo phenotypic screening approach in a new startup -Melior Discovery. Compounds are chosen based on clinical safety and chemical attractiveness and the experimental phenotypic screening is serendipitous and not biased toward mechanism. A single compound is profiled across 35 multiplexed in-vivo mouse screens using about 600 mice in total per single compound. The approach is very much like screening in the 1970’s except much more efficient. In part because of the very large target opportunity space we find a success rate of 30% in finding a new use for an old drug.
	9:40 A Transcriptional Connectivity Map for Biomedical Discovery  Justin Lamb, Ph.D., Senior Scientist, Cancer Program, and Leader, Connectivity Map Project, Broad Institute of MIT and Harvard  Genome-wide transcriptional analysis provides a com prehensive molecular representation of cellular activity, suggesting that mRNA expression profiling could serve as a practical universal functional bioassay. High-throughput high-density gene expression profiling solutions raise the possibility of capturing the consequences of small molecule and genetic perturbations at library and genome scale, respectively, and associating these disparate perturbagens with each other and external organic phenotypes—through the transitory feature of common gene expression changes—to discover decisive functional connections between chemistry, genes and diseases. The talk will describe our technology platform, analysis methods and interpretive tools, and illustrate how our solution can be used to identify new and valuable activities of bioactive small molecules, with particular emphasis on existing pharmaceuticals.
10:10 Coffee Break
	11:00 In Silico Approaches to Drug Repositioning John Overington, Ph.D., Vice President, Drug Discovery, Inpharmatica Ltd.  The concept of polypharmacy of many drugs is beyond dispute, however it is not yet clear how to maximally  align a drug to its eventual commercial indications throughout its discovery and development. Our approach to repositioning molecules relies on datamining of a carefully curated database of drugs, their approved indications, affinities, selectivities, and molecular targets. We have developed a series of algorithms to apply this database, using a broad range of input data. For example, from an observed novel pharmacology to a new predicted target mechanism, or the application of clinical microarray data to identify new applications of existing drugs. We have recently extended this database to include a large number of clinical development candidates. During the presentation the issues of generating this database will be detailed, along with several validation examples of the application of this approach.
	11:30 Phenotypic Screening for Drugs to Combat Neurodegenerative Diseases Rita Sattler, Ph.D., Department of Neurology, Johns Hopkins University  Glutamate is the principal excitatory neurotransmitter in the central nervous system. Inactivation of synaptic  glutamate is achieved by transporting glutamate into astroglial cells via membrane spanning glutamate transporter proteins. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumors and epilepsy. Despite the critical role of these transporters in normal and abnormal synaptic activity, no drugs have previously been developed against this target. In a blinded screen of 1,040 drugs and nutritionals, most FDA-approved, we identified a number of small molecule compounds as potent stimulators of glutamate transporter expression. This action appears to be mediated through increased transcription of the transporter gene. We have advanced several of the active drug classes into in vitro and in vivo neurotoxicity models and were able to demonstrate biological activity. Thus we have identified existing drugs, none currently used for neurological indications that can be advanced as neurotherapeutics into clinical trials.

1:30 Chairperson’s Comments
Andrew L. Hopkins, Ph.D.

1:40 Repositioning Sildenafil from Angina to Erectile Dysfunction to Pulmonary Hypertension Peter Ellis, Ph.D., Executive Director, Sex Health and Urology, Pfizer Sandwich U.K. The case history of sildenafil citrate is a remarkable story of a drug suspended during development for the treatment of angina but which found a new lease of life as Viagra for the treatment of erectile dysfunction. Over 2 million prescriptions were dispensed in the US within 10 weeks of launch and Viagra became a household name. The sildenafil story continues with the launch in 2005 of Revatio for the treatment of Pulmonary Hypertension. Who knows what will be next…?

2:10 ATI Antagonists in the Treatment of the Multisystem Manifestations of Marfan Syndrome and Related Disorders Harry C. Dietz, M.D., Investigator, Howard Hughes Medical Institute and Department of Genetics and Pediatrics, Johns Hopkins University School of Medicine  Recent evidence suggests that many of the manifesta tions of Marfan syndrome, including pulmonary emphysema, skeletal muscle myopathy and aortic aneurysm, are caused by increased activation of and signaling by the TGFbeta family of cytokines. Furthermore, these findings can be prevented in a mouse model of Marfan syndrome by TGFbeta antagonism in vivo using a neutralizing antibody. We now find that losartan, an ATI antagonist in widespread clinical use to treat hypertension, achieves similar protection at least in part by attenuating TGFbeta signaling. In addition to preventing aortic aneurysm, losartan also improved lung development and skeletal muscle regeneration in Marfan mice. This protection extends to other diseases associated with increased TGFbeta signaling.

2:40 Refreshment Break

CASE STUDY

3:10 Therapeutic Strategies for Sleep Apnea  The Drug Repositioning and Specialty Pharmaceuticals Link: Pharmacologic Discovery to Commercial Opportunity  Thomas Logan, Ph.D., Vice President, Business Development and Project Management, BTG International  As the first generation specialty pharmaceutical products are beginning to reach their anticipated market potential, the demand for new product opportunities by this sector is growing. A case study detailing a drug repositioning derived novel therapy for obstructive sleep apnea will be presented. Key issues that will be addressed through the study are:  • Selection of product candidates, indications and markets  • Value and timing of formulation strategies • Integrating intellectual property with formulation strategies • Integration of clinical development, formulation and intellectual property to    optimize value potential • Lessons learned