FEATURED PRESENTATION
Lee E. Babiss, Ph.D., Vice President, Preclinical R&D, F. Hoffmann La Roche Inc. 
KEYNOTE PRESENTATION
Frank L. Douglas, Ph.D., M.D., Executive Director, Center for Biomedical Innovation, Massachusetts Institute of Technology, former Executive Vice President of Aventis 
SESSIONS INCLUDE
FROM SERENDIPITY TO STRATEGY
TECHNOLOGIES FOR FINDING NEW INDICATIONS
CASE STUDIES AND SUCCESS STORIES
Pre-Conference Workshop
Market Protection for Repositioned Drug Candidates

Distinguished Faculty
Frank L. Douglas, Ph.D., M.D., Executive Director, Center for Biomedical Innovation, Massachusetts Institute of Technology, former Executive Vice President of Aventis 
Lee E. Babiss, Ph.D., Vice President, Preclinical R&D, F. Hoffmann La Roche Inc. 
Marcel van Duin, Ph.D., Executive Director and Head, Department of Pharmacology, NV Organon 
Prof. Camille Georges Wermuth, Faculty of Pharmacy, Louis Pasteur University, Strasbourg, and President and Chief Scientific Officer, Medicinal Chemistry, Prestwick Chemical 
Andrew L. Hopkins, Ph.D., Associate Research Fellow, Knowledge Discovery, Pfizer Global R&D 
Josep Prous, Jr., Ph.D., Executive Vice President, Prous Institute for Biomedical Research 
Bryan Roth, MD., Ph.D., Professor, Department of Biochemistry, Comprehensive Cancer Center and National Institute of Mental Health Psychoactive Drug Screening Program, Case Western Reserve University Medical School 
Louis A. Tartaglia, Ph.D., Senior Vice President and General Manager, Drug Repositioning & Selection, Gene Logic Inc. 
Christopher A. Lipinski, Ph.D., Scientific Advisor, Melior Discovery and Adjunct Senior Research Fellow, Exploratory Medicinal Sciences, Pfizer Global R&D Groton Labs 
Justin Lamb, Ph.D., Senior Scientist, Cancer Program, and Leader, Connectivity Map Project, Broad Institute of MIT and Harvard 
John Overington, Ph.D., Vice President, Drug Discovery, Inpharmatica Ltd. 
Rita Sattler, Ph.D., Department of Neurology, Johns Hopkins University 
Peter X. Ellis, Ph.D., Executive Director, Sex Health and Urology, Pfizer (tentative) 
Harry C. Dietz, M.D. Howard Hughes Medical Institute and Department of Pediatrics, Johns Hopkins University School of Medicine 
Thomas Logan, Ph.D., Vice President, Business Development and Project Management, BTG International 
Rudi Scherhag, Ph.D., Executive Vice President, Department of Project and Business Development, Heidelberg Pharma GmbH

SCIENTIFIC ADVISORY BOARD
Frank L. Douglas, Ph.D., M.D., Professor of the Practice and Executive Director, Center for Biomedical Innovation, Massachusetts Institute of Technology 
Andrew L. Hopkins, Ph.D., Associate Research Fellow, Knowledge Discovery, Pfizer Global R&D 
Louis A. Tartaglia, Ph.D., Senior Vice President and General Manager, Drug Repositioning & Selection, Gene Logic Inc. 
Marcel van Duin, Ph.D., Executive Director and Head, Department of Pharmacology, NV Organon

Monday, October 16

Pre-Conference Workshop* * Separate Registration Required 
8:30 am - 11:30 am Market Protection for Repositioned Drug Candidates
The main goal of this workshop is to explore several approaches that may be utilized to obtain effective market protection for repositioned drug compounds that carry a patent history for their original indications. This can be accomplished through: 
1) A review of U.S. and European patent and regulatory considerations surrounding the protection of new drugs 
2) An examination of intellectual property protection options for repositioned compounds 
3) An interactive discussion around optimizing IP and regulatory strategies for maximizing business objectives in multiple world markets 

8:30 How to Protect Repositioned Drugs in the U.S. 
Kate H. Murashige, Partner, Pharmaceutical & Healthcare, Morrison & Foerster LLP 
Patents can be obtained to protect repositioned pharmaceuticals, but some strategic approaches are needed to be successful. Earlier disclosures relating to the new indication are often found, either by coincidence or because a patent on the drug itself contains a "laundry list" of indications. These can often be circumvented by including diagnostic steps, undisclosed symptomologies, new associated effects, or surprising results. Formulations that are critical for success can also be protected. In sum, patents on new molecules are straightforward and powerful, but method of use patents can serve to protect new indications just as effectively.

9:30 Integrating International Patent, Regulatory and Product Life Cycle Strategies to Maximize Market Protection
Herwig von Morzé, Ph.D., International Patent Consultant
The market for repurposed and repositioned drugs is a global one, and pharmaceutical companies must consider international practices and rules. Repositioned drug candidates, as well as drugs with impending expirations, can benefit from optimizing IP strategy. This IP strategy should be closely integrated with the regulatory and product life cycle strategies and aligned with business goals. The discussion will focus on:
• International IP strategy for repurposed drugs and drugs with impending patent expirations 
• Maximizing strength, duration and international geography of protection (patent, utility model, patent term extension opportunities, 
  supplementary protection certificates and regulatory exclusivity) with international IP tools 
• Pluses and minuses of international market or exclusivity protection compared with United States protection 
• Mandatory integration of international patent, regulatory and product life cycle strategies to achieve business objectives 

10:30 Regulatory Issues Relating to New Uses--Market Protection for Approved Uses and Risks from Unapproved Uses
Donald O. Beers, Partner, Arnold & Porter LLP 
New uses for existing drugs can be the subject of market and patent protection, but there are significant limitations on the value of such protections. This talk will discuss the available options and the limitations. Sometimes new uses do not lead to FDA approval, but are simply adopted by the physician community based on available data. But significant off-label uses lead to risks to pharmaceutical companies. The risks, and steps to control those risks, will be discussed.

11:30-1:00pm Lunch on Your Own

FROM SERENDIPITY TO STRATEGY

1:00 Chairperson’s Opening Comments
Louis A. Tartaglia, Ph.D., Senior Vice President and General Manager, Drug Repositioning & Selection, Gene Logic Inc.

1:10 Keynote Presentation
Frank L. Douglas, Ph.D., M.D., Executive Director, MIT Center for Biomedical Innovation (CBI), Massachusetts Institute of Technology, former Executive Vice President of Aventis 
• Challenging the business models and organization structure
• Exploiting off-label uses; serendipity vs. strategy
• Learn about biology from how drugs work in vivo
• Developing new methodologies for indications discovery

1:45 Finding New Applications for Canceled Development Candidates 
Marcel van Duin, Ph.D., Executive Director and Head, Department of Pharmacology, NV Organon 
Taking advantage of serendipitous findings and obser vations is, at least in part, an important element 
behind innovation in the pharmaceutical industry. Continued research efforts with development candidates (DC's) are the motor behind this process. Given that these DC's are only the tip of the iceberg in terms of the number of compounds synthesised by Pharma, but that failed somewhere in the process, it is indeed appealing to address the question of what could be discovered if also compounds that did not make it to the market would be subjected to the three R concept (Reprofiling, Repositioning and Repurposing). Strategies and efforts along these lines will be discussed.

2:15 New Leads from Old Drugs: The SOSA Approach
Prof. Camille Georges Wermuth, Faculty of Pharmacy, Louis Pasteur University, Strasbourg, and President and Chief Scientific Officer, Medicinal Chemistry, Prestwick Chemical 
Selective optimization of side activities of drug molecules (the SOSA approach) is an intelligent and potentially more efficient strategy than HTS for the generation of new biological activities. Only a limited number of highly diverse drug molecules are screened, for which bioavailability and toxicity studies have already been performed and efficacy in humans has been confirmed. Once the screening has generated a hit it will be used as the starting point for a drug discovery program. Using traditional medicinal chemistry as well as parallel synthesis, the initial “side activity” is transformed into the "main activity" and, conversely, the initial "main activity" is significantly reduced or abolished. This strategy has a high probability of yielding safe, bioavailable, original, and patentable analogues.

2:45 Refreshment Break

3:15 Casting Nets to Catch Hypotheses: Building an Infrastructure for Indications Discovery 
Andrew L. Hopkins, Ph.D., Associate Research Fellow, Knowledge Discovery, Pfizer Global R&D 
Drug discovery and development is commonly mod-eled as a linear pathway from idea to approval. Analysis of the source of ideas in drug discovery, however, shows the source of new drugs often comes from a network of ideas rather than a single inspiration. Serendipity plays a far larger role in drug discovery than acknowledged by the linear school of portfolio management. Therefore, it is a strategic question to ask, how can we engineer organisations to encourage serendipity? In this talk we will explore a range of experimental and informatics approaches that can be employed to engineer serendipity. The merits of methods from text mining for hypothesis generation to the in vivo screening of chemical tools will be discussed.

3:45 Epistemic Drug Discovery: A New Way to Improve R&D Productivity Josep Prous, Jr., Ph.D., Executive Vice President, Prous Institute for Biomedical Research 
Over the past decade, and despite major advances in new technologies, the pharmaceutical sector has witnessed 
how the number of new drugs introduced in the market every year has stayed level or decreased while the cost of drug discovery and development has doubled. The safety of drugs used in clinical practice is under constant scrutiny and the withdrawal of several compounds in recent years confirms the serious productivity challenges faced by modern biomedical research. A knowledge-based project was initiated to overcome these productivity bottlenecks and to contribute to the faster discovery of new and safer drugs, as well as the finding of new uses for known molecules. In-house developed datamining algorithms have led to a model thatcharacterizes 300 different molecular mechanisms of action simultaneously. Millions of molecules are being used to develop the project. Models have been built that discriminate between active and inactive compounds for specific pharmacological activities, and to differentiate drug from non-drug compounds. Quantitative models for experimental pharmacology parameter determination have also been developed. Importantly, ADMET properties can be traced with the system with a high degree of accuracy. The development and application in explaining antipsychotic therapy-induced diabetes and the finding of new therapeutic applications for angiotensin AT1 antagonists will be presented.

4:15 Repositioning in the Public Sector
Bryan Roth, M.D., Ph.D., Professor, Department of Biochemistry, Comprehensive Cancer Center and National Institute of Mental Health Psychoactive Drug Screening Program, Case Western Reserve University Medical School 
With the annotation of the human genome approaching completion, public-sector researchers - spurred in part by various National Institutes of Health Roadmap Initiatives - have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of 'drug-like' compounds can be readily screened to yield chemically novel scaffolds, transforming these 'chemical probes' into drugs is a daunting endeavour. A more efficient approach involves screening libraries of approved and off-patent medications; both phenotypic- and molecular target-based screening of 'old drugs' can readily yield compounds that could be immediately used in clinical trials. Using case studies, we describe how this approach has rapidly identified candidate medications suitable for clinical trials in disorders such as progressive multifocal leukoencephalopathy and amyotrophic lateral sclerosis. This approach has also led to the discovery of the molecular targets responsible for serious drug side effects, thereby allowing efficient 'counter-screening' to avoid these side effects.

4:45 Discussion with Speakers: Focusing on Failure
• How to manage risk and turn failures into success stories
• How you can best take advantage of techniques available
• Which approach or combination of approaches or technologies is best?

5:15 Reception Sponsored by 

6:30 Close of Day One

Tuesday, October 17

TECHNOLOGIES FOR FINDING NEW INDICATIONS

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 comprehensive 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.

12:00 Luncheon Presentation Sponsored by
Teaching an Old Dog New Tricks or How to Reposition a Drug for a New Indication 
Lee E. Babiss, Ph.D., Vice President, Preclinical R&D, F. Hoffmann La Roche Inc. 
While there are many approaches for discovering new medicines that are being pursued by both pharma and biotech's, each has very different risk and value propositions. The repositioning of drugs that have not met their primary clinical endpoints, but were deemed safe, represents a cost-effective and limited risk approach to quickly establish proof of concept in the clinic. In my talk, I will discuss our relationship with GeneLogic and internal genomic efforts that provide the starting point for considering new indications and some of the challenges of getting organizational buy-in.

CASE STUDIES AND SUCCESS STORIES

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 (tentative) 

3:10 
CASE STUDY
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

2:40 Refreshment Break

CASE STUDY
3:40 Application of Enhanced Pro-Drug Technology to Rescue Failed Compounds
Rudi Scherhag, Ph.D., Executive Vice President, Department of Project and Business Development, Heidelberg Pharma GmbH
Enhanced Pro-Drug (EPD) Technology was developed at Boehringer Mannheim (now Roche) as an important tool to reduce the attrition rate of research and development compounds, revive already discontinued projects, or to exploit the potential of development compounds or approved drug substances. Critical properties of drug compounds that can be addressed and solved by application of EPD Technology to parent compounds are: Unacceptable toxicity and insufficient general tolerability, in particular, undesirable myelosuppression; insufficient ADME properties, such as too short plasma half-life; extensive first pass metabolism; plasma instability, e.g., due to enzymatic degradation; insufficient distribution to intracellular targets as well as certain physicochemical properties. Particular and extensive experiences have already been made in the field of anti-infectious and antitumor agents, including demonstration of clinical proof of concept.

4:00 Close of Conference