Institute for Scientific Exchange, Inc. Presents:

4th International Drug Discovery and Development Summit: Picking the Perfect Drug Candidate November 30 – December 2, 2005 Tampa, FL , USA Symposium Venue:  Renaissance Tampa Hotel International Plaza

The following institutions are represented:  Abbott Laboratories; Biacore AB; Bristol-Myers Squibb; CEA-Saclay; ChemSilico LLC; DiscoveRx Corp.; Eppendorf Array Technologies; GeneGo Inc.; Gene Logic Inc.; GlaxoSmithKline;  Iconix Pharmaceuticals; Lexicon Genetics; Merck & Co. Inc.; Millennium Pharmaceuticals, Inc. ;Novartis Institutes for Biomedical Research; Pfizer Global Research and Development; Pharmaceutical Profiles Inc.; Qualyst, Inc; Simulations Plus, Inc.; Wyeth Pharmaceuticals

 

   PARTICIPATING EXHIBITORS:

 

 

                                   

 

 

 

Wednesday, November 30, 2005

 

8:00 AM – 9:00 AM - Registration

 

8:00 AM – 5:00 PM – Exhibits

 

8:50 AM – 9:00 AM – Exhibitor Presentation – Qualyst, Inc.

 

 

 

9:00 AM – 9:30 AM Key Note Lecture

The Importance of ADME/PK in Reducing Attrition and Optimizing Success Rate (Alan G.E. Wilson, Lexicon Genetics; The Woodlands, TX) In recent years there has been increasing interest and application of ADME/PK and toxicity screening earlier in the drug discovery process. This is in response to the observation that ADME/PK and toxicity issues continue to be significant factors in overall attrition and success rates.  In recent years we have seen an Increasing in an integrated strategy involving in silico, in vitro and in vivo approaches. The ability to incorporate in silico, in vitro and in vivo data into PK and PK/PD model development provides the opportunity to improve the utility and translation of preclinical data to clinical scenarios. This talk will discuss the strategic application of in silico, in vitro and in vivo data in ADME/PK and toxicity evaluation. Opportunities to optimize the utility of ADME/PK and toxicity data in reducing attrition and optimizing success rate will be discussed.

 

 

 

9:30 AM – 10:00 AM

Pharmaceutical Profiling in Drug Discovery: Using High-Throughput Screens to Improve Drug-Like Properties (Mark Tischler, Wyeth Pharmaceuticals; Pearl River, NY) We have developed a Pharmaceutical Profiling program within Wyeth to evaluate pharmaceutical properties of discovery compounds using high-throughput screens. These screens assist project teams in the design, synthesis and prioritization of lead compounds with improved drug-like properties. A review of the assays used for this program and their impact will be presented.

 

10:00 AM – 10:30 PM

Collective Utilization of In Vitro ADME Tools to Predict In Vivo DMPK Drug Properties in Early Discovery
(Jianling Wang, Novartis Institutes for Biomedical Research, Cambridge, MA) The increased costs in the discovery and development of a new drug and the high attrition rate of drug candidates in development have changed the current drug discovery and development paradigm by shifting towards the parallel assessment of efficacy and comprehensive absorption, distribution metabolism and excretion (ADME) properties of drug candidates.  Multiple predictive filters of ADME properties (such as in silico, high-throughput in vitro and low throughput follow-up assays) are established in the various stages of drug discovery and development process to flag and address the potential ADME issues of new chemical entities (NCEs).  It is critical that such a landscape will lead to the most efficient prediction of in vivo ADME matters, with timely and cost effective fashions.  Collective utilization of those predictive tools will improve the productivity of drug discovery and development by prioritizing the drug-like NCEs.  In this presentation, the latest automated ADME suite will be introduced.  Case studies will also be presented to demonstrate the impacts of those early in vitro predictive tools on the success of drug discovery projects.

 

10:30 AM – 10:50 AM – BREAK

 

10:50 AM – 11:20 AM

In Vitro Blood-Brain Barrier Models (Aloïse Mabondzo, CEA-Saclay, Yvette Cedex, FRANCE) A major challenge in the design and development of CNS-drugs is the prediction of their brain penetration. Since it is not possible to screen directly in humans in vivo, the development and the validation of models of the human BBB is crucial to test compounds for CNS diseases. The presentation will summarise the status of in vitro BBB models. Particular emphasize will be given to the in vitro human BBB model. This model will be placed in a schematic system allowing both an overview of available systems and guidance in the selection of an in vitro model suitable for specific applications.

 

11:20 AM – 11:50 AM

In Vitro Screening for Acceptable Metabolic Stability (Chuang Lu, Millennium Pharmaceuticals, Inc.; Cambridge, MA) Determining intrinsic clearances (CLint) of drug candidates helps to evaluate if metabolism is the main clearance pathway, when compared with total body clearances CLp in vivo.  It also helps in rank ordering metabolic stabilities of drug molecules.  Lastly, it helps in assessing species differences in metabolic clearance and for projecting metabolic clearances of drug candidates in humans.  The advantages and limitations of using microsomes, S9, and hepatocytes for determining intrinsic clearances will be discussed.  A high-throughput automated system using commercially available hardware and software for incubation and LC/MS/MS analysis will also be presented.

 

11:50 AM – 12:20 PM

B-CLEAR(tm): Sandwich-Cultured Hepatocytes for Assessment of Drug Transport and Hepatobiliary Disposition (Kenneth R. Brouwer, Qualyst, Inc; Research Triangle Park, NC) Rapid hepatic uptake and extensive biliary excretion by drug transporters can limit the therapeutic potential of many drug candidates.  Active transport systems are responsible for the translocation of many compounds across the sinusoidal membrane into the hepatocyte, and across the canalicular membrane into the bile. Qualyst has developed B CLEAR(tm), a patented in vitro sandwich-cultured hepatocyte approach, to study the hepatobiliary disposition of drug candidates, predict in vivo uptake, excretion and biliary clearance, and to evaluate the potential for drug-drug interactions.  B CLEAR(tm) (US Patent No. 6,780,580 and other worldwide patents both issued and pending) maintains hepatocytes in culture between two layers of gelled collagen (a sandwich configuration), resulting in the formation of extensive canalicular networks, and expression and function of multiple transporter systems including Ntcp, Oatp, Mrp2, Bsep, Pgp and many others.  The in vitro B-CLEAR(tm) approach can accurately predict the in vivo hepatobiliary disposition of drug candidates.  In vitro investigations using B-CLEAR(tm) to evaluate drug candidates' cross-species hepatobiliary disposition and drug-drug interaction potential will allow better prediction of the drug candidates' in vivo hepatobiliary disposition, bioavailability, and potential hepatotoxicity.

 

12:20 PM – 1:50 PM – LUNCH BREAK

 

1:50 PM – 2:20 PM

Systems Biology for Prediction of New Compounds’ Metabolism and Toxicity (Yuri Nikolsky, Ph.D., GeneGo, Inc.) Accurate early prediction of human metabolism and toxicity for new compounds in human is a long term goal in drug discovery. Traditional in silico, in vitro and in vivo ADME/Tox methods are now complimented with high-throughput experimental approaches such as toxicogenomics, proteomics, metabonomics and pharmacogenomics which can provide a global view of the complete biological system being modulated by a compound. Functional interpretation and relevance of these complex multidimensional data to the observed phenotype in human is the focus of the budding field of Systems ADME/Tox. I will overview this novel systems approach, including available resources, major public and commercial efforts in the area. I will also demonstrate the case studies with toxicogenomics and compounds data using MetaDrug, as systems pharmacology suit developed at GeneGo.

 

2:20 PM – 2:50 PM

Optimizing the Hit-to-Lead Process Using SPR Analysis (Stefan Löfås, Biacore AB, Sweden) The surface plasmon resonance (SPR)-based technology is now established as an important tool in drug discovery and development. This optical biosensor technology enables label-free rapid detection and information-rich characterization of molecular interactions. It provides affinity and kinetics data for lead selection and high-content compound characterization. This presentation gives an overview of the use of Biacore’s SPR technology within the hit-to-lead process. Important key applications will be presented to show how the technology has been implemented for improved focused screening, hit validation, lead optimization and binding selectivity information.

 

 

2:50 PM – 3:20 PM

The Use of Calculated Molecular Features to Predict the Success or Failure of Extrapolating Human Pharmacokinetic Properties from Preclinical Animal Data (Larry J. Jolivette, GlaxoSmithKline, King of Prussia, PA) Despite advances in in vitro and in silico modeling, the use of preclinical animal pharmacokinetic data has remained the primary means for projecting human pharmacokinetics.  An approach wherein calculated molecular features are used to assess the likelihood of success or failure of preclinical data to project human pharmacokinetics has been investigated.  Data will be presented that suggest that such an approach may be useful to predict extrapolative outcome for human plasma clearance, as well as to prospectively aid in the selection of an approach preclinical species from which to project human clearance.

 

3:20 PM – 3:40 PM – BREAK

 

3:40 PM – 4:10 PM

Microdosing as a Tool in Early Development (Steve Matheson, Pharmaceutical Profiles Inc.; Nottingham, Notts UK) The Global Pharmaceutical Industry is amidst a challenging era in its history. Producing new drugs continues to be an expensive and time consuming process. Social and Economic pressures demand new medicines faster and at a cost competitive price.  Yet, for all its innovation, the Pharmaceutical Industry is arguably inefficient. In 2002 only 17 New Molecular Entities (NME’s) were registered with the FDA and the cost of drug development has been estimated to be in the region of $900 million. Why do new drugs cost so much?? A high proportion of this figure can be attributed to previous development failures. Additionally, upwards of 30% of new drugs in clinical development fail due to poorly defined human pharmacokinetics. The Drug Development process rapidly requires new paradigms to enhance candidate selection prior to Phase 1 clinical trails. Human Microdosing represents one such model that can easily be incorporated into development plans with excellent results. Microdosing exploits favorable Regulatory environments in Europe and now the USA to enable pharmacokinetic evaluations in man to be undertaken prior to safety and tolerability in Phase 1. This presentation will focus on the use of Microdosing as a tool in Early Development. The definition of such Phase 0 studies will be explored including the Preclinical and analytical requirements to make a successful study. Finally, the presentation will examine a real study example and exemplify the power of this new paradigm in Drug Development.

 

4:10 PM – 4:40 PM

Evaluation of Microdosing Strategies for Studies in Preclinical Drug Development (Punam Sandhu, Merck & Co. Inc.; West Point, PA) The primary objective of this study was to examine whether Compound A (a nucleoside analogue) displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study.  The present study is the first in providing a comparison of the PK of a development candidate at pharmacological versus sub-pharmacological doses employing microdosing strategies.  The data demonstrated that the PK properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that for Compound A, the kinetics appear to be linear across this 50-fold dose range.

 

4:40 PM – 5:10 PM

The Bioanalytical Support of Microdose Studies Using Conventional Triple-Quadrupole LC/MS/MS Techniques (Christopher L. Holliman, Pfizer Global Research and Development, Ann Arbor, MI) Low sub-pharmacological dosing, microdosing, minimizes the risk to the subject and can be used to predict human pharmacokinetics at the therapeutic dose.  When the ionization efficiency of the compound is high, these studies can be supported with conventional triple-quadrupole LC/MS/MS.  In this presentation we share our experiences developing and validating assays to support microdose studies.  For each case study presented we will discuss why the microdose strategy was selected and the quantitation requirements for the bioanalytical assay.  There will be a focus on assay development issues around analyte extraction and assay selectivity.  Validation and study data will be presented.

 

5:10 PM – 5:40 PM - PANEL DISCUSSION: Session I

 

END OF DAY

Thursday, December 1, 2005

 

 

8:00 AM – 9:00 AM - Registration

 

8:00 AM – 5:00 PM – Exhibits

 

8:50 AM – 9:00 AM – Exhibitor Presentation – Simulations Plus, Inc.

 

9:00 AM – 9:30 AM   Key Note Lecture

Challenges in Early Discovery Toxicity Testing (Christopher A. Lipinski, Pfizer Global R&D (Ret.), Groton, CT) Toxicity along with lack of efficacy and lack of commercial attractiveness are the current three major causes of attrition in drug discovery / development. Lack of commercial attractiveness is the most intractable of these because data bearing on this area only surfaces late in clinical studies. Drug discovery organizations would love to push detection of toxic compounds into discovery as early as possible. Unfortunately there are all kinds of problems many of which have nothing to do with the technical aspects of toxicology. A listing of barriers to early detection of toxic compounds would include the following: 1) the pathetically low supply of compounds currently made in medicinal chemistry; 2) the iffy purity quality control of compounds; 3) the very dodgy assurance that the compound in a DMSO stock solution is really what the registration system says and the lack of assurance that the compound concentration is even close to what is assumed; 4) the 30 – 60% concordance of well run triplicate HTS assays; 5) the difficulty in eliminating compounds from testing that are sources of false positives; 6) the discordance between mechanistically unfocused and mechanistically focused assays and 7) the difficulty of convincing chemists to pay attention to early toxicity assays.

 

 

9:30 AM – 10:00 AM

New Technologies and Screening Strategies for Hepatotoxicity: Use of In Vitro Models (Donna Dambach, Bristol-Myers Squibb; Princeton, NJ) Hepatotoxicity remains one of the most common causes for drug withdrawal during clinical trials.  This is due, in part, to inherent physiological differences between humans and preclinical species leading to inadequate prediction of adverse responses in humans.  To address this issue, there is a need to develop robust screening assays, investigative tools, and biomarkers that are predictive of human hepatotoxicity and may be utilized throughout the discovery and development periods to select the safe drugs.  This presentation will describe the application of in vitro-based strategies using human and preclinical species hepatocyte cultures in lead optimization screening in conjunction with ADME profiling, and identification of potentially useful biomarkers as predictors of hepatotoxicity preclinically and humans.

 

10:00 AM – 10:30 AM

Development of Cellular ADME/Tox Assays Using b Galactosidase Enzyme Fragment Complementation (EFC) (Lindy Kauffman, DiscoveRx Corp.; Fremont, CA) b Galactosidase (b gal) fragments recombine to form competent b gal, via EFC. A small b gal peptide, termed ED, may be recombinantly fused to proteins of interest. Both EA and ED-fusion proteins can be expressed in mammalian cells, with expression of the former localized to either membrane or nucleus. ‘Positional’ complementation thus only occurs when the ED: protein fusion translocates, providing assays to monitor protein expression, or modulation thereof by compound-induced toxicity or induction of metabolic enzymes. Trafficking to the cell exterior can also be monitored using fusion protein expressed in a suitable extracellular loop, flanked in series by consensus protease cleavage sites. Appearance on the cell surface of critical toxicity markers, including potassium channels, is monitored by addition of a protease and subsequent detected by EFC. As none of these methods employ imaging, they are amenable to high throughput automation and enable researchers to assess intracellular events using simple, luminescence plate readers.

 

10:30 AM – 10:50 AM – BREAK

 

10:50 AM – 11:20 AM

Recent Results on In Silico Models for Hepatotoxicity for both Rodent and Humans. (Joseph R. Votano, ChemSilico LLC, Tewksbury, MA) Drug-induced toxicity and adverse drug reactions are the primary causes of post-market withdrawal of drugs and account for over 50% of the acute liver cases in United States. In silico models were developed employing 1100 chemicals in rat studies and 320 therapeutic drugs. Validation testing gave accuracies of 80% in determining whether a chemical would have mild, moderate or several hepatotoxic effects using 20% and 12% of compounds in the rat and human datasets. Given the wide differences in dosage and duration for compounds studied, the results indicate that predicting hepatotoxicity, in a global sense, is not an intractable problem.

 

11:20 AM – 11:50 AM

Automated Machine Learning Techniques Applied to Prediction of Drug ADME and Toxicity (Robert Fraczkiewicz, Simulations Plus, Inc.; Lancaster, CA) The interest of pharmaceutical companies in time- and cost-effective methods of in silico drug lead screening has been growing rapidly.  Methods for in silico estimation of ADMET properties before respective molecules are actually synthesized play a pivotal role in this process. Recent years witnessed the emergence of machine learning tools enabling pharmaceutical researchers the construction of high-quality predictive models. Full automation of this complex process of mathematical model building makes these tools accessible to non-expert users and minimizes its time and cost.

 

11:50 AM – 1:30 PM – LUNCH BREAK

 

 

1:30 PM – 2:00 PM

Application of Toxicogenomics Towards Drug Safety Evaluation (Jeffrey F. Waring, Yi Yang, Stephen Abel and Eric Blomme; Abbott Laboratories, Abbott Park, IL) Toxicity remains a major hurdle for the successful discovery and development of new pharmaceuticals.  We are using gene expression signatures generated using isolated rat hepatocytes to evaluate compounds in vitro for their toxic properties.  These signatures were originally developed using microarray technology, but have since been transferred to a gene expression platform with higher throughput, lower cost, and amenable to customization.  The identification and characterization of compounds with the potential to cause toxicity early in the drug discovery process will lead to a more rationale selection of compounds and ultimately should result in drugs with a better safety profile.

 

2:00 PM – 2:30 PM

DNA Microarrays as a Tool in Toxicogenomics Rat Hepatocyte (Francoise de Longueville, Eppendorf Array Technologies; Namur, BELGIUM) Toxicogenomics is an emerging technology that defines the use of novel genomic techniques to investigate the adverse effects of xenobiotic on gene expression. Toxicogenomics is based on the fact that most of relevant toxicological effects of a compound affect directly or indirectly the gene expression. The most common methods to profile gene expression at the transcript level are Northern Blotting and the Real time-PCR. While commonly used and well accepted, these techniques are now superseded by new technologies allowing the analysis of the expression for multiple genes simultaneously. DNA microarrays are now developed for simultaneous gene analysis but inherent to such multiple assays, their quantitative aspect and their relevance for toxicogenomics have been questioned. We will review here recent studies on their use for toxicogenomics and examine the possible future of such technology in complementation with the other toxicology methods.

 

2:30 PM – 3:00 PM

Use of a Chemogenomics Reference Database to Improve Drug Candidate Selection and to Understand Mechanisms of Chemical Toxicity and Action (Brigitte Ganter, Iconix Pharmaceuticals; Mountain View, CA) Chemogenomics is the study of pharmacology and toxicology using a combination of traditional drug development practices and new genomic tools.  As a result, chemogenomics can uncover previously unappreciated properties of a candidate, both good and bad.  We have created a database on over 600 drugs, chemicals, and toxicants in short term rat studies and have mined this database creating a library of gene expression based biomarkers (Drug Signatures™).  This talk will describe the benefit on drug development when a reference database is used to contextually analyze gene expression of drug development compounds.

 

3:00 PM – 3:20 PM – BREAK

 

3:20 PM – 3:50 PM

Use of Toxicogenomics In the Rat to Detect Idiosyncratic Hepatotoxicants Prior to Human Exposure (Donna L. Mendrick, Gene Logic Inc.; Gaithersburg, MD)  Human idiosyncratic hepatotoxicants are not detected in classical preclinical testing or, for the most part, in human clinical trials.  Their effect, unfortunately, is recognized only after thousands or more patients have been exposed to the drug.  New approaches are needed to detect such drugs prior to human exposure.  Toxicogenomics applied to a preclinical species (rat liver and primary rat hepatocytes) has shown the ability to detect idiosyncratic drugs.  This presentation will show examples of prototypical compound and demonstrate how genomic changes in the rat liver or primary rat hepatocytes can lead to their detection.

 

3:50 PM – 4:20 PM - PANEL DISCUSSION: Session I

 

END OF DAY

Friday, December 2, 2005

 

 

8:00 AM – 9:00 AM - Registration

 

8:00 AM – 5:00 PM – Exhibits

 

9:00 AM – 9:30 AM  Key Note Lecture

Industrial Viewpoint: Strategies for the Selection of Drug Candidates for Development (Chandra Prakash, Pfizer Global R&D, Groton, CT) The drug development process is scientifically complex and full of risks, and is therefore, very time consuming and expensive. Recent data indicate that the discovery and development of a new drug costs around 900 million dollars and takes 10-12 years for the drug to reach the marketplace.  In addition, 90% of all drugs in clinical development fail to make to the market. Even after a drug is marketed there is the possibility of some undesired side effects, which were not seen in earlier clinical trials.  In these cases the drug is either withdrawn from the market or acquired a warning label.  Efforts are being made to reduce attrition of drug candidates during the various stages of drug discovery and development, and to bring safer drugs to the market. The major reasons for the attrition and serious side effects are sub-optimal drug metabolism and pharmacokinetic (DMPK) profile, poor clinical efficacy and the formation of reactive metabolites. Given the inherent inefficiency of the development, it is essential to optimize/minimize such factors early in drug discovery process.  This has led to greater integration of DMPK functions into early stages of drug discovery process and in addition to potency and selectivity; drug candidates are selected on the basis of DMPK properties, e.g. low clearance, good oral bioavailability, optimum half-life, and an acceptable metabolism profile in preclinical species and humans.  This presentation will summarize the in vivo/in vitro techniques used for rapid determination of the DMPK profiles including absorption, metabolic stability, metabolite structures, cytochrome P450 inhibition/induction, and pharmacokinetics and role of these studies in the selection of the drug candidates for further development. Knowledge of metabolic profiles of these candidates in an early stage of drug discovery is essential to select compounds with favorable pharmacokinetic credentials and to aid medicinal chemists for rational drug design.

 

9:30 PM – 10:00 AM

Current Strategies for Candidate Selection from the Industry Perspective: Bristol-Myers Squibb
(Donna Dambach, Bristol-Myers Squibb; Princeton, NJ) This presentation will overview an example strategy for candidate lead optimization during the discovery process and will provide prospective on the foundation behind the strategy, as well as examples of data interpretation and integration that result in an advancement recommendation related to safety issues.

 

10:00 AM – 10:30 AM

Current Strategies for Candidate Selection from the Industry Perspective: Millennium Pharmaceuticals, Inc. (MPI) (Frank W. Lee, Millennium Pharmaceuticals, Inc.; Cambridge, MA) MPI DMPK has adopted the Discovery Assay by Stage (DABS) paradigm to support the discovery effort.  The DABS provides the team with a rationale for the types of studies to be done during hit-to-lead, early and late lead optimization stages of discovery, as well as outlining the deliverables (objectives) at those stages.  DABS has proven to be efficient in the utilization of resources and tracking of the progress of compounds and projects.

 

10:30 AM – 10:50 AM – BREAK

 

10:50 AM – 11:20 AM

Optimizing Candidate Selection: Current Strategies and Approaches (Alan G.E. Wilson, Lexicon Genetics; The Woodlands, TX) Improving success rate by optimizing candidate selection remains a significant challenge for drug development.  It is becoming increasingly apparent that we need to improve the value and translation of early screening and preclinical data, to optimize clinical efficacy, ADME/PK and safety properties. Over the past decade, the value of early screening has been demonstrated in the decrease in attrition due to ADME/PK issues. We are in an exciting era of drug discovery and development with a plethora of new technologies and approaches. These herald the opportunity to significantly transform our drug discovery process and the translation of preclinical data to improve clinical success. This presentation will discuss current strategies, technologies and approaches being utilized to optimize candidate selection and improve the translation into the clinic.

 

 

11:20 AM –12:20 PM - ROUNDTABLE DISCUSSION – ALL Speakers Invited to Participate

 

END OF CONFERENCE

 

 

POSTER PRESENTATIONS:

 

Poster Presentations are always encouraged.  Please submit your poster abstract for approval by the organizing board by October 30^th.  Poster size should be no larger than 4 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 Tuesday, November 29^th or before the first session begins on Wednesday, November 30^th. Poster presenters will have ample time for discussion during breaks and the Welcome reception.

 

Submit posters abstracts for approval to Nola Mahaney, VP, Operations; ISE, Inc.; 5707 Calverton Street, Suite 2C; Baltimore, MD 21228 or