DDDS-2009 Program agenda

Institute for Scientific Exchange, Inc. Presents:

DDDS-2009

Drug Discovery and Development Summit:

Accuracy Assessment of Human Drug Properties in Preclinical Studies:

Current Practice and Promising New Strategies

Santa Fe, New Mexico, September 23-25, 2009 – La Fonda Hotel

REGISTRATION DISCOUNT UNTIL AUGUST 22, 2009

ISE, Inc.

8775 Centre Park Drive, # 713

Columbia, MD 21045

DDDS-2009 MEDIA PARTNER SCE178tucson8

Featuring Experts from the Following Institutions: APSciences/ In Vitro ADMET Laboratories, LLC.; The Hamner Institutes for Health Sciences; University of Tokyo; University of Toronto; Pfizer Research & Development; Calistoga Pharmaceutical , Inc.; Millennium Pharmaceuticals, Inc.; Lovelace Respiratory Research Institute; Chugai Pharmaceutical Co., Ltd; Simulations Plus, Inc.

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OPENING REMARKS (Albert P. Li, APSciences, Inc./BRIVAL/IVAL, Columbia, MD)

Keynote Lecture I: In Vitro Tools for Toxicity Testing and Dosimetry: New Directions from the NAS Report, “Toxicity Testing in the 21^st Century (Melvin Andersen, The Hamner Institutes for Health Sciences; Research Triangle Park, NC) The 2007 NAS report, “Toxicity Testing in the 21^ST Century – A Vision and A Strategy”, outlined new initiatives for use of in vitro methods to evaluate toxicity pathway responses, to apply computational systems models to assess dose response of pathway perturbations by drugs and environmental agents, and to ground extrapolations in in vitro-in vivo dosimetry extrapolations. On-going dialog over the past two years among interested parties has extended and re-shaped some of the ideas about implementation strategies for the NAS vision. In this talk, the speaker, a member of the NAS Toxicity Testing committee, describes key report recommendations for in vitro biology and for the interpretive tools necessary for using this in vitro results in risk and safety assessments.

Strategies to Reduce NCE Attrition Due to Mitochondrial Toxicity-Novel Screening Methods (Yvonne Will, Pfizer Global Research & Development, Groton CT) Early identification of new chemical entities (NCEs) that perturb mitochondrial function is of significant importance in drug discovery if attrition due to toxicity is to be avoided. We have tested oxygen sensors to measure mitochondrial respiration in isolated mitochondria and cells, immunocapture of individual electron transport chain proteins that can identify inhibitors of mitochondrial electron transport and metabolic profiling using solid oxygen and pH measurements. We discuss the strength and limitations of new HTS applicable screens and provide recommendations of where to position these assays within drug development.

Assessment of Toxicity during Drug Development: Experience in Large and Small Pharma: (Roger Ulrich, Calistoga Pharmaceuticals Inc.; Seattle, WA) Toxicity represent a major issue in drug development. Early development relies on a combination of in vitro and in vivo models and hepatocytes, especially human hepatocytes, represent a gold standard for the early evaluation of human hepatotoxic potential as well as for the early identification of metabolites and intrinsic drug clearance. Successes and challenges with the use of in vitro hepatic models and other in vitro and in vivo systems in the preclinical evaluation of human toxic potential of drug candidates in large and small pharma settings will be reviewed. Promising strategies and technical approaches will be highlighted.

Predictive Toxicology Approaches for Oncologic Therapeutics (Carl L. Alden, Millennium Pharmaceuticals; Cambridge, MA) Oncology chemotherapeutic research represents the greatest opportunity today in the developed world for pharmaceutical companies to significantly impact morbidity and mortality. Because of the daunting unmet medical need, rapid disease course and typical absence of cancer tissue specific targets, the research and development paradigm differs substantially compared to other therapeutic areas. A successful discovery stage toxicology testing paradigm and development decision criterion specific to oncology will be defined.

Keynote Lecture II: Transporter-related Adverse Drug Properties (Yuichi Sugiyama, University of Tokyo, Tokyo, Japan) Recently, there is an avalanche of knowledge on the science of transporters and the associated clinically significant adverse drug properties. The state-of-the field of transporters will be reviewed. Novel approaches to evaluate transporter-related drug-drug interactions and drug toxicity will be described.

Human-based In Vitro Experimental Models for the Evaluation of Human Drug Toxicity (Albert P. Li, Advanced Pharmaceutical Sciences Inc. and In Vitro ADMET laboratories LLC; Columbia, MD) Human-specific drug properties, by definition, cannot be evaluated with nonhuman animals. Human-based in vitro experimental systems therefore represent the only available approach for the assessment of human-specific drug properties during the preclinical phases of drug development. The current status of human-based in vitro systems for the evaluation of ADME and drug toxicity will be reviewed. A novel technology, the Integrated Discrete Multiple Organ Co-culture (IdMOC) for the co-culturing of multiple cell types as an in vitro model of a human or a human organ, will be described.

Hepatocyte-based Assays: Value and In Vitro-in Vivo Correlations (David Duignan, Pfizer Global Research & Development; Groton, CT) Human hepatocytes represent a useful model for hepatic metabolism, transport and toxicity. Routine and higher-throughput assays using human hepatocytes have been established at Pfizer. The overall performance and value of these assays in drug discovery & development will be discussed.

Assessment of the Ability of Human In Vitro Systems to Predict Human In Vivo Metabolites (Ping Kang, Pfizer Global Research & Development; San Diego, CA) An early understanding of key metabolites of drugs is crucial in drug discovery and development. It is generally believed that hepatocytes and the subcellular fractions (liver microsomes or the S-9 fractions when fortified with appropriate cofactors) provide an accurate view of the major metabolites and metabolic pathways for most compounds. However, a comprehensive performance evaluation of standard in vitro drug metabolism experiments to predict in vivo metabolic profiles has not been done. A retrospective analysis was conducted in the current study using 27 compounds in the Pfizer data-base and 21 additional commercially available compounds to assess the ability of in vitro systems to predict human circulating and excretory metabolites. The results demonstrated the strengths and weaknesses of the three in vitro systems with regard to generating metabolite profiles that are relevant to in vivo. The analysis also suggests that in vitro systems can produce in vivo metabolites adequately and provides sufficient confidence in the prediction of human metabolic profiles and routes using these systems.

(Walter Woltosz¹,Robert Fraczkiewicz¹, Dechuan Zhuang¹, Jinhua Zhang¹, and Michael Bolger¹,¹Simulations Plus, Inc., Lancaster, CA) A model-building methodology that provides robust structure-property classification models for unbalanced data sets has been developed. Unbalanced data are data where a given outcome falls into discrete classes (usually two, such as toxic and nontoxic), but the numbers of observations in the classes are significantly different. The method involves a combination of weighting of each data point’s contribution to the objective function with a new statistic for the evaluation of classification models that is similar to the Matthews Correlation Coefficient, but can be extended to models with more than two classes. Several examples will be presented.

Hepatocyte Imaging Assay Technology (HIAT): What It Is and What It Can Do? (Xiaomin Shawn Deng, Pfizer Global R&D, Groton, CT) An in-depth look at the recently published HIAT test for predicting drug-induced liver injury (DILI), its designs, critical features, advantages, and predictions to human clinical DILI. Case studies of the applications of HIAT in drug discovery and development will also be presented.

Preclinical In Vitro Assessment of Cardiotoxicity: Comparison of Cytotoxicities in Cardiomyocytes with that in Hepatocytes in Rats (Tomoaki Inoue,Chugai Pharmaceutical Co., Ltd; Shizuoka, Japan) Cardiotoxic compounds show higher cytotoxicity in the cardiomyocytes than in the hepatocytes, and hepatotoxic compounds show higher cytotoxicity in the hepatocytes than in the cardiomyocytes. The ratio of IC50 values (IC50 in the cardiomyocytes/IC50 in the hepatocytes) would be a good predictor of cardiotoxic and hepatotoxic compounds.

In vitro Pulmonary Cultures for the Assessment of Inhaled Toxicants (JeanClare Seagrave, Lovelace Respiratory Research Institute; Albuquerque, NM) Inhaled toxicants are unique in that the nasal passages and the lungs are the first organs of contact, and that the toxicants entered the systemic circulation via an air-liquid interface. The current status of in vitro pulmonary cultures, including cultures with air-liquid interface, for the evaluation of the toxicity of inhaled substances, will be reviewed.

Evaluation of Human Specific Metabolites: A Practical Consideration (Dennis Smith, Pfizer Research & Development; Kent, UK) FDA recently proposed that human specific (or human predominant metabolites) for a drug, when present in a certain proportion compared to parent, need to be considered for further evaluation. Ultimately this may require tests for safety of the metabolite in laboratory animals. The current opinions on this concept of Metabolites In Safety Testing (MIST) will be described. Criteria for the determination of the need for testing will be suggested.

Evaluation of Human Specific Metabolites: Pharmacokinetic Considerations (Sandy Pang, University of Toronto; Toronto, Canada) FDA requires human-unique metabolites to be synthesized and subjected to traditional safety testing (MIST). This is a resource and time consuming endeavor and may not be scientifically valid. The pharmacokinetics of metabolites will be described and the need for MIST will be discussed from the pharmacokinetic point-of-view.

About the Institute for Scientific Exchange

The mission of The Institute for Scientific Exchange, Inc. is to advance science via communication – (i. e. symposia, training courses, publications). The events held by the Institute are highly selective, timely, and of the highest professional caliber. One major goal of the Institute, as exemplified by this symposium, is to foster communication among industrial, regulatory, and academic practitioners. Please visit our web site at www.isciencex.com.

Poster Presentations are always encouraged. Please submit your poster abstract for approval by the organizing board by August 15^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 Tuesday, September 22^nd or before the first session begins on Wednesday, September 23^rd . 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.; 8775 Centre Park Drive, #713, MD 21045 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.

Santa Fe, New Mexico has long been considered the crown jewel of the American Southwest. For lodging, dining and entertainment, La Fonda hotel – a landmark structure, grandly situated on the historic Plaza – is the Santa Fe vacation destination of choice. The “grande dame” of Santa Fe hotels, La Fonda is just steps from museums, galleries, shops and restaurants. A showcase for the work of local artisans, La Fonda is loved for many of the same reasons that Santa Fe is loved: award-winning pueblo-style Spanish architecture and décor, luxurious, inviting ambience, and warm hospitality. While admiring the art and history at La Fonda, guests also appreciate thoroughly modern technology, including high-speed wireless Internet access throughout the hotel.

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., 8775 Center Park Drive; #713, Columbia, MD 21045, USA

Cancellation Policy

All cancellations are subjected to a $250.00 cancellation fee. Longer than 30 days, 100% refund (less cancellation fee). 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 April 25, 2009. Please submit cancellation and refund requests including transferring of registration to: Fax: 410-869-9560; E-mail: nola@isciencex.com; Cancel Deadline: April 25, 2009

Registration Form AVAILABLE ONLINE AT WWW.ISCIENCEX.COM/REGISTER.HTM Email to nola@isciencex.com with remittance to: ISE, Inc. 8775 Centre Park Drive; #713, Columbia, MD 21045, 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.

Event(s)	Until August 22^nd	After August 22^nd
DDDS-2009-Main Conference	$1,250.00	$1,550.00

Exhibitor	$2,000.00	$2,500.00