Symposium I: Stem Cells as Tools for Drug Discovery

Wednesday, October 15, 2008 (8:00 AM - 11:30 PM)                                     Back to the Top

Symposium Chairperson

In the recent years, several non-cardiovascular drugs have been withdrawn from the market because of unanticipated cardiotoxicity. These drugs are often associated with prolongation of the electrocardiographic QT interval, which could potentially induce fatal arrhythmias. Therefore, evaluation of cardiotoxicity has become one of the principal concerns for the pharmacological industry. Assessment of cardiotoxicity is traditionally carried out in models that use modified cells as surrogates for human cardiomyocytes due to limited supplies of the latter; human embryonic stem cells (hESCs) present a new resource for addressing this issue. hESCs offer considerable advantages over primary or immortalized cells owing to their extensive proliferation capacity and ability to differentiate into multiple cell types. hESCs are able to generate large amounts of cardiomyocytes with relevant physiological phenotypes. This may translate to more reproducible and accurate evaluations of targets in a more cost-effective manner. For application of hESC-derived cardiomyocytes in drug discovery, several critical procedures have to be worked out. These include stably expanding undifferentiated hESCs, generating cardiomyocytes in a highly efficient and enriched manner, and extensively characterizing these cells. In this talk, I will present progress we have made along this line focusing on optimization of growth and differentiation conditions for hESCs.

Mark Mercola, Burnham Institute for Medical Research

9:00

The Use of Stem Cells in Drug Discovery

9:30

Networking Refreshment Break & Exhibit Viewing

10:00

Single ES Cell Profiling Reveals Unique microRNA Expression Signatures and Heterogeneities

We describe a new method for simultaneously quantifying 237 mouse microRNAs (miRNAs) and 21 messenger RNAs (mRNAs) from single embryonic stem (ES) and differentiated cells. The method is based on multiplex RT, multiplex preamplification, and singleplex real-time TaqMan® PCR assays. Assays are quantitative for a dynamic range of at least four logs. Single cell expression signatures could classify individual ES, embryoid body (EB), or somatic cells. Significant inter-cell variations of both miRNA and mRNA expression were observed within ES cell lines, indicating the heterogeneity of ES cells. Higher variability was observed among EB cells, demonstrating that EB cells undergo differentiation at different stages. Interestingly, ES marker gene Oct4 and signaling gene Tdgf1 were co-expressed. Both were absent in 3T3 and splenocyte cells, highly expressed in ES cells, and significantly reduced in EB cells. Furthermore, there was no correlation in the expression levels between miRNAs and their predicted target mRNAs, thereby supporting a translational repression model. The total number of expressed miRNA genes in ES, EB, and somatic cells remained constant. However, their expression levels were significantly elevated during differentiation, further suggesting the involvement of miRNAs in cellular development and specification. Our results provide new insight into both miRNA and mRNA expression patterns at the single cell level.

10:30

Targeting Adult Stem Cells for Cardiomyogenesis

Potential treatments for cardiovascular disease may involve targeting stem cells for cardiomyogenesis. The widespread application of cardiovascular stem cell therapies will likely be based on pharmacological approaches to enhance the capacity of endogenous cardiac stem cells. Optimally, these treatments will be capable of promoting stem cell function in those with the greatest medical needs, including elderly and diabetic individuals.

- Cardiomyogenesis and Cardiac Care
- Pharmacologically Directed Cardiomyogenesis
- Targeting Cardiomyogenesis for High Risk Populations

11:00

Using a Neurogenesis Based Platform to Develop Novel Therapeutics for Depression

The discovery of neurogenesis in the adult mammalian central nervous system (CNS) has led to a dramatic shift in our understanding of brain plasticity and the role it plays in mood disorders. Research in the field continues to suggest the possibility of developing improved treatments for disorders of the CNS based on pharmacological modulation of the process of neurogenesis. Isolation and subsequent culturing of neural progenitor cells in vitro has opened up the field to the study of underlying molecular and cellular mechanisms involved in neural fate determination, targets associated with these effects, and compounds that can influence those targets. These exciting new approaches to human neural stem cell biology are particularly important for drug discovery, providing researchers with tools to explore the effects of compounds on neurogenesis and interpreting the relevance of preclinical rodent studies in the context of human disease.
- Neurogenesis is a regulated process strongly associated with mood disorders in humans.
- Neurogenesis can be modulated in mammals through small molecular intervention.
- The use of neural progenitor cells in cell-based screening systems can accelerate the drug discovery process.
- The study of therapeutics in both animal behavior models and neurogenesis studies provides new opportunities to better predict clinical efficacy.
- Discovery of modulators of neurogenesis with effects in human neural stem cells in vitro, as well as effects on behavior and neurogenesis in animal models could lead to improved treatments for CNS and mood disorders.

11:30

End of Symposium I

Symposium II: Imaging Technologies

Wednesday, October 15, 2008 (8:00 AM - 11:30 PM)                                     Back to the Top

Symposium Chairperson

Chang-Deng Hu, Assistant Professor, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy

8:00

Bimolecular Fluorescence Complementation – A Novel Imaging Technology for Visualization of Protein Interactions in Living Cells and Living Animals

Protein-protein interactions are key mechanisms implicated in almost all cellular processes. Given that small molecule inhibitors of protein interactions are valuable tools for dissecting signaling pathways and for therapeutic purposes, protein-protein interactions, in principle, are ideal molecular targets for drug discovery. However, targeting protein-protein interactions has been largely unexplored or avoided in pharmaceutical industry because of an unsuccessful history. One contributing factor to this is the lack of available technologies that can be used for the design of specific and cost-effective screening systems for identification of small molecule inhibitors of protein-protein interactions. We have used fluorescent proteins and developed a bimolecular fluorescence complementation (BiFC) assay for visualization of protein interactions in living cells. Over the past few years, the BiFC and BiFC-based technologies have been successfully used for visualization and identification of protein interactions in living cells and living organisms. This presentation will introduce the basic principle of BiFC assay, new applications of BiFC-based technologies, potential applications of BiFC-based technologies for drug discovery, and a comparison of multicolor BiFC-based high throughput screening system with other protein interaction-based high throughput screening systems.

Chang-Deng Hu, Assistant Professor, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy

8:30

Ultrasound-Based Molecular Imaging

9:00

Imaging in CNS Drug Development: Applications and Prospects for Process Improvement

9:30

Networking Refreshment Break & Exhibit Viewing

10:00

The Role of Small-Animal SPECT/CT in Pre-Clinical Drug Discovery

While possibly the least-heralded molecular imaging modality, recent technical advances in small-animal SPECT instrumentation offer picomolar sensitivity combined with nanoliter resolution. This presentation focuses on the role of small-animal SPECT in the molecular imaging through a discussion of image system performance, SPECT imaging agents, direct and indirect comparisons to other imaging modalities and results from multiple pre-clinical case studies using the technology. We provide a detailed discussion of specifications and advancements in areas of image resolution, sensitivity, absolute quantification, multi-modality registration, cardiac and respiratory gating. Of equal importance we present a recently developed on-line SPECT radiopharmaceutical database of imaging agents posted to expedite the dissemination of both commercial and novel imaging agents amongst our user base. Ideally, molecular imaging would consist of radio-labeling and imaging a compound of interest in such a manner that adding the signaling molecule or isotope would not affect the kinetics or dynamics of the unlabeled compound. While in rare circumstances this is possible, we show multiple examples of more practical applications in which SPECT allows a quantifiable, longitudinal evaluation of the pharmacodynamics of an intervention by assessing the changes in the pharmacokinetics of a well-characterized radiopharmaceutical. Case studies and applications in oncology, cardiology, neurology as well as multi-purpose imaging agents are presented.

Benefits:
1. Gain general understanding of single photon emission computed tomography (SPECT).
2. Learn current imaging and chemistry availability in pre-clinical SPECT.
3. Multiple SPECT case studies in pre-clinical molecular imaging.
4. Comparison of SPECT to other currently available imaging modalities.

10:30

In Vivo Imaging of Microglial Activation in the Mouse Central Nervous System using Multiphoton Microscopy

In recent years, in vivo imaging using multiphoton microscopy has revolutionized our understanding of the brain’s physiology and pathology. In this talk I will introduce the technological advances that made imaging of living cells in their unperturbed environment possible. I will mention representative in vivo imaging studies that have changed our perception of how the brain is hardwired and how it responds to environmental stimuli both physiologically and in animal models for disease. I will use our study of microglia in the living mouse brain as an example of how in vivo imaging can reveal not only structural but also mechanistic details that underlie the brain’s responses to traumatic injury. I will also discuss the technical challenges that have been restricting the application of in vivo imaging to the spinal cord of animals. Finally, I will present a novel technique that allows stable imaging of fluorescently labeled cells in the living mouse spinal cord that requires minimal surgery and essentially no image post-processing. This technique can be used to repetitively image axons, glia and the vasculature in the spinal cord of anesthetized mice, thereby allowing the application of multiphoton microscopy to study the spinal cord in physiology, injury and disease.

11:00

Time-Resolved Contrast-Enhanced Magnetic Resonance Imaging and Perfusion

Time-resolved magnetic resonance imaging has been used clinically for many applications such as contrast-enhanced MR angiography, perfusion in tumors and drug delivery. In this talk I will first introduce some background on MR imaging (including T1 and T2 relaxation times, image formation, contrast agent, etc) and dynamic imaging. In the second part I will discuss the fast dynamic imaging techniques developed in our group and their applications. Technical issues such as temporal and spatial resolution will be addressed. In the third part, I will discuss a novel technique called ultrashort TE (UTE) imaging, which can be used to image tissues with such short T2 relaxation times that they are typically undetectable with clinical magnetic resonance pulse sequences. This technique can be used to image the contrast dynamics in bone, meniscus, tendons, ligaments, etc. This allows perfusion quantification of a large group of short T2 tissues, which can be of great clinical potential for assessment of drug delivery in the musculoskeletal system (MSK).

Jiang Du, Ph.D., Assistant Professor, Department of Radiology, University of California,
San Diego

11:30

End of Symposium II

Symposium III: Regulation & Policy in Drug Development

Wednesday, October 15, 2008 (8:00 AM - 11:00 PM)                                     Back to the Top

8:00

Quality By Design: Here's What's In It For You

Currently pharmaceutical firms are achieving drug products of reasonable quality at great cost due to batch failure and regulatory delays. Quality by Design (QbD) is a program described in ICH guidances and encouraged by the FDA. It is a system of critical analysis and scientific rationale.
Although still a work in progress at the FDA, and it has some risks of its own, it can be implemented gradually with benefit. QbD can change the way firms and regulators do business and is a win for both.

We will discuss what QbD is and explain the lingo such as “design space.”
We will describe some of the perils of the old system and the risks and benefits of QbD. QbD is useful to pharmaceutical firms big and small.
How firms go about implementing QbD will be addressed.

Benefits:
1.Quality by Design will be described.
2 The concept of Design Space will be discussed
3.QbD and the Common Technical Document will be explained
4.The audience will learn risks involved with QbD

Marilyn A. Apfel, Ph.D., xFDA

8:30

QbD: It Doesn’t Have To Turn Development Into Research - Examples From Early Development

Quality by Design (QbD) is promoted to reduce review time and increase lifecycle regulatory flexibility, but is sometimes seen as an opportunity to turn development into research and to stimulate unlimited review questions – an especially unattractive alternative to the status quo at a time when discovery-to-market timelines must be reduced. QbD is really just an encouragement to integrate requirements, risk assessments, predictive models, measurements, and data analysis to the extent that the tools contribute to a better understanding of product performance. QbD’s real value is as a carefully considered shift from “do the right thing” to “know the right thing,” and QbD is completely consistent with improved decision making and reduced timelines. There are many QbD tools that can be used in early drug development and these will be discussed.
Define requirements for development tasks without creating new opportunities for OOS crises
Find value-adding analyses between the extremes of box-checking and paralysis by analysis
Consider the use of predictive and design-of-experiments tools in analytical and formulation development

9:00

How to Fail an FDA Inspection . . . and 10 Steps to Make Sure You Don’t!

Maybe worse – or as bad as – a pop quiz in school is an unannounced inspection of your facility by FDA.
The vision for the Office of Regulatory Affairs is direct: Vision: “All food is safe; all medical products are safe and effective; and the public health is advanced and protected.” One of the ways it achieves these objectives is through an inspection of a regulated facility.

The program will review the 2008 version of the Investigations Operations Manual to identify what it is that ORA can – and cannot – do in conducting an inspection. Other topics include:
1. Learning inspection basics
2. What is the appropriate scope of an Inspection
3. Refusal to Permit Entry or Inspection; Refusal to Permit Access to or Copying of Records.
4. Developing Inspection Procedures
5. Considering Optional Policies
6. Be Ready for Inspectional Observations
7. Information Inspection procedure templates and Sample policies
8. How to Fail an FDA Inspection: Fundamental failures of inspections

10:00

Special FDA Regulatory Disclosure Issues for Life Sciences Companies

10:30

Effective Communication with FDA

11:30

End of Symposium III

Back to the Top

Over the last several decades we have seen an increase in life expectancy and significant progress in treating the most common causes of death in United States. A fair portion of this progress has been directly due to the development of innovative new medications from our industry. Now, however, as we design treatments for today’s leading illnesses, we bear not only the significant challenge of elucidating the scientific and clinical benefits of the new medications, but also of maintaining a higher awareness of the social and economic impact. Genentech and others in the biotech and pharmaceutical industry still seek to develop innovative medications. In this presentation we will (i) review historical drug development costs and its impact on society, (ii) assess the current environment for drug development - is innovation in the pharmaceutical industry threatened?, and (iii) consider trends we can impact to maintain a company’s focus on scientific progress and improved treatments for patients.

4:30

Networking Reception, Poster Session & Exhibit Viewing

7:00

Registration & Breakfast

During the last two decades there has been a dramatic change in preclinical research and drug discovery. Major scientific advancements have been made in our molecular understanding of biology in health and disease. In parallel there has been a revolution of the drug discovery techniques. This has lead to a considerable increase in the number of therapeutic targets as well as a major increase in the number of drug candidates. Drug discovery has consequently entered into an era when very complex and highly novel therapeutic approaches can be brought forward into development. However, it is well known that overall productivity is rather on the decline, with major issues in most development pipelines of the industry today; high attrition, pipeline gaps, resource constrains, escalating costs, increased regulatory hurdles, etc. Although the reasons for this remain to be fully understood, a key element is high attrition in early development phases. In particular, target validation and the coupled question on compound action at target remain main challenges, as shown in different industry benchmarking analyses pointing at lack of clinical efficacy as a major reason for program terminations. An aim has therefore been to improve qualitative aspects of drug R&D, with a focus on the transition phase between research and development. Consequently, various translational science strategies have been implemented, aiming at smoothing the transition from in vitro and animal pharmacology to human studies. A linked approach has been to strive to achieve signal of clinical efficacy (proof-of-concept; PoC) as early as possible.
All these changes have posed major challenges in traditional R&D organizational models and processes; and indeed in the overall strategies of pharmaceutical companies. The strategic questions center on driving further into the innovation alley, or to invest into moderate improvements of existing therapeutic principles, life cycle management or move into generics. Even with an innovative strategy, the blockbuster model is challenged with stratified and personalized medicine advancements. Most major pharmaceutical companies are currently undergoing restructuring, often with the aim of enhancing innovative aspects by decentralizing research, while maintaining the benefit of scale in infrastructure support for research, e.g. by having competence centers for costly technologies, and by establishing large development organizations. The translational medicine and PoC parts of the organizations are however difficult to position, and various models have been implemented. The options for small, start up, companies are on the other hand very limited. Generally, their operations balance innovative research with slim development programs (unless a partnered-out). Mid-sized pharmaceutical companies are positioned at the cross road of these options; their size often precludes decentralized models, while they can only build certain in-house capabilities. The R&D toolbox has to be highly streamlined and fit-for-purpose, combined with innovative processes and trial designs, as well as outsourcing of certain platforms. Hence, even with focused, but restricted, investments it is still possible to systematically generate human/clinical evidence to reach decisive PoC, to decide if a compound should progress into full development.

Thursday, October 16, 2008                                                                       Back to the Top

Session I - Targeted Biologics: Antibodies & Beyond

10:00

Harnessing New and Old Technologies to Accelerate the Discovery and Characterization of Therapeutic Antibodies

Jean-Phillipe Stephan, Research Senior Scientist (Technology), Genentech, Inc.

10:30

Selection and Conjugation of Human Antibodies for Highly Potent Therapeutics

Transgenic mice expressing human immunoglobulin genes have been used to generate human antibodies to a large number of targets of potential utility in cancer therapy. Screening methodology has been devised to rapidly evaluate and select antibodies with desirable properties, tailored for different potential mechanisms of action. For example, rapidly internalizing antibodies have been identified for a number of different tumor-associated antigens and these have been shown to be capable of specifically delivering chemotherapeutic agents. Antibody-drug conjugates with DNA minor-groove binding alkylating agents are a novel class of conjugates with attractive properties for development. Anti-CD70 conjugates with promise for therapy of renal cell carcinoma as well as a number of lymphomas will be described, as well as anti-PSMA conjugates for prostate cancer, and CD19 directed conjugates for B-cell tumors. These conjugates are capable of efficient delivery of the chemotherapeutic agent with a large therapeutic window, and have the advantage of not being subject to the major mechanisms of drug resistance.

David King, Senior Director, Mol. Biology & Biochemistry, Medarex, Inc.

11:00

An Antibody Target for the Treatment of B-cell Hyper-Proliferative Diseases

There is a plethora of diseases that are caused by B-cell hyper-proliferation. Because of the regenerative nature of the haematopietic system obliteration of the B-cell pool to get rid of the diseased cells has not been found to be a limiting factor. However, it would be desirable if one could selectively target only the diseased B- cells or a fraction of the B-cell pool leaving the rest unharmed. This presentation will deal with a class of B-cell surface molecules and describe studies to validate these as targets for antibody based drugs for the elimination of specific types of B-cells.

Partha S. Chowdhury, Principal Scientist, Antibody Discovery and Protein Engineering,
MedImmune, Inc.

Session II - Immunogenicity and Humanization

11:30

Humanization of Antibodies via Specificity-Determining Residues Usage Resurfacing

In recent years, The Food and Drug Administration (FDA) have approved more than 20 antibodies for therapeutic applications in humans. This remarkable progress of the biopharmaceutical industry has been highly facilitated by antibody humanization methods. In fact, humanization methods have been diversified and the number of humanized antibodies has shown a continuous steady growth during the last decade. This talk presents a new method to humanize antibodies. The method, called Specificity-Determining Residues Usage Resurfacing (SDRR), combines three main components that differ from previous methods, including: (1) selection of residues targeted for transferring the specificity from a non-human antibody into the human framework, (2) procedure to select human framework regions and (3) method to retain, restore or increase the affinity of the humanized product.

Juan C. Almagro, Ph.D., Research Fellow, Head of the Antibody Design Group, Centocor R&D, Johnson & Johnson

12:00

Targeting FGF19 in Cancer

The ectopic expression of fibroblast growth factor 19 (FGF19) in the skeletal muscle of transgenic mice leads to the development of hepatocellular carcinoma. While FGF19 bound only to FGF receptor 4 (FGFR4), its apparent liver specific activity could not be explained solely by the distribution of this receptor. We recently identified Klotho beta (KLB) as a novel FGFR4 co receptor required for FGF19 binding, intracellular signaling, and downstream modulation of gene expression. The tissue specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. To investigate the utility of FGF19 as a potential cancer-therapeutic target we developed an FGF19 neutralizing antibody. This antibody abolished FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression in vitro. It also inhibited in vivo FGF19-mediated modulation of gene expression, growth of tumor xenografts, and development of hepatocellular carcinomas in FGF19 transgenic mice. These studies describe the molecular mechanism responsible for the tissue-specific activity of FGF19 and suggest that inhibiting its ability to signal may be beneficial for the treatment of cancer.

Luc Desnoyers, Scientist, Molecular Oncology, Genentech, Inc.

12:30

Lunch

Session III - Novel Protein & Peptide Therapeutics

2:00

Discovery and Development of Liraglutide, the First Once-Daily GLP-1 Analog

Discovery and development of liraglutide, the first once-daily GLP-1 analog:
• Discovery of GLP-1 and the incretin effect
• Lack of incretin effect in type 2 diabetes
• Multiple effects of GLP-1 in the control of blood glucose and body weight
• Importance of pharmacokinetics for GLP-1
• Design of liraglutide
• Preclinical and clinical effects of liraglutide

Lotte Bjerre Knudsen, Senior Principal Scientist, Diabetes Biology & Pharmacology Mgt., Novo Nordisk A/S

2:30

The Development of ZT-031: A Novel PTH Analog for the Treatment of Bone Diseases

The bone formation activity of parathyroid hormone (PTH) has been established for several decades but it is only in the last five years that it has become established as an osteoporosis therapeutic. ZT-031 is a novel cyclic 31amino acid PTH analog that has also demonstrated marked bone formation activity in preclinical studies but with reduced evidence of toxicity mediated by increases in serum calcium. In a 12 month study in postmenopausal women daily subcutaneous injection of ZT-031 produced large increases in spine bone mineral density. Modest increases in serum calcium, leading in some cases to isolated episodes of hypercalcemia, were observed but the overall benefit to risk profile was considered appropriate to move forward into Phase 3 registration studies. From platform provided by this clinical database we are now exploring the use of ZT-031 in other clinical settings and as an intranasally administered peptide. This expanded program will complement our continued development of ZT-031 for the treatment of osteoporosis with the goal of expanding the range of clinical uses of PTH analogs.

Brian MacDonald, CEO, Zelos Pharmaceuticals

3:00

TBA

Chris Holmes, Senior Director, Chemistry, Affymax

3:30

New Technologies in Liquid Drug Delivery: Preservative Free Nasal and Ophthalmic Systems

Another aspect covered is an overview of existing technologies available for both preserved and unpreserved ophthalmic preparations, taking advantages and constraints of recent developments into account, before taking a closer look at a new technology behind novel dispensing devices with a purely mechanical function, allowing a multidose application of unpreserved ophthalmic preparations. Matthias will show details of how ophthalmic solutions can be kept sterile during use, plus whether and how the systems are compatible with current filling technologies.

Matthias Birkhoff, Director, Business Development Pharma Division, Pfeiffer-Group

4:00

Networking and Refreshment Break

4:30

6:00

End of Day 2 - Biological Therapeutics Track

Friday, October 17, 2008

7:00

Registration & Breakfast

8:00

9:30

Networking and Refreshment Break

Session IV - Drug Delivery Technologies for Biologics

10:00

Non-Invasive Peptide Delivery, Reformulation, and the Pharma Finance Environment

While reformulation of non-peptide small molecule drugs to improve suboptimal pharmacodynamics has been a mainstay of life cycle management for “big pharmas” as well as “specialty pharmas”, particularly fruitful but more challenging reformulation opportunities exist in the case of peptide and protein drugs. New technologies to overcome the inherent challenges of achieving adequate bioavailability, preventing peptide aggregation and minimizing immunogenicity have been developed. A growing class of alkylsaccharide delivery enhancement and protein stabilization agents designated Intravail® and ProTek® excipients, respectively, permit intranasal delivery – or more broadly, transmucosal delivery of peptide and protein drugs having molecular weights up to and, in some instances, in excess of 20 kDa, and long-term room temperature stability and reduced immunogenicity for many peptides and proteins. Reformulation of injectable peptide or protein drugs into more patient-friendly forms such as metered nasal sprays, oral and flash-dissolve sublingual or buccal formulations, offers a particularly large, attractive and as yet untapped opportunity, for all stakeholders in the pharmaceutical field – drug delivery and specialty pharma companies, ‘big pharma’ companies, physicians, patients and third-party payers.
Topics to be discussed include:
• Addressing the key Issues in peptide reformulation such as achieving adequate bioavailability, preventing peptide aggregation, and minimizing immunogenicity.
• Opportunities and benefits of reformulation of peptide drugs amenable to 505(b)2 FDA regulatory treatment such as minimized business, regulatory, and clinical risks; expanded clinical indications; greater patient acceptance; increased product sales, and maximized value extraction from an already existing product franchise.

Edward Maggio, Ph.D., President & CEO, Aegis Therapeutics

10:30

Pharmacokinetics and Biodistribution after Parenteral Administration of Drug Nanoparticles and Microparticles

Suspensions with drug particles have been administered by intramuscular and subcutaneous route for sustained delivery (depot). Although one would anticipate impact of particle size on dissolution rate and hence rate of release and duration of pharmacokinetic exposure, very few examples illustrate this. Classical approaches for solubilization of poorly soluble drugs for parenteral delivery include use of salt forms, pH modifications and use of colsovents, however recent scientific literature have shown use of dispersed systems such as liposomes, microemulsions and nanoparticles for delivery of poorly soluble drugs. Due to the small size of dispersed phase, differences in dissolution rate and distribution into various tissues would be anticipated and thus some of these dispersed systems such as liposomes have been shown to provide drug targeting. The presentation will review the pharmacokinetics and biodistribution of various nanoparticle and microparticle based formulations after intravenous and intramuscular dosing from literature and case studies. The results demonstrate that the type of changes in pharmacokinetics and biodistribution that can be observed with various particulate delivery systems depends on the route of administration, nature of the physical system and particle size of the dispersed phase.
The audience will benefit in the following areas:
• Learn about physical nature of different dispersed systems for parenteral administration
• Learn about effect of physical nature of systems on pharmacokinetic processes and parameters
• Awareness of why understanding delivery is essential to selecting an appropriate technology
• Correlating properties of formulation to its in vivo performance

Session V - Modern Vaccine Development

11:00

Structure Based Vaccine Design for Difficult Targets

Indresh Srivastava, Head, Expression, Purification & Analytics, Novartis Vaccines & Diagnostics

11:30

Pneumococcal Pili and Novel Approaches for Protein-Based Vaccines against Streptococcus pneumoniae

Streptococcus pneumoniae is one of the most important human pathogens and a major cause of morbidity and mortality worldwide, causing respiratory tract infections, pneumonia, and invasive diseases. The emergence of multi-drug resistant clinical isolates and the limitations of existing polysaccharide-based pneumococcal vaccines prompt the urgent need for different prophylactic strategies, like protein-based vaccine formulations broadening protection.
Although the pneumococcus is a well-studied bacterial pathogen, pili on its surface were discovered only recently. Pili are elongated structures extruding from the bacterial surface and were found to be important virulence factors of both Gram-positive and Gram-negative bacteria. Bacterial pili are considered to participate in bacterial adhesion to a host, a crucial step in bacterial infection. Yet little is known about the structure of native Gram-positive pili.
We used native purified pili of pathogenic pneumococcus TIGR4 to study structural and functional characteristics: Pili were found to be composed of protofilaments that are arranged in a coiled-coil superstructure with adhesive properties mainly mediated by surface located ancillary protein RrgA.
Recombinant pilus subunits showed protection against lethal challenge with S. pneumoniae in a mouse model of infection after both active and passive immunization. Data obtained could help designing a novel effective protein-based pneumococcal vaccine.

12:00

A DNA Vaccine for Multiple Sclerosis: How To Find A Competitive Edge In An Already Crowded Development Field

The world-wide multiple sclerosis (MS) market is large with over $6 billion in sales annually. However, there are six drugs already approved for the treatment of MS, and several promising therapies in late-stage phase 3 and phase 2 clinical trials. The competition that any new potential therapy faces within this crowded field is very steep.
We are developing BHT-3009, a DNA vaccine for multiple sclerosis (MS) encoding full-length human myelin basic protein. In a recently completed 48 week phase 2 trial of relapsing-remitting MS patients, BHT-3009 was shown to cause antigen-specific immune tolerance and to reduce the number of lesions on brain MRI in a select group of patients. In addition to these results, the competitive advantages that BHT-3009 could provide within the MS field will be discussed.
• What are the current and emerging therapies for MS?
• How can a potentially new therapy compete in a crowded development field, such as MS?
• How do the results from the BHT-3009 phase 2 trial indicate that it will be competitive in this field?

12:30

Lunch

1:30

MVA-based Immunotherapy of Cancer. Kinetics of Antigen Expression and Ensuing Immune Response to Better Identify Adjuvant

Vaccinia-based immunotherapy is a promising approach to target cancer and chronic infectious diseases. Transgene SA has developed MVA products that are in clinical trials targeting either cancer or HCV-chronic hepatitis. To further improve the efficacy of this vector type, it is important to understand its mechanisms of action in the context of its clinical application. To address these points, we used the murine preclinical models in which the cancer immunotherapy proof of concept was done. At the site of injection, histology and flow cytometry analyses allowed to define the infected cell population as well as the infiltrating population. The ensuing reaction in the draining lymph node and the mode of antigen presentation have been deciphered. This information is crucial for the identification of adjuvants that could boost appropriately this type of vector. Our adjuvant screening platform will be discussed.

2:00

End of Conference

Thursday, October 16, 2008                                                                     Back to the Top

Session I - Target Identification & Validation

10:00

Utilizing Multiple 1536well RNAi HTS Assays to Identify New Regulators of the Wnt Pathway

The Wnt/Beta-Catenin cell signaling pathway is involved in cancer, development, tissue regeneration, bone and stem cell biology. Several genome-scale siRNA screens were carried out to elucidate the genes regulating this pathway. A total of four different cell lines were developed with a Beta-catenin activity reporter (BAR) driving luciferase expression. Two of these cell lines had an APC loss-of-function (LOF) and therefore demonstrated constitutively active, Wnt-independent Beta-catenin activity. Two additional cell lines had Wnt-dependent -catenin activity, which was induced by the addition of conditioned media containing Wnt3a. In order to select genes independent of cell background, reduce data variation associated with prolonged operation of siRNA screens (typically several weeks), and introduce robust statistical selection of primary hits, the assays were miniaturized to 1536w plate format and screens were performed in triplicate (N=3) for each cell line. The ultra high throughput assay also allowed us to quickly test different siRNA collections to compare performance and identify possible siRNA activities due to off-target effects. The result is a very efficient siRNA screening paradigm that has identified new genes involved in the Beta-catenin pathway.

Shane Marine, Merck & Co.

10:30

Developing Translational Targets for Psychiatric Diseases

A critically important aspect of drug discovery is the development of predictive preclinical models with suitable biomarkers to assess the efficacy of novel therapeutics. The complexity of human CNS diseases compounds the challenge of evaluating responses in behavioral assays developed for non-human subjects. Electroencephalography (EEG) provides a non-invasive method to monitor cortical brain activity that is translatable across preclinical species and into humans. The power of genetics, gene expression and quantitative phenotyping can be combined with EEG data to identify causal targets underlying CNS function and disease. Additionally, EEG can be used effectively preclinically to validate new mechanisms and as a clinical biomarker to demonstrate target engagement. The presentation will describe how this approach can alter neuroscience drug discovery across a variety of CNS therapeutic indications.
This presentation will highlight new approaches for identifying and developing CNS drug targets, show how to combine genetic and behavioral data to identify underlying gene networks and discuss EEG as a translatable biomarker for neuroscience discovery and development

Christopher Winrow, Research Fellow, Merck & Co., Inc.

11:00

Experimental Design and Instrument Performance Considerations for Mid/High Complexity Flow Cytometry Applications in Translational Medicine

The positive impact that flow cytometers have made in the research and clinical arena is unambiguous. The enabling value of this analytical platform continues to rise alongside parallel development of additional fluorochromes and newer instrumentation. Although the marriage between flow cytometers and translational medicine programs is intuitive, the lack of accuracy standards for such experiments is recognized and troubling. With this in mind, sharing / debating the emerging logic surrounding experimental design and instrument set-up for higher-complexity experiments on the newer generation of multi-detector digital platforms is of high value. Otherwise, investigators could find themselves in situations where datasets cannot be corroborated. The purpose of this presentation is to illustrate the challenges of building a mid-complexity multicolor antibody panel that includes dim staining populations. Emphasis will be placed on the utility of a commercially available software-assisted approach that allows each user to better characterize their instrument and increase their confidence that the cytometer is optimally set-up for data acquisition. The ramifications of spectral overlap issues from poor fluorochrome choice and the potential consequences of violating manufacturer guidance for instrument set-up will be included.

John Ferbas, Associate Director, Clinical Immunology, Amgen, Inc.

Session II - Biomarkers

11:30

Non-Invasive Molecular Imaging: It’s Role as a Biomarker, in Validating Molecular Biomarkers, and as a Valuable Tool to Objectify Pre-Clinical Disease Models Against Clinical Data

Innovations in the discovery and use of biomarkers will dramatically affect the study and understanding of pathophysiology. Imaging biomarkers have the extraordinary potential to objectify complex clinical studies and to support the development and use of better-correlated pre-clinical disease models. Furthermore, imaging studies have the distinct advantage of enabling real-time, longitudinal analyses in live animals.
Through a series of case studies across a number of therapeutic areas, this presentation will address the challenges of integrating classical and imaging biomarkers, and the role of multi-modal, small-animal imaging in drug discovery and development. The presentation will demonstrate the use of molecular imaging to measure drug efficacy and toxicity, mechanism of action, and tissue distribution, and to monitor PK/PD. Finally, the presentation will review how advances in SPECT image resolution, sensitivity, quantification, co-registration, and gating have elevated the value of this modality.
This talk will give the audience an appreciation for the complexity of pathophysiology, the challenges of developing and validating drug discovery innovations, and the breath of impact that molecular imaging can have on drug discovery and development.

Paul L. Domanico, Ph.D., President, Paul Domanico Consulting, LLC

12:00

Determining Cross-Species Exposure-Receptor Occupancy Relationships for a Dual-Pharmacology CNS Compound: An Exercise in Translational Medicine

The development of preclinical models to identify cross-species biomarkers linked to human efficacy is critical in clinically evaluating with high confidence the mechanism of a medicinal target. This presentation will discuss the methodology developed and employed to determine the relationship between plasma concentration and receptor occupancy (RO) of a specific clinical candidate (1) simultaneously inhibiting the serotonin (5-HT) transporter (SerT) and antagonizing 5-HT2A in rats, monkeys and humans. The developed rat ex vivo binding PK/PD modeling methodology, which was predictive of both SerT and 5-HT2A ROs of 1 in monkeys and humans as determined by PET imaging, was then used to simulate monkey and human RO for back-up candidates allowing the possibility of using only monkey PET imaging for target biomarker studies.

Christopher L. Shaffer, Dept. of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global R&D

12:30

Lunch

2:00

Urinary Transforming Growth Factor-beta 1 (TGF-β1) as a Biomarker for Chronic Kidney Disease, Measurement and Stability

Transforming growth factor (TGF)-Beta1 plays a central role in the pathogenesis of chronic kidney disease (CKD), and assessment of urinary levels of this cytokine may guide prognosis and therapy. Analysis of urinary TGF-Beta1 in human urine has not been standardized, resulting in possible data inconsistencies between studies. Here, we describe a highly specific immunoassay, employing MesoScale detection technology, that reliably detects TGF-Beta1 in urine at levels down to 1 pg/ml. TGF-Beta1 was consistently detected in the urine of healthy donors, without the requirement of an ex-vivo concentration step.
1) Developing a diagnostic urinary assay.
2) Assay design considerations
3) Assay sensitivity
4) Clinical trial sample handling considerations
     -  Stability of urinary TGF-Beta1

Thomas Lee, Assistant Senior Scientist, Eli Lilly & Co.

2:30

Predictive Translational Biomarkers in Neurodegenerative Diseases

The absence of authentic biomarkers of neuronal degeneration has contributed to the slow and disappointing track record for development of new therapies in Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s (PD). Optimally, drug discovery begins with the understanding of disease mechanisms. A therapeutic agent can have an effect on neuron degeneration if it interrupts a specific disease process or corrects a specific deficit. New monitoring techniques that provided insight into pathophysiology, disease progression and treatment response would represent a major advance in the area of neuro-restorative drug development. We have developed a novel stable isotope/mass spectrometric assay to measure dynamic pathway fluxes in vivo prior and during neuronal degeneration. A novel pathway-based screening in vivo was identified (microtubule dynamics in neurons) that has potent functional consequences in neurodegenerative conditions (Fanara et al. JBC 282, 2007). This pathway-based screening represents an alternative to the high attrition of the molecular target-based discovery paradigm. Biomarkers that reflect the activity of underlying pathophysiologic processes that drive disease progression (i.e., play an etiopathogenic role), have a number of potentially important uses. In the case of neurodegenerative diseases, a biomarker of this type could help to rapidly evaluate promising therapeutic approaches, optimize dose and regimen for drug candidates (by permitting quick-kill or decisions to advance agents, based on activity in proof-of-therapeutic-concept studies). In principle, it is true that one can never be sure whether the control systems discovered in an animal model will apply to humans. A key feature of pathway-based screening in vivo described here, however, is that most of the techniques for measuring flux rates through disease pathways in vivo in animal models can be used in identical fashion in human subjects. This translatability of methods results in the capacity to test immediately, and with modest expense, time and number of subjects, whether data from preclinical models apply in human. These authentic biomarkers would have substantial impact, for the evaluation of new treatments and to reduce drug development costs.

Patrizia Fanara, Ph.D., Director of Neurodegenerative Diseases, KineMed, Inc.

Session III - Predictive Safety & Toxicology

3:00

Drug-Induced Mitochondrial Impairment: A Novel Model for Idiosyncratic Drug Toxicity

Many widely-prescribed therapeutics have “off target” effects on mitochondria that undermine function via several mechanisms. Antibiotics and antivirals can inhibit mitochondrial biogenesis by blocking mtDNA replication or translation. More acutely, metabolic therapeutics such as thiazolidinediones and biguanides, as well as cholesterol lowering statins, variously uncouple and/or inhibit respiration. Retrospective analysis of drugs withdrawn from the market, and those having received a Black Box Warning because of adverse events, indicates that many are mitochondrial toxicants, and that such toxicity can fully account for the clinical disposition. Bioenergetic and mitochondrial assessments should be done early in drug development to avoid such toxicity, and several techniques amenable to drug discovery/development arenas have been developed. Drug-induced mitochondrial impairment offers new insight into the etiology of idiosyncratic drug toxicity.

Also Discussed:
1) Unanticipated mitochondrial liabilities of many types of drugs
2) Why this drug-induced mitochondrial toxicity was not detected pre-clinically
3) Recently developed techniques to assess mitochondrial function in high-through[put modes

James Dykens, Associate Research Fellow, Pfizer Global R&D

3:30

The Nrf2-ARE System – A Novel Biomarker for Reactive Metabolites?

Adverse drug reactions (ADRs) continue to pose a major impediment to drug development, and the clinical management of marketed products. ADRs are typically divided into two categories: type A and type B. Type A represents acute dose dependent reactions while type B reactions are characterized by their occurrence in only a small percentage of patients, these being most likely mediated by the immune system. Both types of reaction are thought to be due to the generation of reactive metabolites from an administered drug.
The Nrf2 transcription factor plays a key role in the detoxification of reactive chemical species within the cell. Nrf2 is a highly labile protein that is rapidly stabilized upon exposure of cells to electrophilic species. This allows Nrf2 to accumulate in the nucleus and activate the expression of a number of genes encoding Phase II xenobiotic metabolizing enzymes and proteins with antioxidant capacity. Therefore, monitoring of Nrf2 protein levels and expression of its downstream target genes may provide a physiologically relevant biomarker to indicate the generation of reactive metabolites within a particular cell population.
This talk will aim to describe current challenges in detecting reactive metabolites and predicting ADRs during drug development. An overview of the Nrf2 system and its potential for detecting reactive metabolites will be given. Finally, some preliminary data supporting the hypothesis that Nrf2 is a valid biomarker for reactive metabolites will be presented.

1) What impact do preclinical/clinical ADRs have on the drug development process?
2) What is the role of reactive metabolites in ADRs?
3) What are the current strategies used to detect reactive metabolites?
4) What is the role of the Nrf2 transcription factor in combating reactive species within the cell?
5) Can Nrf2 be used as an in vivo biomarker to detect reactive metabolites and therefore predict toxicity?

Paul Nioi, Ph.D., Senior Scientist, Schering-Plough Research Institute

4:00

Networking and Refreshment Break

4:30

6:00

End of Day 2 - Translational Medicine Track

October 17, 2008

7:00

Registration & Breakfast

8:00

9:30

Networking and Refreshment Break

Session IV - Developing Predictive Preclinical Models

10:00

Immunotherapy of Cancer: Challenges and Needs

The application of vaccines to cancer is now an attractive possibility thanks to advances in molecular engineering and a better understanding of tumor immunology.
Transgenic animal models have played a critical role in establishing basic paradigms of tumor immunology because they provide an in vivo milieu that cannot be reproduced in vitro. As novel immunotherapies and cancer vaccines have been developed, animal models have also played an important role in pre-clinical testing for therapeutic efficacy.
Most of the current studies are performed in rodents. However, scaling up experimental protocols from rodents to humans is often not a straightforward procedure, and this particularly applies to cancer vaccines, where vaccination technology must be especially effective to overcome a variety of immune suppressive mechanisms.

This workshop addresses key questions for the development of cancer immunotherapy and predictivity of pre-clinical models:
1) Are cancer vaccines efficacious when scaling up protocols to humans?
2) Which type and extent of immune response are expected in patients by vaccinating against a tumor associated antigen?
3) Are cancer vaccines safe?
4) Which strategies can be acted to enhance the efficacy of cancer vaccines?
5) What are the industrial challenges for the development of a cancer vaccine product?

Luigi Aurisicchio, Ph.D., Oncology Department, Merck & Co.

10:30

Intrastriatal Delivery of L-DOPA as a Predictive Preclinical Model to Investigate Dyskinesia in Parkinson’s Disease

Treatment of L-DOPA-induced dyskinesia (involuntary choreiform and dystonic movements) is one of the unmet medical needs in Parkinson’s disease (PD). In humans and in laboratory rats with severe neurodegeneration of the nigrostriatal pathway dyskinesia develops over time and can be evoked by systemic L-DOPA administration.
In this presentation the effects of local delivery of L-DOPA, dopamine (DA) and metabolites into the brain (striatum) via in vivo microdialysis probes will be shown in freely moving rats lesioned with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA).
L-DOPA as well as DA administration at the 6-OHDA lesioned side led to a significant appearance of dyskinetic behaviour, whereas DA metabolites were ineffective. Intrastriatal inhibition of the enzyme aromatic amino acid decarboxylase (AADC) by benserazide, which blocks the conversion of L-DOPA to DA, prevented the expression of L-DOPA-induced dyskinetic movements at the lesioned side.
Thus, intrastriatal L-DOPA itself is not able to induce dyskinetic movements, whereas the increase of intrastriatal DA levels is instrumental for L-DOPA- and DA-induced dyskinetic behaviour.

Boris Ferger, Head of Preclinical In Vivo Parkinson's Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG

Session V - Clinical Integration - From Bench to Bedside

11:00

From Bedside to Bench and Back: Validation of Emerging Biomarkers in Animal Models and Patients – How Predictive are Biomarker Data from Preclinical In Vivo Models?

For various reasons Biomarker (BM) research has become an extremely important topic for the decision makers in pharmaceutical research organization. Though initial investment for the complementary animal model and patient based validation of BMs is necessary, there is no doubt that BMs have the potential to increase speed of preclinical & clinical development of new chemical entities by supporting go / no go decisions and therefore save costs in drug development.
The official authorities such as FDA and the EMEA are well aware of BMs relevance for pharmaceutical innovation and recognize that though obviously a lot of research in this field is undertaken only few new biomarker candidates are reported. Therefore BM qualification processes were established to encourage research organizations to submit voluntarily explorative biomarker research data.

Using examples from cardiovascular biomarker research the following topics will be discussed:
1) To which extent can new preclinical in vivo models contribute to the identification & validation of BMs?
2) BM validation in the patient: What are ethical & regulatory aspects that have to be considered when relevant patient specimen are acquired
3) Barriers between preclinical researchers & clinicians / dealing with fears in the clinical development department
4) Are there regulatory hurdles for the use of exploratory biomarkers in clinical studies?

Frank Kramer, Ph.D., Research Scientist, Institute for Target Discovery - Biomarker,
Bayer HealthCare

11:30

Development of a Cardiac Imaging Agent: from Concept to Clinic

Cardiovascular diseases are the leading cause of mortality in USA. Nuclear cardiac imaging provides a unique tool in a non-invasive and repeatable manner for early disease diagnosis, treatment stratification and progression assessment. Cardiac imaging has been successfully used for monitoring myocardial perfusion and molecular changes, like glycolytic or lipid metabolism, norepinephrine transporter and ß-adrenergic receptor levels. However, the currently available cardiac imaging agents have limitations. To develop a new imaging agent, the concept should initiate from identification of a molecular target which represents flow for a perfusion agent or alters following disease progression. The potential agent should have high selectivity for the target. In addition, limitations of similar available imaging agents, selection of a favorable imaging modality and species specificity should also be considered. Recently, a myocardial perfusion imaging agent, BMS-747158-02, has been developed and is in phase I clinical trial. This imaging agent took advantage of the PET technology to enhance image quantification over the current SPECT agents. This agent was radio-labeled with 18F, a radioisotope with longer half-life than similar PET agents, for easy commercial application. Due to high mitochondrial content in the heart and the myocardial retention of mitochondrial complex I (MC-I) inhibitors correlated well with flow, MC-I was selected as a target. BMS-747158-02 had high affinity for MC-I in in-vitro and was retained well in the heart of rats. Cardiac imaging with BMS-747158-02 showed strong myocardium uptake with minimal background interference in multiple species including rat, rabbit and nonhuman primate. Myocardial perfusion deficit areas were clearly identified in animal models of ischemia and myocardial infarct. Consistent with animal studies, the myocardium was well-defined in cardiac imaging with BMS-747158-02 in human. Thus, development of a novel nuclear cardiac imaging agent requires translational consideration from a preclinical concept to clinical application.

Ming Yu, Sr. Research Investigator, Lantheus Medical Imaging, BMS

12:00

Ph I Trials in Asia: Opportunities and Challenges

The demand of Ph I trials in Asia is experiencing an explosive growth recently. Those trials are mainly used 1) to satisfy the local registration needs, 2) to support submissions in US/EU etc, and 3) to obtain first-in-man and/or proof-of-concept information on those compounds originating from local R&D centers. While opportunities exist for multi-national companies (MNC) to tap into the vast patient pools and potentially speed up drug development and save costs, the key is how to manage challenges. This workshop provides an overview on the current status in major Asian countries and shares experience in managing the challenges associated with regulatory environment and trial centers.
- Opportunities and challenges of Ph I trials in Asia:
1) Why should we be interested in running Ph I trials in Asia?
2) What are the current regulations relevant to the Ph I trials?
3) What are the processes involved?
4) Can we run a first-in-man study in Asian countries such as China?
5) How are the patient pools and clinical trial centers in the region?

Hequn Yin, Principal Fellow, Novartis

12:30

Lunch

1:30

Revisiting Old Drugs as Novel Agents for Retinoblastoma: From HTS Hits to the Clinic

Retinoblastoma affects every year about 5,000 patients worldwide and is the most common pediatric ocular cancer. Because enucleation remains necessary to treat patients with advanced disease, better therapeutics for retinoblastoma are needed. In this study we aimed at identifying new indications for the treatment of retinoblastoma among approved drugs. We have identified several drugs with potent in vitro cytotoxic activity toward established retinoblastoma cells. We concentrated our initial efforts on cardenolides, historically associated with the treatment of congestive heart failure, as a new class of compounds to treat patients with retinoblastoma. We will present and discuss our findings and propose this approach as a rapid way to reposition old drugs for new uses.

Christophe Antczak, Senior Research Scientist, HTS Core Facility, Memorial Sloan-Kettering Cancer Center

2:00

It is Really Possible to Select Better Clinical Trial Subjects?

One of the promised benefits of biomarkers is targeting patients who are more likely to respond to drugs. Although biomarkers for drug metabolism and drug-target interactions are valuable in refining lead compounds, clinical trial variance is often due to inclusion of diverse phenotypes. Genetic biomarkers that influence key leverage points in the biology may provide predictors of disease progression phenotypes and thereby enrich for subjects more likely to have progression events during the trial. Such biomarkers may also enrich for subjects who innately exhibit a greater magnitude of response because of an increased elasticity of response. This presentation will discuss genetic biomarkers that are highly prevalent in the population and that substantially enrich for disease progression for multiple diseases, including osteoarthritis and cardiovascular disease. For example, disease modifying osteoarthritis drugs are under development by several companies. We have identified a set of high frequency genetic biomarkers that distinguish two groups of OA patients, the first has an approximate 50% likelihood of progressing to severe disease and the second group has an approximate 15% likelihood of severe disease. These markers will be beneficial in clinical trials and will guide earlier use of disease modifying drugs in clinical practice.

1) Disease progression genetic biomarkers and how they can improve clinical trials?
2) What is “disease elasticity” and how does it affect clinical outcomes?
3) Currently available genetic biomarkers that stratify clinical trial subjects
     - Osteoarthritis
     - Cardiovascular disease
     - Weight loss in obesity
4) How genetic disease progression biomarkers may be used to enhance early clinical use of drugs to reduce disease complications

Ken Kornman, DDS, Ph.D., Chief Scientific Officer, Interleukin Genetics

2:30

Deconstructing and Redesigning Cancer Vaccines

The field of cancer vaccines initiated by the discovery of first tumor associated antigens almost two decades ago, promoted excitement behind the idea of harnessing tumors by deploying immune responses. Despite numerous efforts, therapeutic cancer vaccines are still to show conclusive proof of concept in advanced clinical development. The substantial heterogeneity of platform technologies and targets proved to be rather a challenge in light of the complexity of the mechanism of action and the suboptimal knowledge-base, warranted to effectively advance these investigational drugs. Recent observations on the anecdotal efficacy or limitations of vaccines and related platform technologies – adoptive T cell therapy, antibody based immunotherapy and immune modulating drugs – must be factored in, along with the experience with therapeutic vaccines in preclinical models, representing idealized scenarios. The importance of target selection, biomarker-based patient stratification and optimizing immunization, have been underestimated in the quest to rapidly bring drugs to market. Altogether, these suggest that a radically different mechanistic-driven approach needs to be implemented in order to redesign and spearhead cancer vaccines. In the end, if proven successful, the deployment of cancer vaccines in clinic will break new grounds at several levels, including their positioning within the arsenal of therapies in oncology.

Adrian Bot, Senior Director, Translational Medicine, MannKind Corporation

3:00

End of Conference

Thursday, October 16, 2008                                                                       Back to the Top

Session I - Tools for Successful Partnering

10:30

Beyond the Beaten Path: The Merits of Early Stage Technology Partnering with an Animal Health Company

Bridging the gap from invention to early development has become a significant financial challenge for biopharmaceutical start-ups in times of tighter budgets and limited venture capital funds. The rapidly growing specialty pharma business for veterinary products with over $16 billion dollars in annual sales is presenting a unique option to advance early-stage pharmaceutical drugs and technologies in a novel way. Collaborations between the animal health and the biopharmaceutical industry provide opportunities for early proof of concept of therapeutic targets in natural disease (e.g. oncology), the possibility of diluting research costs (e.g. toxicology) and manufacturing expense (e.g. CMC), and the opportunity to generate income through out licensing of derivatives of core technologies to a non-competing business.
The presentation provides insights into:
• The animal health pharmaceutical and vaccine industry
• The open innovation concept used by mid to large size animal health companies
• The benefits of partnering with animal health as well as
• Examples of successful partnering, highlighting university, biotech and big pharma transactions.

Holger Lehmann, DVM, PhD, Head External Research, Intervet/Schering-Plough

11:00

Recent Research and Early Stage Collaboration at Bristol-Myers Squibb Recent Case Studies

The presentation will provide an overview of recent deals and collaborations in the areas of diabetes and obesity, including deal structure and terms. The presentation will also describe the current licensing landscape, covering the key mechanism of action currently under investigation in biotechnology and pharmaceutical companies. Finally the current trends in financing of biotechnology companies in the diabetes and obesity areas will be reviewed.
The presentation will benefit delegates by:
- Providing a history of recent deals in the metabolic disease areas
- Providing insight into the current licensing landscape and its likely future.

Timothy Herpin, Director, Cardiovascular & Metabolic Disease Licensing, Bristol Myers Squibb

11:30

University-Industry Partnering Opportunities

University-Industry partnerships can provide mutually beneficial interactions and results. They offer a cost-effective way of building the technological foundation of a new company or of bolstering an existing company’s internal R & D programs. They allow university researchers to contribute to solving commercially-focused problems that are of current interest and may have broad marketplace applicability. This presentation will discuss what universities can offer to companies as a component of their business strategies.
Key ways in which universities and industry can partner to their mutual benefit:
- In-licensing by industry of university innovations
- Sponsored and collaborative research projects
- Grant teaming opportunities

Jane Moores, Assistant Vice Chancellor – Intellectual Property, UCSD

Session II - Different Methods of Financing

12:00

In today’s environment, funding of drug discovery and development is a real challenge. VC and angel investors alike are looking for exits in a much shorter time frame than traditional drug discovery and development would allow. Additionally, the risk is generally perceived as higher with these companies.
In this presentation, Jack Florio, investor and board member with San Diego Tech Coast Angels will share with you parameters around which these types of deals can be and have been funded. SDTCA has funded a number of these deals and he will tell you why – and also where they have not funded, why not.
From this presentation you will learn:
1. How to package the opportunity your business will provide investors in both an accurate and most favorable light.
2. How to identify discrete fundable milestones in your business that will attract angel investors.
3. The key aspects of a drug development business that attracts angel investors.
4. What are some of the critical features of a drug development deal that would make it very unlikely to get funding.
5. Why all angel groups are not alike and what to look for in an angel group that can add value to your business.

Jack Florio, Vice President, Brinson Patrick Securities

12:30

Lunch

2:00

Panelists:

Chair: Jack Florio, Vice President, Brinson Patrick Securities
Nils Peter Debus, Ph.D., Senior Director, Global Business Development & Licensing, Office of Technology USA, Bayer HealthCare
Aron Knickerbocker, Senior Director, Business Development, Genentech, Inc.

3:00

Networking and Refreshment Break

4:30

6:00

End of Day 2 - Partnering, Licensing & Outsourcing Track

October 17, 2008

7:00

Registration & Breakfast

8:00

9:30

Networking and Refreshment Break

10:00

Panelists:

Chair: John Kaiser, Vice President of Strategic Marketing & Corporate Development, ACADIA Pharmaceuticals
Paul Resnick, M.D., MBA, Senior Director, Worldwide Business Development, Pfizer, Inc.
Alexander Schuth, Genentech

Session III - Alliance Management & Types of Partnerships

11:00

A Lilly Perspective on Partnering with Japanese Companies

Lilly has a wealth of experience in creating and managing productive partnerships with a variety of Japanese companies. Lilly’s collaboration structures have evolved over the years to match the changing needs of the business, but the focus has always remained on meeting patient needs and maximizing the value to both parties. The company continues to emphasize the importance of external innovation to its success, and views the ability to collaborate productively as a critical core competence. Attendees of this session will learn:
- Different partnership structures that Lilly has used in Japan and in global partnerships with Japanese companies
- The importance of understanding Japanese companies’ perspectives in a collaboration
- How Lilly’s deal structures have evolved to meet the changing needs of its Japanese affiliate
- Lilly’s approach to managing each alliance in a unique manner

Nick Lemen, Manager, Corporate Business Development, Eli Lilly & Co.

11:30

Opposites Attract – Making Alliances Between Small/Mid-size Biotech and Big Pharma Work

Alliance Management is becoming increasingly accepted within and adopted by big pharma because in-licensing has evolved as a critical pipeline booster to the largest pharmaceutical companies. Many of today’s in-licensing opportunities originate from highly innovative small or mid-size biotech companies. In view of these in-licensing opportunities, one might think there is a great marriage between big pharma and small or mid-size biotech; small or mid-size biotech companies contribute products and important IP while big pharma adds the development capabilities, commercialization infrastructure and financial resources necessary to bring products to market. Challenges begin, however, once the ink on the agreement forming a new partnership dries. The partners inevitably discover their differences. What looked like the perfect collaboration is becoming a relationship stressed, among other things, by differences in business goals, strategies, organizational structures, processes, behaviors, norms, and last but not least, assumptions.
Today, Nektar Therapeutics has twenty six active collaboration programs with twenty two alliance partners. In this presentation, you will learn how a small to mid-size biotech company like Nektar can (a) successfully handle such a large alliance portfolio through pro-active alliance management, (b) align itself with all its partners even though each of them is unique, and (c) effectively resolve conflicts without jeopardizing working relationships and programs.

Gal Cohen, Director of Corporate Business Development and Alliance Management, Nektar Therapeutics

12:00

Panelists:

Chair: Sameeh Salama, Vice President NAEJA Pharmaceuticals
John Wehrli, Partner, Latham & Watkins
Michael Crowley, Associate Director Business Development, Genentech, Inc.

12:30

Lunch

Session VI- Outsourcing & Licensing

1:30

Biopharmaceutical companies around the world are compelled to look for various cost containment measures in attempts to further reduce R&D expenditures and gain efficiency improvements. Several market forces are playing an integral role in this growth: pharma’s revenue is decelerating; rising R&D costs and volume of activity; and a growing public distrust and concerns about safety. As a result, drug development strategies and plans are changing resulting in extending the clinical trial process into commercialization period. Many companies are actively seeking alliances that complement their core competencies in a mutually beneficial and cost competitive manner. As a result, there is increase in the number of licensing and outsourcing strategies and co-development agreements are being undertaken. While cost reductions and risk sharing were on the list as key benefits, many companies are focused on growth and competitive advantages as additional benefits that can provide access to a new technology, specialized capability, or simply speed to the market.

This presentation reviews the various types of strategic partnerships and the forces driving growth. Specifically, the session explores the:
• Key trends driving growth for collaborations and partnership strategies;
• Review of the partnership strategies and the impact on bringing drugs to the marketplace;
• Key advantages of partnership with a CRO-- to the biopharmaceutical company, research center, and the patient community.

Learning Objectives:
• Understand the various types of partnership strategies and the benefits they offer to the clinical research enterprise and patient community
• Understand the market forces driving the rapid growth such collaborations and discuss the trends changing the drug development process

2:00

Top 10 Tips for Negotiating a Successful Collaboration

John Wehrli, Partner, Latham & Watkins

2:30

End of Conference

Thursday, October 16, 2008                                                                       Back to the Top

Session I - Screening & Hit Identification

10:00

High Throughput Screening of Chemically Modified siRNAs for Target Validation In Vivo

At Sirna, we have been engaged in the development of siRNAs as tools for both target validation siRNAs against ~100 novel targets both in tissue culture cells and in vivo. This approach allows for the rapid and as therapeutic agents. Here I report on progress made at Sirna in screening chemically modified validation of target genes by determining the phenotypic effect in a mouse model without the time consuming production of knock-out mice.
In addition, Sirna uses a novel pattern of chemical modifications to produce siRNAs with high efficacy, high potency, long duration in vivo and abrogation of release of cytokines normally seen with delivery of siRNAs in vivo. The effect of various patterns of modification individually and in conjunction with other modifications on the above parameters will be described.

• Chemically modified siRNAs
• siRNA delivery
• Target validation
• Therapeutic siRNAs

Walter Strapps, Merck & Co.

10:30

High Content Data Management: Where Terabits Meet Panacea

With advances in automated microscopy and its now routine usage in drug discovery, high content data acquisition and analysis remain a major bottleneck. Typical screening laboratories are designed and built using tools capable of acquiring and managing data sets in the megabit size range far from the terabits generated from single high content screening campaigns. This file size differential presented us with a challenge. I will present and discuss how we streamlined our current screening data management system to overcome this challenge and integrate microscopy based data in the overall work flow.

Hakim Djaballah, Ph.D., Director, HTS Core Facility, Memorial Sloan Kettering Cancer Center

11:00

Use of Statistical Approaches to Identify Novel Hits for CCR5: Shifting the Odds in your Favor

The CC chemokine receptor CCR5 is activated by chemokines RANTES, MIP 1α and MIP 1β, and is a co-receptor for macrophage tropic human immunodeficiency virus type I (HIV-1). Hence, one of the most promising approaches to block HIV-1 entry is to use small molecule antagonists for CCR5. Presently, Maraviroc from Pfizer is a marketed drug that inhibits HIV via antagonizing CCR5 receptor. Other compounds like Vicriviroc and Applaviroc from Schering and GSK respectively have also gone through clinical trials. To facilitate development of the next generation of antagonists for HIV-1, we undertook a HTS screening against Roche’s compound library. After an initial statistical analysis identified potential actives from the screen, several methods were applied to expand the compound pool, including nearest (structural) neighbor and Bayesian approaches. Both approaches yielded promising compounds, yet the Bayesian method identified more compounds more efficiently and most importantly identified several novel hits for CCR5. A comparison of these approaches, their benefits and disadvantages, will be discussed with examples from our efforts to identify potential, new CCR5 antagonist compounds.

The audience will hear about:
1) New method to analyze HTS data.
2) A discussion and comparison of statistical methods to analyze HTS data.
3) Structural moieties of small molecule CCR5 antagonists.
4) Approaches to “rescue the singletons” from HTS screens.

Hans Bitter, Principal Scientist, Group Research Information, Roche

11:30

Challenges of In Silico Hit Finding and Hit Optimization

In silico methods are becoming important tools for accelerating and lowering the cost of drug discovery. Virtual screening, the in silico version of high throughput screening, is used for fast “hit” identification that can allow a project to start before the high throughput screening is done. Virtual screening is done by identifying compounds with best fit to a pharmacophore and/or into the binding site of the target. Compounds are ranked using scoring functions that try to quantify the best fit to the pharmacophore, shape or into the binding site of the target. The success of the virtual screening depends on the searching technique, the scoring function, and the target structure used. Studies comparing the outcome of a virtual screening as a function of the above mentioned parameters help choose the best setup for maximizing the enrichment factor. Hit-to-lead optimization is probably the most challenging part of drug discovery. In silico ligand and structure-based methods are used to quickly generate directions of hit optimization. The improvement of scoring functions and docking methods allow better binding mode predictions that are crucial for target structure-based hit optimization. Successful applications of these techniques will be presented.

Challenges of In Silico Hit Finding and Hit Optimization
- Scoring functions are not yet accurate enough for rank ordering compounds
    o Why virtual screening is successful in identifying active compounds?
    o How the structure of the target can influence the outcome of virtual screening?
    o Which methods have been used for dealing with protein flexibility?
    o How can we incorporate in silico ADME tools in hit finding and in hit-to-lead optimization?

Istvan Enyedy, Senior Scientist, Biogen Idec

12:00

Longer Wavelength FRET Substrates for HTS: Application to Protease, and Protease-Coupled Assays

We investigated a variety of fluorescent and quenching dyes as FRET partners in hydrolase substrates in order to reduce the effects of compound interference in standard and ultra-high density screening formats. We found that one dye pair, QSY-7/TAMRA, provided a particularly good balance between cost of reagents, ease of synthesis, sensitivity and minimal optical interference from screening compounds. To date we have developed substrates for twelve targets using QSY-7/TAMRA of which nine have been used for full screening of the nearly one million compounds in our collection. The applicability, utility and limitations of these substrates for HTS and routine screening will be discussed.

Paul L. Richardson, Research Investigator, Advanced Technology, Abbott Laboratories

12:30

Lunch

2:00

Synergistic Use of Lead Discovery Technologies in Fragment-based Drug Design: Strategies and Tactics

A lack of novel small molecule drugs emerging from target-based high-throughput screening of large libraries of compounds is a great disappointment of the post-genomic era, particularly in the discovery of antibacterial agents. Fragment-based drug discovery (FBDD) is a rapid, resource efficient and productive route to novel ligand-efficient hits in the early drug discovery process. Progressing fragment hits into viable leads requires integration of disparate research technologies including NMR, X-ray crystallography, biophysics and computational sciences. Pfizer has developed a flexible integrated fragment-based lead discovery platform that is applied to multiple target types across diverse therapeutic areas. In our presentation, we will discuss several case studies and provide examples of successful practices supporting fragment library design, fragment screening, fragment-to-lead evolution and lead optimization.
The objective of this presentation is to provide comprehensive solutions to the following questions:
1) Why do molecular "drug-like" fragments provide a new paradigm for drug discovery of some targets?
2) What are the fragments and what are practical aspects for design of Fragment Libraries?
3) What are the key technologies in FBDD and how are they utilized to advance fragment hits into viable leads?
4) What are some effective strategies and tactics for efficient fragment to lead optimization that one can use in drug discovery?

Igor Mochalkin, Pfizer

Session II - Hit to Lead

2:30

A Multidisciplinary Approach Leading to the Discovery of a Novel RSV Fusion Inhibitor

Human Respiratory Syncytial Virus (RSV) is a negative-sense enveloped RNA virus, member of the Paramixoviridae family. Human RSV causes a spectrum of respiratory tract diseases in people of all ages throughout the world. In healthy adults, a relatively mild infection results in symptoms similar to the common cold. However, in infants, immunosupressed and elderly people, RSV infection can induce severe bronchiolitis or pneumonia, resulting in significant morbidity and mortality. Current treatment options have considerable limitations and there is a clear need for innovative drugs to treat RSV infection. Our RSV inhibition program led to the discovery of a series of benzimidazoles with nanomolar activity against the virus. The lead compound of this series, JNJ-2408068, was selected for pre-clinical studies. As the long elimination half-life from several tissues was cause for concern, efforts were made to improve the pharmacokinetic profile of JNJ-2408068 in terms of tissue retention, while maintaining excellent anti-viral activity. Through combination of molecular modeling and medicinal chemistry, this program led to the discovery of TMC353121 a novel RSV fusion inhibitor with potent in vitro and in vivo activity, currently undergoing further evaluation in clinical trials.

- Discovery of TMC353121, a novel RSV fusion inhibitor
  o Why is it important to fight Respiratory Syncytial Virus?
  o How were we able to improve the pharmacokinetic profile of our former lead compound?
  o What was the impact of Molecular Modeling?
  o What is the profile of this new clinical candidate?

Jean-Francois Bonfanti, Medicinal Chemistry, Johnson & Johnson

3:00

Structure-Guided Optimization of a Series of 1,5-Benzodiazepine Inhibitors of HCV NS5B Polymerase

HCV NS5B polymerase is an unusual target protein for drug discovery, in that there are several distinct binding sites currently being explored in ongoing drug discovery efforts by various research groups. Our efforts have recently led to the discovery of a new series of non-nucleoside inhibitors of this target enzyme. These compounds are based on a poly-substituted 1,5-benzodiazepine (1,5-BZD) scaffold, and were found to bind to one of the previously described allosteric sites, close to the active site of the enzyme. Using high resolution crystal structures of enzyme-inhibitor complexes to guide molecular design, a medicinal chemistry effort aimed at optimizing the potency of this chemical series was undertaken. Analysis of 1,5-BZD’s bound to genotype 1a and 1b NS5B polymerases provided some insight on genotypic differences in inhibitor potency across these 2 genotypes. This presentation will provide a brief overview of the current public structural data relevant to HCV polymerase, as a context for our own studies, and then describe some results from our recent structural and medicinal chemistry efforts aimed at exploiting this target for anti-HCV drug discovery.

Maxwell Cummings, Ph.D., Computational Chemistry, Tibotec BVBA, Johnson & Johnson Pharmaceutical R & D

3:30

The Impact of Quantitative Drug Design on the Design of Highly Specific Protein Ligands

The fundamental goals of computational chemistry are the design of novel molecules and the prediction of their binding affinities. Ligand design is to a large extent driven by human imagination, with a little help from computational tools. Efficiency in drug design depends highly, therefore, on our ability to identify those designed ligands that will be active, while at the same time minimizing the enormous effort of synthesis and testing. We have previously described a method for rapidly computing the interaction free energies of molecular fragments with proteins in the gas phase [M. Clark, et al., 2006]. This was a first step in developing tools for the robust, predictive computation of binding affinities. In addition to binding free energies for fragments, however, it is also necessary to compute the entropy and enthalpy changes when fragments are assembled into full-sized molecules, the translation of binding affinities from the gas phase to the aqueous phase, and the effects of protein flexibility. In this presentation, we will present solutions to each of these three problems and demonstrate their efficacy in the design of highly selective kinase inhibitors.

Benefits:
• Exemplifies design of selective kinase inhibitors
• Introduces methods for the calculation of the elusive entropy term
• Demonstrates that free energy can be computed in explicit water
• Provides approaches for dealing with “the protein flexibility problem”

Jeff Wiseman, Ph.D., Vice President Technology & Corporate Development, Locus Pharmaceuticals

4:00

Networking and Refreshment Break

4:30

6:00

End of Day 2 - Drug Design & Lead Discovery

October 17, 2008

7:00

Registration & Breakfast

8:00

9:30

Networking and Refreshment Break

Session II - Hit to Lead (Cont'd)

10:00

A Genomics Approach to Compound Prioritization: Learn More Early to Fail Less Later

Efficient compound selection remains a key challenge in drug discovery today. The goal is to identify developable drug candidates early in the screening process while simultaneously flagging compounds with off-target effects indicative of liabilities (or alternate indications). This goal overlaps but is distinct from the goal of toxicogenomics which is focused primarily on identifying toxicity burden at high doses of lead candidates in key tissues. We propose a framework where compound-induced global changes in gene expression in key assay systems can be used as an objective metric for early compound prioritization. We call this metric the Relative Transcription Index (RTI). RTI is a measure of the relative activity of compounds as ascertained by their effects on transcription at a genome-wide level. Compounds with a low RTI affect the expression of only a few genes whereas compounds with a high RTI affect the expression of a large number of genes. This information is useful for differentiating compounds that, based on phenotypic assays alone, might appear to be equally efficacious. Since compounds with high RTI are more likely to display off-target effects, the RTI metric, if implemented early in the screening process, can become a valuable tool for compound selection.
Benefits:
• A simple yet meaningful application of genomics in the drug discovery process
• A powerful approach for improving compound selection
• Can be immediately implemented in lead discovery programs
• Knowledge gained upstream can direct downstream interrogations of the compound

Sujoy Ghosh, Medical Genetics Advisor, GlaxoSmithKline

Session III - Lead Optimization

10:30

Homology Modeling and Mutation Data to Drive SAR for CCR5: Is It Crystal Clear?

The CC chemokine receptor CCR5 is activated by chemokines RANTES, MIP 1α and MIP 1β, and is a co-receptor for macrophage tropic human immunodeficiency virus type I (HIV-1). Hence, one of the most promising approaches to block HIV-1 entry is to use small molecule antagonists for CCR5. Presently, Maraviroc from Pfizer is a marketed drug that inhibits HIV via antagonizing CCR5 receptor. Other compounds like Vicriviroc and Applaviroc from Schering and GSK respectively have also gone through clinical trials. To facilitate development of next generation antagonists for HIV-1, we explored how the above mentioned compounds antagonize CCR5 by mapping their binding site using site directed mutagenesis and receptor protein modeling. Here we describe a receptor mutation data driven approach for modeling receptor – ligand interactions. Furthermore, these receptor–small molecule interactions are used to identify the binding modes for three compounds from Pfizer, Schering and GSK. While the three antagonists share a common binding site, the nature of specific interactions within the pocket is different. The extent of binding derived from these interactions is variable among the three antagonists. The fully mapped binding pocket for CCR5 was used as a structure based design tool for lead optimization for the in-house compounds.

The audience will hear about:
1) The structure of CCR5 and the putative small molecule binding pocket.
2) The receptor mutation data driven approach for identifying binding modes for CCR5 antagonists and the applications in structure based design.
3) The specific interactions between the small molecules and the CCR5 receptor will be highlighted.
4) The SAR similarities and differences between various compounds.

Rama Kondru, Principal Scientist, Computational Chemistry Group, Roche

11:00

Addressing Physicochemical and Pharmacokinetic Issues Early on in a Series of P2X7 Receptor Antagonists

HTS screening of our compound file provided an attractive lead compound with modest P2X7 receptor antagonist potency, high selectivity against a panel of receptors and channels, high human plasma protein binding and pharmacokinetic properties that would predict a short half-life. Parallel synthesis was used to address the potency, physicochemical and pharmacokinetic properties simultaneously. The focus of this presentation will be on the medicinal chemistry efforts that led to potent P2X7 receptor antagonists with good PK properties that are also potent in the presence of human blood.

Allen J. Duplantier, Associate Research Fellow, Pfizer Global R&D

11:30

Lessons in Anti-cancer Compound Design, Synthesis and Testing: Why an Army Marches on its Stomach

Time is ever critical in the lead optimization (LO) phase of drug discovery, and ‘campaign optimization’ is becoming widely used as a means of reducing timelines and decreasing uncertainty in make-test cycles. In this context, the application of parallel synthesis to lead generation has been comprehensively described; hitherto, reports of its application in LO have been sparse.
This talk will debunk some of the myths and folklore surrounding the application of high capacity synthesis in LO. The vehicle for the discussion will be a case history describing the campaign optimization of Histone Deacetylase (HDAC) anticancer agents. All aspects of the design-make-test-analyze cycle will be explored, with particular emphasis on data analysis. The talk will culminate with the discussion of an orally-active small molecule development candidate.

Benefits:
1) What are the best tactics for coping with data redundancy?
2) Large scale lead optimization synthesis – how practical is it?
3) The power of pre-synthesis property prediction will be illustrated
4) Computational analysis of large data arrays is important – is there still a place for human judgment and the ability to spot outliers in the data set?

David Andrews, Associate Director, Cancer & Infection Chemistry, AstraZeneca

12:00

MCH-R1, hERG and Useful Drug Properties: The Long and Winding Road

Obesity is now progressively developing into a global pandemic affecting the lives of about 1.1 billion people worldwide and exerting a spiraling financial burden on health systems and patients. Pharmacological intervention would therefore be highly advantageous to address the needs of an ever-increasing patient population. Melanin-Concentrating Hormone Receptor 1 (MCH-R1) antagonists have recently attracted widespread attention as a potentially viable treatment, as the MCH system was shown to be critically involved in the fine regulation of food intake and in balancing energy homeostasis in mice. A major hurdle to the development of MCH-R1 antagonists has been the simultaneous optimization of pharmacodynamic, pharmacokinetic and safety-related parameters. The presentation will outline experiences from AstraZeneca MCH program: the lead optimization efforts around the 4-amino-piperidine series; the different strategies to tackle hERG inhibition including physicochemical modulation and pharmacophore mapping, the delicate balance between efficacy (MCH-R1 potency), safety (hERG inhibition) and other key drug parameters, and the lessons learned.

MCH-R1, hERG and useful drug properties: the long and winding road
• How easy is to discover potent MCH-R1 antagonists?
• How hard is to optimize them?
• How to design hERG inhibition out, if you can?
• Persistency and wisdom: when to give in to data, if you can?

Fabrizio Giordanetto, Associate Principal Scientist, AstraZeneca

12:30

Lunch

1:30

TRANSIL Brain Absorption: A Novel Hybrid Model for Predicting CNS Penetration

The presentation introduces a new hybrid in vitro and in silico model for the blood brain barrier. The model is based on an assay kit containing reconstituted brain phospholipids as well as on polar surface area estimates. A statistical model is used to predict plasma/brain equilibrium distribution (logBB) and the compounds’ free fraction in brain. The model has been build on a validation data set of more than 40 compounds including several transporter substrates. We found the model with four input parameters to be highly significant with a p-value of less than 10-10. Leave one out cross validation revealed an average prediction error of 0.22 logBB units, which is comparable to in vivo logBB measurement errors. Predicted free fractions in the brain correlated with in vivo free fraction in rat with r2=0.94. Statistical tests for relative importance of variables revealed that affinity to brain lipids is orthogonal to polar surface area. Therefore, the predictive power of the hybrid model is substantially higher than in silico models alone. Also, we found that membrane structure is primarily responsible for the brain endothelial cells membranes’ tightness. Only true and natural phospholipid bilayers can mimic the interaction with ionized or non-ionized compound species during the passage through the membrane well. Hence, models for passive transport across the blood brain barrier have highest prediction power when based on natural membranes. As also actively transported compounds have to enter the brain endothelial cell’s membrane before being translocated by membrane carriers, the model’s estimate of passive transport is also indicative of active transport.

Hinnerk Boriss, CEO, Sovicell

2:00

Recent Advances in Data Modeling and Molecular Modeling for New Lead Optimization

There are two disparate but complementary approaches to New Lead Discovery: High-throughput Screening (HTS), and “Structure-based Drug Design” (SBDD). SBDD uses a 3-D structure of the lead compound bound to its target to assess the binding and to propose more active analogs. Because this approach was typically not sufficiently predictive, researchers have embraced HTS, where large, diverse chemical libraries are screened to find quality leads. For both these methodologies to reach their potential, we need better modeling and analysis methods. This talk will review recent progress on both fronts.

Benefits:
1) Learn how HTS and SBDD approaches can be complementary
2) Learn about advances in pulling structure-activity information out of large, noisy datasets
3) Learn about advances in providing more accurate drug-receptor binding “scores”

Peter Gund, Gund Discovery Services

2:30

Profiling Native Kinase Activity and Interactions with Nucleotide Based Probes: Drug Selectivity Profiling and Beyond

The central role of protein kinases in signal transduction pathways has generated intense interest in targeting these enzymes for a wide range of therapeutic indications. We have recently reported a method for identifying and quantifying protein kinases in any biological sample or tissue from any species. The procedure relies on acylphosphate nucleotide probes, prepared from biotin and ATP or ADP, that react selectively and covalently at the ATP binding sites of at least 80% of the known human protein kinases. Reaction of these probes with target kinases in complex proteomes can be quantitatively assessed using a sophisticated mass spectrometry based platform. In this presentation, examples highlighting the differences in behavior of protein kinases derived from native proteomes versus recombinant systems will be highlighted.

Matt Patricelli, Director of Technology, ActivX

3:00

End of Conference