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In the recent years, several non-cardiovascular drugs have been withdrawn from the market because of unanticipated cardiotoxicity.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