Organizing Chairs:
Alan G.E. Wilson, Lexicon
Genetics
Albert P. Li, The ADMET Group
Dale Johnson, Emiliem,
Inc.
Sunday, November 26,
2006
Registration 3:00 PM - 5:00 PM
Monday,
November 27, 2006
7:00 AM – 8:00 AM – Registration
Pre-Conference Workshop: Intellectual Property and Critical Paths
(Edwin Ching, Emiliem, Inc.;
Emeryville, CA)
Patent protection over
discoveries is a major driver for technology development. The fundamentals of
patent law will be introduced, followed by a description of the practical
relevance to the researcher and drug developer. A description of intellectual
property opportunities created by critical path technologies, with a focus on
biomarker strategies, will then follow.
12:00 PM
– 1:30 PM – LUNCH BREAK
Drug Discovery and Development Summit:
Critical Paths and Approaches
for Successful Drug Development
Monday,
November 27, 2006
1:30 PM
– 1:45 PM
Welcoming Remarks: Critical Paths for Successful Drug Development (Alan GE
Wilson, Lexicon Genetics, The Woodlands, TX)
1:45 PM
– 2:30 PM
Keynote Speaker: Critical Paths for Drug Development: Concepts and
Practices (Ellen Feigal, Critical Path Institute;
Tucson, AZ) Modernizing the medical product development toolkit to take
advantage of recent scientific and technological advances must occur to
accelerate the development of more effective and safer medical products. The
research and development costs for medical products continues to rise; however,
the number of new molecular entities submitted to the FDA has markedly declined,
success rates for moving from the first in human studies to regulatory approval
and clinical application has declined, and post-market safety remains a
concern. The reasons are complex, and there is not a
single solution; there will be multiple ways to change and optimize the system.
Technologies including molecular imaging, gene expression profiling, and genetic
tests are emerging as critical tools to change this landscape. In this
presentation, examples will be given of unique public-private partnerships to
inform drug development, patient selection, dosing and evaluation of efficacy
and safety.
Session I: Industry and Regulatory Perspectives (chair: Alan GE Wilson)
2:30 PM – 3:00 PM
Impact of Critical Path
Initiative on Drug Discovery and Development
(Dale Johnson, Emiliem, Inc.; Emeryville, CA)
This
presentation will highlight scientific work that has been done to create new
approaches to getting better answers about how the safety and effectiveness of
new products can be demonstrated, in faster time frames, with more certainty,
and at lower costs. These will include methods such as animal or computer-based
predictive models, biomarkers for safety and effectiveness, and new clinical
evaluation techniques. The talk will highlight an approach to conduct Phase I
trials that are indeed proof-of-concept, which requires that the entire process
starts right at the target discovery stage, understanding how certain subsets of
patients may respond both from an efficacy and safety standpoint.
3:00 PM
– 3:30 PM
Regulatory Framework
for Development of Personalized
Therapies (Lois
M. Hinman, Hoffmann-La Roche, Inc.; Nutley, NJ)
There is a recent growing trend
in the pharmaceutical industry to consider development of personalized therapies
in which a molecular diagnostic is used to help select an optimal therapeutic.
The regulatory environment is moving forward quickly in this area and in both
the US and Europe, a process for voluntary discussions of exploratory genomic
data is now in place to facilitate discussion of scientific issues. FDA is
currently developing guidance on co-development of drug and diagnostics. In
this talk, the regulatory initiatives supporting personalized medicines in the
US, and the rest of world will be reviewed. The aim of the talk is to provide
some insight on the regulatory strategies to support this new development
paradigm.
3:30 PM
– 3:50 PM – BREAK
3:50 PM
- 4:20 PM
Integrating Critical Path
Technologies: Biodefense as a Springboard to New Drug Development Paradigms
(Lynne
Gilfillan; BioRosettex,
Arlington, VA)
The threat of
emerging infectious diseases and bioterrorism has made the high costs and long
timelines of drug and vaccine development a national security concern. Major
advances in the technological, business, and regulatory dimensions of the
critical path are required to bring safe and effective countermeasures to bear
for known threats, while even more radical innovations are necessary to address
naturally emerging or genetically engineered pathogens with a rapid
“Bug-to-Drug”Ó
response. This talk will introduce some of the unique elements of biodefense
drug development and describe a new effort to identify, evaluate, and integrate
breakthrough technologies and promote new public-private partnerships for
revolutionizing development of biodefense products.
4:20 PM - 4:50 PM–
PANEL DISCUSSION: Session I
END OF
DAY
Tuesday, November 28,
2006
Session II: Critical Approaches
for Safety Assessment (chair: William B. Mattes)
7:00 AM
– 8:00 AM – Registration
8:00 AM
– 8:30 AM
A Comprehensive Approach to Drug Safety Evaluation (William B. Mattes,
The Critical Path Institute, Tucson, AZ)
Drug safety is a
critical determinant for successful drug development. Efficacy without
acceptable safety or vice versa will lead to clinical failure. Toxicity should
be evaluated hand-in-hand with drug efficacy, involving a scientific team with
expertise not only in toxicology, but in all relevant disciplines including
chemistry, pharmacology, genetics, drug metabolism and pharmacokinetics. This
comprehensive approach, if applied in all phases of drug discovery and
development, should lower the chances of clinical failure due to unacceptable
adverse effects.
8:30 AM – 9:00 AM
New Trend Analysis Approach to
Predict Changes in ADME/Tox properties When Altering Lead Compounds (Joseph
R. Votano,
ChemSilico LLC, Tewksbury, MA)
Small chemical alterations of
drug-like compounds can lead to unexpected changes in ADME/Tox properties in the
process of improving a lead compound. A new trend analysis approach using novel
neural net techniques is now able, in a semi-quantitative manner, to predict the
trend in several ADME/tox (e.g., aqueous solubility, absorption, protein
binding, LogP) with changes in a atom types or fragments in a lead compound.
This is a very important tool to assist medicinal chemists in the optimization
in drug discovery.
9:00 AM
– 9:30 AM
In Silico Models to Identify Potential P-glycoprotein Substrates and
Inhibitors for Supporting Drug Design (Patrizia Crivori, Nerviano Medical
Sciences; Nerviano,
ITALY)
Multi-drug
resistance mediated by ATP-binding cassette (ABC) transporters such as
P-glycoprotein (P-gp) represents a serious problem for the development of
effective anti-cancer drugs. In addition, P-gp has been shown to influence the
pharmacokinetic properties of several drugs. Consequently, there is a great
interest in anticipating whether drug candidates are P-gp substrates or
inhibitors. In this respect, two different in silico discriminant models have
been set-up. The models, extensively validated using data not included in the
training sets, showed percent accuracies ranging from 72 to 82. These models
allowed also the identification of some key molecular features that
differentiate a substrate from non-substrate and inhibitor, which should be
taken into consideration in the design of new candidate drugs. This presentation
addresses the principles and technical aspects of these models and their
rational applications within a discovery project.
9:30 AM
– 10:00 AM
Evaluation of Compound Toxicity
using Functional Datamining Techniques (Yuri Nikolsky, GeneGo, Inc.;
St. Joseph,
MI)
Accurate early
prediction of toxicity for new compounds in human is a long term goal in drug
discovery. Traditional in silico, in vitro and in vivo
ADME/Tox methods are now complimented with high-throughput experimental
approaches such as toxicogenomics, proteomics, metabonomics and pharmacogenomics
which can provide a global view of the complete biological system being
modulated by a compound. Functional interpretation and relevance of these
complex multidimensional data to the observed phenotype in human is the focus of
systems pharmacology. I will briefly overview this novel systems approach,
including available resources, major public and commercial efforts in the area.
Next, I will demonstrate the case studies of functional analysis of rat
toxicogenomics data produced in collaborations with researchers from FDA, Wayne
University and NIEHS. Finally, I will describe in brief the workflows for
functional analysis of chemical and biological data for generating hypotheses of
drug mode of action and side effects, using multiple tools integrated by
“pipeline” software such as PipelinePilot (Scitegic/Accelrys) and Inforsense.
10:00 AM – 10:20 AM
– BREAK
10:20 AM
– 10:50 AM
Computational Modeling of Kinase Inhibitors for Efficacy and Safety In
Cancer (Sucha Sudarsanam, Emiliem Inc;
Emeryville, CA)
The role of protein kinases in
cancer has now been firmly established and several drugs targeting kinases have
been approved for oncology indications. Over a decade of research in kinase
biology and chemistry along with clinical data on efficacy and safety of kinase
inhibitors has resulted in a rich set of information detailing biological
consequences of kinase inhibition. In this talk, we outline strategies for using
this accumulated knowledge for designing novel kinase inhibitors to modulate
cancer pathways.
10:50 AM – 11:20 AM
Applications of Pathways Analysis Tools in the Drug Discovery and Development
Process to Reduce Attrition (Brigitte
Ganter,
Ingenuity
Systems, Inc.; Redwood City, CA)
Ingenuity Pathways Analysis (IPA) leverages a semantically-structured database
of manually curated biological information and allows functional interpretation
of complex multi-dimensional data through the buildup of biological networks.
Functional interpretation of these affected biological networks at the level of
cells, tissues, organs and the whole living organism is achieved through the
analysis of genes, proteins, chemicals, drugs and other molecules. IPA can be
used to analyze novel molecular profiling datasets for systems-level functional
modeling of healthy, disease, and therapeutically-treated biological systems.
This presentation will focus on the molecular toxicology extension of this
technology for drug safety evaluation and how it can be applied to gain
understanding of drug mechanism of action and toxicity to reduce attrition.
11:20 AM
– 11:50 AM
Toxicogenomics,
Biomarkers, and the Critical Path in Drug Development (William B. Mattes,
The Critical Path Institute; Tucson, AZ)
Toxicogenomics has been particularly successful in
identifying genes or patterns of genes differentially regulated by treatments
that result in toxicity. The conversion of such observations into robust and
accepted biomarkers requires qualification of these biomarkers for certain uses;
and regulatory acceptance. This, in turn, requires a formal venue for sharing
data, assays and samples across multiple pharmaceutical companies; a process for
FDA review of qualification studies; and points for application in regulatory
decision-making. The Predictive Safety Testing Consortium (PSTC) was organized
through the Critical Path Institute to accomplish these goals.
11:50 AM
– 12:20 PM
Targeted Drug
Development From a SuperAntibody Technology Platform (A. Charles Morgan,
InNexus
Biotechnology, Inc.; The Mayo Clinic; Scottsdale, AZ)
Monoclonal
antibodies have been hailed as the "Magic Bullet" to replace other less specific
drug approaches and it is estimated that within 10 years 30% of all new
pharmaceutical products will be derived from antibodies. SuperAntibody
Technology ("SAT") is an antibody modification approach that creates antibodies
in form that are therapeutically active without conjugation to toxic agents.
SuperAntibody, instills the ability into an antibody to cross-link its target
antigen giving rise to improved properties such as strengthened binding and
better retention on and in targeted cells and tissues, a pronounced ability to
trigger apoptosis, as well as enhanced opsonization and phagocytosis. In vivo
models indicate that the potency of antibodies can be increased logarithmically.
InNexus Biotechnology Inc.'s focus is product development and ultimately
out-licensing in return for licensing, milestone and royalty payments. This
platform is being applied to cancer, cardiovascular disease and viral and
bacterial infections.
12:20 AM – 12:45 PM – PANEL DISCUSSION-
Session II
12:45 PM – 2:00 PM – LUNCH BREAK
Session III: Critical Approaches for Successful Clinical
Trials
(chair: Dale Johnson)
2:00 PM – 2:30 PM
First in Man Approaches - Early
Clinical PK Studies (Professor Colin Garner, Xceleron Ltd; York ,UK) The lack of new drug
registrations and the escalating costs of research and development have made
pharma and biotech companies re-examine their drug development processes. Some have decided that simple re-engineering
of these processes will get them out of their fix whilst others are taking more
radical steps. There is a general
recognition that front-loading more resource into early clinical studies may
assist in preventing later stage failures.
However what is not agreed are the types of studies that could help to
sort good drug candidates from those that are destined to fail in Phase 2 or
Phase 3. Everyone is keen to see human
Proof of Concept studies done as early as possible but these still require a
considerable battery of preclinical tests before they can be conducted. The FDA’s
Exploratory
IND should permit early POC investigations but considerable debate
nevertheless is taking place as to the value of the E-IND. In my presentation I will review the
scientific and regulatory background relating to early clinical PK studies
focusing on microdosing, metabolite profiling, combined Phase 1 / mass balance
and absolute bioavailability studies.
Examples of how these approaches have been used will be presented as
well as cost-benefit analyses.
2:30 PM – 3:00 PM
Integration of Molecular Biology in
Clinical Trials (Craig Webb, Van Andel Research Institute; Grand
Rapids, MI) The ability to efficiently utilize the
accumulating knowledge gained in the post genomic era requires highly efficient
integration of disparate biomedical and molecular data, as well as coordination
of the necessary translational expertise and infrastructure. In this
presentation, I will discuss the Integrated TransMed Program being
practiced in our insitute that permits rapid discovery and
application of biomarkers in the areas of molecular-based diagnostics and
innovative clinical trials, as well as a path to realizing the promise of
personalized medicine in the area of a compassionate care initiative in
oncology.
3:00 PM – 3:30 PM
Translational
Biomarkers for Drug Discovery and Development (Scott Turner, KineMed;
Emeryville, CA) In this talk I will describe advances in the development of
a new class biomarkers, kinetic biomarkers, and their successes to date in
discovering therapeutic actions of agents and predicting clinical response.
Kinetic biomarkers measure fluxes through complex pathways in living organisms,
including humans, by use of new stable isotope-mass spectrometric techniques. We
have developed novel methods for measuring flux through a number of pathways
recognized to be critical in disease – including reverse cholesterol transport
(RCT), tissue fibrogenesis, hippocampal neurogenesis, axonal microtubule
dynamicity, synaptic plasticity, insulin-mediated glucose utilization,
mitochondrial biogenesis, pancreatic beta-cell proliferation, skin turnover,
joint-space glycosaminoglycan synthesis, adipogenesis, prostate and mammary
epithelial cell proliferation, lymphocyte proliferation, and others. The
development of kinetic biomarkers of flux through key pathways provides targets
and metrics with intrinsic functional significance that can be used for guided
drug development.
3:30 PM –
3:50 PM – BREAK
3:50 PM – 4:20
PM– PANEL DISCUSSION-
Session III
4:20 PM – 5:00 PM – Concluding Remarks: Critical
Paths for Successful Drug Development (Dale
Johnson)
END OF DAY
END
OF CONFERENCE
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