Planning
Committee and Session Chairs:
Albert P. Li,
The ADMET Group, LLC.
Weichao Chen, Arena
Pharmaceuticals
Joseph Tomaszewski,
NIH
Claudia
McGinnis, Novartis Institutes for Biomedical Research
Jim McKim,
CeeTox, Inc.
Thursday,
June 22, 2006
REGISTER
Session 1:
Early Prediction of Organ-Specific Toxicity
Chair: Claudia McGinnis
8:00 AM
9:00 AM REGISTRATION
8:00 AM 5:00 PM EXHIBITS
8:45 AM 8:55 AM Exhibitor Presentation Advion BioServices
8:55
AM 9:00 AM Welcoming Remarks
9:00 AM 9:30 AM
The Use of Primary Human Cells in
Early Toxicology Screening for Prediction of Livertoxicity and Hematopoietic Liabilities
(Claudia McGinnis, Maria Eckert, Novartis Institutes for Biomedical Research; Cambridge MA) Side effects such as livertoxicity and bone marrow
suppression cause serious limitations in the development of new drugs. Early
toxicology screening characterizes early drug candidates for potential
liabilities and supports the lead optimization process towards a cleaner
compound profile. Two cell-based, high-throughput luminescence assays for the
detection of liver- and bone marrow toxicity were developed using primary human
cells, cryopreserved human hepatocytes and fresh human bone marrow. In vitro
toxic effects of test compounds were tested in a microplate format and cell
viability determined by quantitation of cellular ATP. Data will be presented on
the validation of these assays with a set of marketed drugs and Novartis
compounds. The assays are implemented as a global, routine service for lead
finding and optimization phases.
9:30 AM 10:00
AM
In Silico Models for the Prediction of Dose‑Dependent Human Hepatotoxicity (Ailan Cheng, CZ Technologies, LLC. State College, PA) This talk will present a new, fully‑general in silico model which is able to predict
the occurrence of dose‑dependent human hepatotoxicity with greater than
80% accuracy. Utilizing an ensemble
recursive partitioning approach, the model classifies compounds as toxic or
non‑toxic and provides a confidence level to indicate which predictions
are most likely to be correct. Only 2D
structural information is required and predictions can be made quite rapidly,
so this approach is entirely appropriate for data mining applications and for
profiling large synthetic and/or virtual libraries.
10:00 AM 10:30 AM
A
Microarray-based Approach to Understanding Drug Bioactivation in Rodent Liver (Greg Slatter
and Wei Tang, Rosetta Inpharmatics LLC (A subsidiary of Merck & Co., Inc.)
Seattle,
WA,
and Drug Metabolism Research, Merck Research Laboratories,
Rahway
NJ) Gene
expression profiling using DNA microarrays has the potential to improve how the
pharmaceutical industry relates preclinical hepatic effects to underlying
factors such as drug concentration, reactive metabolite formation, and
oxidative stress. Dose-related effects on compound-specific transcriptional
fingerprints can be correlated with diverse biological phenotypes to define
differences within structurally- or pharmacologically-related compounds. As
such, the biological sequelae and underpinnings of chemical exposure can be
elucidated earlier in development and in greater detail than ever before.
10:30 AM 10:50 AM BREAK
10:50 AM
11:20 AM
QT Prolongation: A Roche Perspective on Predictive Assays (Heather Guthrie, Hoffmann-La
Roche Inc.; Nutley, NJ) The prediction of clinical QT prolongation through
preclinical assays has been under debate due to the lack of correlation in
identifying drug candidates producing adverse cardiovascular events in human.
Although QT prolongation has been associated with IKr
block, hERG inhibition has been considered a weak biomarker in detecting proarrhythmic risk. More sensitive assays are required to
elucidate events which lead to QT prolongation, such as triangulation,
reverse-use dependence, dispersion of repolarization, beat-to-beat instability,
etc. In compliance with the ICH S7B guidelines (Oct. 19, 2005), Roche has
implemented the Langendorff isolated heart assay to be used in used in
conjunction with the hERG assay and non-rodent radiotelemetry
model as a core battery cardiovascular derisking strategy.
11:20 AM 11:50
AM
New Cell Models &
Assays in Cardiac Safety Profiling (Thomas Meyer,
Multi Channel Systems MCS GmbH; Sartipy, Peter Cellartis SA; Guenther,
Elke Natural and Medical Sciences Institute at the Tuebingen University;
Reutlingen, GERMANY) The early screening for cardiotoxic side effects of
new medical entities currently requires to compromise between data quality and
throughput. Whereas the gold standard is patch clamp of primary ventricular
cardiomyocytes of suitable species, HTS suitable assays use cell lines stably
expressing the hERG channels for electrophysiological and
non-electrophysiological assays. The limitations of these assays have been
discussed extensively previously. With the combination of the QT-Screen system
(Multi Channel Systems, Reutlingen, Germany)with cardiomyocyte aggregations
differentiated from human embryonic stem cells (Cellartis SA, Gothenburg,
Sweden), a novel assay is going to overcome the species limitation and provide
a functional electrophysiological readout. First results do look promising;
however a thorough evaluation regarding the
development status of the cells, ion
channel expression pattern and reproducibility is still required.
11:50 AM 1:15 PM LUNCH
1:15 PM 1:25 PM Exhibitor Presentation XenoTech LLC
1:30 PM
2:00 PM
Predictive In Vitro
Hemotoxicology and the Concept of In
Vitro Comparative Toxicity, Cross-Platform Technology (Ivan N. Rich, HemoGenix, Inc.;
Colorado Springs, CO) The
HALO Predictive Hemotoxicology Platform (PHP), which can detect and measure up
to 14 lympho-hematopoietic cells populations from 5 species simultaneously, has
been described at previous ETS meetings. The HALO Platform is now joined by 2
new in vitro toxicity platforms,
LUMENESC and STEMTox. LUMENESC detects toxicity on mesenchymal stem cells and
their differentiating elements while STEMTox detects toxicity in proliferating
cells from numerous other organs and tissues. The same luminescence detection
system is common to all 3 platforms, but together can be used to compare
toxicity in over 50 different cell types derived from 14 different human cell
systems.
2:00 PM 2:30 PM
Medium Throughput Automated In
Vitro and Ex Vivo Assays for Frontloading
Bone Marrow Toxicity Screening (Franηois
Pognan,
AstraZeneca, Global
Safety Assessment,
Cheshire UK) Bone marrow toxicity is a cause of late stage compound attrition in the
pharmaceutical industry. This is
typically assessed during the pre-Candidate Drug phase. The objective of
bone marrow early screening in the discovery phase is to identify
chemistry-associated liabilities and to frontload risk assessment. To this
end, a screening tiered approach has been developed that enables a large number
of compounds to be evaluated around early 'Lead Optimisation' phase.
Various cell lines representative of broad bone marrow lineages are used as
pre-assessment of chemicals series (Tier 1). Then, a new and
automated assay using primary bone marrow cells following a similar
principle to the Colony Forming Unit (CFU) assay (Tier 2), is run to
qualify and confirm tier 1 findings. This may also trigger in vivo study frontloading
(Tier 3). This tiered approach allows weeding out early on compounds with
chemistry-related bone marrow toxicity from the research project pipelines.
2:30 PM 3:00 PM
Skeletal Muscle: A Target for Toxicity
by Marketed and Investigational Drugs (Russell Westwood,
AstraZeneca R&D Alderley Park; Cheshire, UK) Skeletal muscle is not as homogeneous as it might
first appear and each drug type can show a different temporal
development and character of muscle fiber toxicity. The changes seen by pathology may give
an indication of mechanism allowing further tailored investigations. The
presentation although focusing on statin induced myopathy will
contrast the findings with those from other drugs.
3:00 PM 3:20 PM BREAK
Session II:
Novel Technologies for Early Toxicity Screening
Chair: Albert P. Li
3:20 PM 3:30 PM Exhibitor Presentation Simulation
Plus, Inc.
3:30 PM
4:00 PM
Microfluidic (Lab-on-a-chip) Screening Technologies (Albert Folch, University of Washington, Seattle, WA) Microtechnology offers the attractive
possibility of modulating the microenvironment of single cells and, for the
same price, obtain data at high throughput for a small cost. Microfluidic or Lab on a Chip devices, in
particular, promise to play a key role for several reasons: 1) the dimensions
of microchannels can be comparable to or smaller than a single cell; 2) the unique physicochemical behavior of
liquids confined to microenvironments enables new strategies for delivering
compounds to cells on a subcellular level;
3) the devices consume small quantities of precious/hazardous reagents
(thus reducing cost of operation/disposal);
and 4) they can be mass-produced in low-cost, portable units. Not surprisingly, in recent years there has
been an eruption of microfluidic implementations of a variety of traditional
bioanalysis techniques. I will review the latest efforts of our laboratory in
the development of cell-based microdevices for cell biology studies, such as
neuromuscular synaptogenesis, axon guidance, and chemotaxis.
4:00 PM 4:30 PM
Integrated Discrete Co-culture Technologies (Organ(s)-on-a-Chip) for
Toxicity Screening (Albert P. Li, The
ADMET Group LLC; Rockville, MD) A novel technology has been developed in our
laboratory to allow the co-culturing of multiple cell types as
physically-separated (discrete) cultures while being interconnected (integrated)
by an overlying medium, a technology termed IDC Integrated Discrete
Co-culture. Using this technology, the
toxic potential of an agent towards multiple cell types can be evaluated under
virtually identical conditions. The IDC
can be applied to evaluate the toxic potential of an agent towards multiple
organs (Organs-on-a-Chip), or multiple cells of the same organ
(Organ-on-a-chip). Data of both
applications will be shown to demonstrate the utility of this novel technology
which has the potential to refine, replace, and reduce the use of animals in
research. The use of human cells in the
IDC will allow the assessment of human toxicity either for multiple key cell
types of a single organ (e.g. evaluation of pulmonary toxicity via the
co-culturing of large airway epithelium, small airway epithelium, pulmonary
microvascular endothelial cells), or multiple organs (e.g. hepatocytes (liver);
kidney (proximal tubule epithelial cells; CNS (astrocytes); vascular endothelium
(aorta endothelial cells; and lung (small airway epithelial cells).
4:30 PM
5:00 PM
Development of an Early Toxicity Screening Cascade for the Assessment of
the Activity of Antibody-Drug Conjugates (May
Sutherland, Changpu Yu, Renee McCormick, Kerry Klussman, Julie McEarchern, Che Law, and
Alan Wahl. Seattle Genetics, Inc.,
Seattle, WA) In order to minimize systemic
toxicity and maximize tumor exposure, we have developed a strategy to deliver
anti-cancer drugs directly to tumors by conjugating them to antibodies specific
for tumor antigens. The potential toxic effects of these antibody-drug
conjugates against normal tissues, however, cannot be wholly identified or
predicted based upon the properties of attached drugs or the antibody itself.
We therefore developed a series of in vitro assays representing known sensitive
organs to evaluate the safety of our antibody-drug conjugates. The development
of assays comprising primary cultures of human and nonhuman primate cells to
assess safety of anti-body drug conjugates will be discussed.
5:00 PM 5:10 PM SHORT BREAK
5:10 PM
5:40 PM
Histologically Defined Biomarkers in Drug Development (Martin Shaw, Biotrin International;
Dublin, IRELAND) Using biomarkers with unique,
histologically defined distributions leads to increased sensitivity,
specificity and easier interpretation of results. This presentation will review
their use in hepatotoxicity and nephrotoxicity testing and the discovery of new
biomarkers by immunohistological screening Histomics@. Data will be presented
demonstrating how histologically defined biomarkers enable toxic compounds to
be detected earlier and at lower doses.
5:40 PM 6:15 PM: Panel Discussion Session 1& 2
END OF DAY
Friday, June 23, 2006
Session 3:
Application of Cell-lines in
Toxicity Screening
Chair: Jim McKim
8:00 AM 9:00 AM REGISTRATION
8:00 AM 5:00 PM EXHIBITS
8:50 AM 9:00 AM Exhibitor Presentation
Qualyst
9:00 AM
9:30 AM
Improving Drug Candidate Selection by Incorporating In Vitro Toxicity
Data into the Discovery Process (Jim
McKim, CeeTox, Inc.; Kalamazoo, MI) Identifying potential adverse properties of new chemical
entities early in the discovery process enhances the candidate selection
process and increases the probability of success in preclinical and clinical
safety studies. This approach requires a robust array of cell-based
screening paradigms that can be tiered in a way that enables researchers to
fine tune the discovery funnel for choosing leads that have been optimized for
both the desired attributes of a drug and for safety. A systems biology
approach combined with multiple endpoint analysis, dose-response, and in vivo
validation can provide an excellent bridge between the in vitro screening
environment and expected in vivo effects. This presentation will focus on a
tiered approach to in vitro screening and demonstrate the in vivo predictive
value of the data obtained.
9:30 AM 10:00 AM
Comparison of In Vitro Assays
of Cellular Toxicity in the Human Hepatic Cell Line HepG2 (Silvia Miret, Unilever R&D; Vlaardingen, The NETHERLANDS) In this study we compared different in vitro assays for cytotoxicity in HepG2 cells. The assays
evaluated included Alamar Blue for the measurement of mitochondrial activity,
ATPlite and ViaLight Plus for the determination of cellular ATP, ToxiLight for
cellular necrosis and Caspase-3 assay, Apo-ONE assay and Caspase-Glo for
caspase-3/7 activity. It was concluded that the best way to evaluate the
potential cytotoxicity of a compound is to employ a battery of assays that
focus on different aspects of cell death. However, the use of ViaLight Plus,
ToxiLight and Caspase-3 assay resulted in the most useful combination.
10:00 AM 10:30 AM
Validation & Regulatory Acceptance of In Vitro Toxicity/Potency
Assays ((Hans
Raabe, Institute for In
Vitro Sciences, Inc.; Gaithersburg, MD) This session will focus on the design
and validation of in vitro bioassays intended for use in the regulated
environment. Bioassay are designed
around four components; a specific cell or tissue, defined exposure conditions,
characterized endpoint measures of the biological effect, and a predetermined
relationship between the endpoint values and the effect being predicted
(potency or toxicity). The assays predictive capacity is dependent on maintaining
consistency in these parameters from assay validation through its routine use
for regulatory submissions.
10:30 AM 10:50 AM BREAK
10:50 AM 11:20 AM: Panel Discussion Session 3
Session 4:
General Early Toxicity Screening Approaches
Chair: Weichao Chen
11:20 AM 11:30 AM Exhibitor Presentation
SOLVO Biotechnology
11:30 AM
12:00 PM
Bioluminescent Approaches
For In Vitro ADME/Tox (James J. Cali,
Promega Corp.; Madison, WI) Bioluminescent assays offer significant advantages for
configuring sensitive, simple to perform assays with ADME/Tox applications.
Cell-based assays will be described that examine test compounds for P450
induction at the enzyme level and for cytotoxicity. In vitro assays will also be described for measuring P450 and
monoamine oxidase inhibition and the stimulation of P-glycoprotein (MDR1)
ATPase activity by test compounds. Each system relies on the light generating
reaction of firefly luciferase, correlating light output with target activity.
This suite of homogeneous assay is sensitive, robust and convenient for small
scale and high throughput applications.
12:00 PM
12:30 PM
The Role of Early In Vivo Toxicity Screening in Drug Safety
Evaluation (Jessica E. Sutherland,
Charles River Laboratories Preclinical Services; Worcester, MA) A properly designed toxicity screening program (including in
vivo studies) can be used to optimize lead compounds in attempt to identify
which should move from discovery into development. Early in vivo toxicity screening is also
useful during pilot and dose range-finding studies or when formulation decisions
are needed. Selection of the proper animal model(s), sample size, route
of administration, and toxicological endpoints is vital to the success of these
early nonclinical assays.
12:30
PM 2:00 PM LUNCH BREAK
2:00 PM 2:10
PM Exhibitor Presentation
CeeTox, Inc.
2:10 PM 2:40
PM
Managing Oxidative Bioactivation in
Drug Discovery (Wei Tang, Merck Research
Laboratories, Rahway, NJ) The rate of success had steadily declined in all phases of the drug
development process during recent years.
One of the underlying causes of attrition is safety-related issues,
which, in some cases, may be attributed to the formation of reactive
metabolites and subsequent covalent modification of proteins. In this regard, compound 1 examined in our laboratory produced a high level of CB in
human liver microsomal incubations. The
CB is likely due to the
formation of an iminium ion resulting from P450-catalyzed oxidation of the
piperidine moiety of compound 1. A joint effort between Medicinal Chemistry
and Drug metabolism eventually led to the identification of a pyrrolidine
analogue 2 as a drug
candidate. Compound 2 not only maintained pharmacological potency and
selectivity but also exhibited a lower propensity to CB. It is hoped that practice of this type will
reduce attrition rate in drug development, while the ultimate goal is to
provide safer medicine to the public.
2:40 PM
3:10 PM
Detection and Quantification of Neurotoxic Ab42 Aggregates (Mary Michael
Brodey, BioSource Cytokines & Signaling; Invitrogen Corporation
Camarillo, CA) Many neurodegenerative diseases can be characterized by fibrillar
inclusions and soluble oligomeric protein aggregates. Soluble aggregates of
beta amyloid are implicated as the etiological agent in Alzheimers disease.
Using a highly sensitive, bead-based immunoassay developed for the LuminexTM
platform, we are able to quantify neurotoxic aggregates of beta amyloid 1-42 (Ab42). The
toxicity of these aggregates is confirmed by monitoring cell metabolism with
alamarBlueTM and MTS, using PC-12 and SH-SY5Y cells. The use of
multiplexed, bead-based immunoassays to monitor activation of signal
transduction pathways and changes in cytokine production profiles will be
discussed.
3:10 PM 3:40
PM
Strategies to Eliminate Toxicity with Structural Modification Approaches
in Drug Discovery (Weichao Chen, Arena Pharmaceuticals, San Diego, CA)
Toxicity of drug candidates
is one of the major problems facing the pharmaceutical industry.
Hepatotoxicity, cardiotoxicity and drug-drug interaction related toxicities are
the three major reasons for the failure of drug candidates. Early
toxicity screening could weed out compounds with potential toxicity, and
structure activity relationship for toxicity could be established with
screening results. Structural modification approaches can be utilized to avoid
potential toxicity of drug candidates. Case studies including both
successes and failures in drug discovery will be presented.
3:40 PM 3:50
PM Exhibitor Presentation
BRI Biopharmaceutical Research Inc.
3:50
PM 4:10PM BREAK
4:10 PM
4:40 PM
A New Approach to Toxicity Testing at the NTP: High Throughput
Screening (Kristine L. Witt, NIEHS;
Research Triangle Park, NC) Since mid-2005, NIEHS/NTP has
formally participated in the NIH Molecular Libraries Initiative (MLI) by
collaborating directly with the NIH Chemical Genomics Center to use high throughput screening
(HTS) to test compounds for activity against defined targets. This collaboration adds toxicity testing
capabilities to MLI, and has allowed rapid implementation of NTPs HTS program
designed to screen large numbers of compounds for toxicity. NTP will link HTS-produced toxicity data to
data from classical in vivo toxicity
tests, with the goal of identifying mechanisms of action requiring additional
investigation, developing predictive models for biological response, and
prioritizing substances for further toxicological evaluation.
4:40 PM 5:10 PM: Panel Discussion Session 4
END OF CONFERENCE
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