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Friday,
March 28
7:00am Registration
(Open until
5:30pm)
8:30am Chairperson's Remarks
Mary Haak-Frendscho, Ph.D., Vice
President, Preclinical Research & Development, XOMA (US) LLC
8:35 Defining and Finding Relevant
Animal Models: The Evolution of "Relevant" During Development
Nancy Wehner, Ph.D., Senior Director,
Non-clinical Safety Evaluation, Elan Pharmaceuticals)
Defining and finding relevant animal
models for biopharmaceutical toxicity testing is a major challenge
for drug development due the the generally limited species
reactivity of these compounds. This challenge can be greatly
heightened when specific safety concerns exist that can抰 be
easily tested due to this limited reactivity or when clinical
events reveal issues that were not identified preclinically in the
chosen "relevant" species. These circumstances can and
should lead to a reevaluation of the animal models being used and
a willingness to examine/utilize less traditional models and
methodologies when appropriate. This talk will examine this
evolution of relevance through case studies.
9:05 Predicting Cardiac Toxicity with
Adjuant Trastuzumab Therapy
Ellie Guardino, M.D., Ph.D.,
Assistant Professor of Medicine, Breast Oncology, Stanford
University
Trastuzumab, a monoclonal
antibody, has been incorporated into the adjuvant treatment of
HER2-positive breast cancer. I will discuss cardiotoxicity found
in the major adjuvant trastuzumab trials reported to date
including NSABP B-31, NCCTG N9831, HERA, Breast Cancer
International Research Group (BCIRG) trial 0069 and the Finland
Herceptin (FinHER) trial. Attempts at reducing the risk of
cardiotoxicity and selecting appropriate patients for treatment
will be discussed.
9:35 Translating Safety
from Animals to FIH Studies of Biologics: Science or Art?
Lauren E. Black, Ph.D., Senior
Scientific Advisor, Navigators, Preclinical Services, Charles River Laboratories
After TGN1412, IL-12, and thrombopoietin, does the future for biologics seem insecure? Do
biologics have to be a perfect "magic bullet" to be a
successful therapeutic advance? No, long term clinical experience
with monoclonal antibodies show how risk and benefit can be
balanced. But we have to acknowledge that sometimes, startling
things can happen when protein drugs enter human trials - why can抰
we prevent every risk? Why aren抰 animals always perfect models
of human response? As regulators and large pharma push for
complete risk prevention, the biologics community can only fight
for risk mitigation. The answer is not "more [animals] is
better". To move forward in these times, we have to use every
muscle - our interdisciplinary experts, new technologies and
history- to craft unique approaches for each biologic IND. There
are simple steps that we can take to mitigate risks that are
couched in traditional science - like the ancient quote from
Paracelsus, "the dose makes the poison." The FDA
"Starting Doses" guidance hold some little-known clues
and is discussed by one of it's authors. The last page lists the
factors which lead to larger safety margins - among them is a hint
that if you can抰 ferret out the dose/response relationship, all
bet's are off (read: "kill the drug"). But if you can,
the Pharmacologically Active Dose can be used as a conservative
index for FIH dosing, a method which is very pertinent to
biologics and other receptor-targeted drugs. This dose
extrapolation index can offer a moderate dose estimate approach
that will appease reviewers without either caving to paranoia or
ignoring the frailties in pre-clinical testing.
10:05 Technology Spotlight (Sponsorship
Available)
10:20 Coffee Break in the Foyer
11:00 Development of an in Vitro
Cytokine Release Assay and its Predicative Value
Jing Min, Ph.D., Principal Scientist, Biotherapeutics, Pfizer
In light of the tragic
FIH clinic outcome of TGN1412, a predictive cytokine release assay
would be beneficial for the early safety assessment of any future
immunomodulators. Using a synthesized anti-CD28 superagonist mAb
as a positive control a human PBMC-based in vitro cytokine
release assay has been developed. The predicative value of the
assay has been further assessed with various control antibodies.
11:30 The Early
Development of Raptiva?(efalizumab) for Plaque Psoriasis
Kathleen Meyer, Ph.D., Director of
Toxicology, XOMA (US) LLC
The early nonclinical
safety evaluation and clinical development of Raptiva?(efalizamub)
will be discussed, focusing on the predictive value of animal
studies to the clinical situation. Raptiva is an immunosuppressive
recombinant humanized IgG1 kappa isotype monoclonal antibody that
binds a human CD11a, thus reducing T cell activation, adhesion and
migration. Raptiva is indicated for the treatment of adult
patients with chronic moderate to severe plaque psoriasis.
12:00pm Luncheon Workshop
(Sponsorship Available) or Lunch on Your Own
1:00 Chairperson's Remarks
Kohkan Shamsi, M.D., Ph.D., President
& CEO, Acunova Life
Sciences Inc. and Director, Symbiotic Pharma Research
1:05 Imaging Biomarkers in Early
Clinical Development of Novel Therapeutic Agents
Jeffrey L. Evelhoch, Ph.D., Executive
Director, Medical Sciences, Imaging, Amgen Inc.
Over the past decade,
biomarkers (objectively measured indicators of a biological/
pathobiological process or pharmacologic response to treatment)
have been recognized as a critical element to improve
predictability and efficiency in the process of developing more
effective, more affordable, and safer therapeutics for patients.
In the early clinical development of novel therapeutics,
biomarkers can provide information critical to internal
decision-making (i.e., establish presence of target, evaluate
biological/clinical activity, dose selection for later phase
trials, stratify study populations, conduct interim analysis of
efficacy and/or safety). Imaging is a powerful biomarker that can
provide information about genetic, biochemical, physiological and
anatomic processes in many diseases including multiple sclerosis,
cancer, arthritis, atherosclerosis, Alzheimer's disease, and
others. This talk will explain how imaging is used as a biomarker
and give several examples of how it can impact decision-making in
early clinical development.
1:35 Imaging in Phase II/III Clinical
Development
Haren Rupani, M.D, FACR, FACNP,
Global Head, Oncology Imaging, Novartis Pharmaceuticals
Corporation
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Standard or Validated Imaging
Modalities
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RECIST and McDonald Criterias
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Role of Exploratory Imaging in Phase
II/III
2:05 Imaging as a Biomarker in
Oncology Drug Trials and Improving Cancer Patient Care
Gary Kelloff, M.D., Advisor, Cancer
Imaging Program, Division of Cancer Treatment and Diagnosis,
National Cancer Institute
New promising imaging
tools for measuring biomarkers have also been developed and are
based on direct visualization by microscopy, nanotechnologies, and
direct and remote imaging. Definitions and classifications of
these biomarkers for use in oncology drug development are
presented, as are activities of the NCI/FDA Interagency Oncology
Task Force; opportunities under the Oncologic Biomarker
Qualification Initiative (OBQI) and Biomarkers Consortium for
establishing public/private partnerships; and
validation/qualification studies of imaging-based biomarkers.
2:35 The Promises and Realities of
Imaging as a Translational Biomarker in Drug Development
Timothy J. McCarthy, Ph.D., Senior
Director and Head of Imaging, Translational and Molecular
Medicine, Pfizer Global R&D
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Overview of the use of non-invasive
imaging in drug development
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Identification of issues around
translational imaging
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Opportunities for future technical
innovations
3:05 Close of Conference
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