The Toxicologist - Society of Toxicology

1374 WIDELY VARYING STRATEGIES IMPLEMENTED IN
DISCOVERY TO REDUCE THE FAILURE RATE OF
CLINICAL LEAD CANDIDATES IN DEVELOPMENT.
A. S. Bass and M. E. Cartwright. Drug Safety, Schering-Plough Research Institute,
Kenilworth, NJ.
The current discovery screening paradigm for the selection of novel molecular candidates
to progress into development is fraught with a high level of failure in the
early-to-late stages of development. The relationship of the number of candidates
entering Phase I to achieve one successful registration varies from one pharmaceutical
company to another. However, published data suggests that for every 12 new
molecular entities entering Phase I, only one successfully achieves marketing authorization.
The significant cost of such an endeavor in terms of operating expenses,
lost time, and missed opportunities to advance the best candidates for the
treatment of devastating diseases is too great to justify continuing with the status
quo. As a result, there has been significant effort devoted across the pharmaceutical
industry to early identification of potential liabilities of promising lead candidates
that may lead to failure of those candidates in development. A goal of this session
will be to advance the topic of discovery risk mitigation introduced in recent years
in an attempt to reduce the number of failures being witnessed in early-to-late development.
Topics include, identifying the potential on-target-related toxicities
during lead finding, deselecting those candidates likely to fail in development due
to on-target or off-target related toxicities, staged approaches to evaluating the
pharmacodynamic safety (safety pharmacology) of potential lead candidates, integrating
safety endpoints into proof of concept studies, and application of structure
activity toxicology (SAT) identifying and mitigating the risk of metabolite-related
toxicity. Presenters will share their experiences in each of these emerging areas of
safety science and engage the audience in a debate of best practices. Important deliverables
will include advancing knowledge in the conceptual and practical approaches
to mitigating the risk of failure of promising new drugs progressing towards
marketing authorization.
1375 MITIGATION STRATEGIES DURING EARLY
RESEARCH: EVALUATION OF NOVEL THERAPEUTIC
TARGETS FOR POTENTIAL ON-TARGET TOXICITY.
J. W. Davis. Drug Safety R&D, PGRD, Chesterfield, MO.
Drug development is a long, complex and expensive process. Typical development
timelines are between 10 and 15 years with attrition rates that are often too high for
companies to sustain productive pipelines. Investigational and discovery toxicology
are extensions of the field of general toxicology, created to fulfill the growing need
for generating higher throughput, integrative, and predictive toxicological information,
in an effort to reduce attrition at later stages of drug development. These novel
ideas have begun to be employed more frequently and its widely anticipated that
this will pave the way for future drug testing paradigms. This presentation will
focus on the challenges and strategies applied to the evaluation of novel therapeutic
targets associated with potential known and unknown toxicities based on publications,
outcome of general safety evaluations, or failure of a candidate progressing to
lead optimization and development. Specific examples of target de-risking activities
will be presented as will the integration of this information into the overall safety
strategy of a project.
1376 MITIGATION STRATEGIES CARRIED OUT IN
DISCOVERY TO ASSESS THE PHARMACODYNAMIC
SAFETY OF PROMISING NEW MOLECULES.
A. S. Bass. Drug Safety, Schering-Plough Research Institute, Kenilworth, NJ.
The precious costs of time and effort realized by the failure of promising new molecules
either in early to late development or after marketing authorization have motivated
the pharmaceutical industry, regulatory authorities and the scientific community
to seek ways of mitigating that risk and optimizing the chances of a
successful and sustained registration of promising new drugs. De-risking includes
not only addressing concerns related to toxicology (e.g., general, genetic and reproductive
toxicology), but also toxicity resulting from the acute pharmacodynamic activity
of the potential clinical lead candidate. The approach to pharmacodynamic
safety testing is multifaceted beginning with an understanding of the pharmacodynamic
properties of a molecule including: the effects of normal and exaggerated activity
at a therapeutic target, its off-target characteristics, the ability of a molecule to
form potential toxic metabolites, and data from other in vitro and in vivo studies
suggestive of a concern for adverse pharmacodynamic effects. A directed study of
pharmacodynamic toxicity will lead to additional critical data which collectively
with the other information will portend a compound’s potential for failure in development
due to unwanted adverse findings. Amongst these potential adverse
events associated with acute pharmacodynamic toxicity, those of the cardiovascular,
respiratory and central nervous systems are highlighted as having the greatest potential
for serious adverse events. However, on a case by case basis, other organ targets
such as the gastrointestinal, renal, and endocrine systems may be evaluated for
undesired pharmacodynamic activity. Finally, integration of all safety data, including
the potential for pharmacodynamic toxicity, serves as a basis for judging
whether a promising new molecule may successfully advance through clinical development
and achieve a sustained presence in the marketplace for the treatment of
devastating diseases for which new therapies are critically needed.
1377 MANAGING RESOURCE LIMITATIONS IN DISCOVERY
TOXICOLOGY: INTEGRATION OF RISK MITIGATION
APPROACHES INTO EFFICACY STUDIES AND OTHER
STRATEGIES FOR NOVEL THERAPEUTIC TARGETS.
B. D. Car. Discovery Toxicology, Bristol-Myers Squibb Inc., Princeton, NJ.
Capital, personnel, consumables, and active drug are key resource limitations in
discovery research targeted to reduce compound attrition. The needs for these limited
resources frequently compete with those of drug development and pharmacology,
which may be considered higher priorities. Superimposed on these resource
limitations are critical time constraints for drug candidate progression. Several
strategies may be applied to addressing these potential limitations. Integration of
safety endpoints into discovery proof-of-concept studies provides an opportunity to
identify on- and off-target effects well prior to the conduct of formal toxicology
studies. However, these models are generally poorly understood from a toxicological
perspective. Strategies that focus limited resources on those most important
causes of attrition or specific studies to address known lead issues in backups may
be applied without significantly increasing risk of attrition, and consideration
should be given to balancing cost and quality of studies for providing minimally interpretable
endpoints. This presentation will include careful consideration of the
best approaches to efficiently and economically generate interpretable safety data in
Discovery, given the constraints of toxicologists and pathologists charged with providing
risk assessment to compounds soon to enter Development.
1378 STRUCTURE ACTIVITY TOXICOLOGY (SAT) AS A
MEANS OF DE-RISKING COMPOUND FAILURE.
M. E. Cartwright. Drug Safety, Schering-Plough Research Institute, Kenilworth, NJ.
Structure activity relationships are applied to identifying the best lead candidates
that have affinity for the therapeutic target site and possess desirable properties deserved
of advancement into development. However, a structural series can also be
fraught with potential for toxicity of the core structure or a metabolite and much is
known of specific structural moieties that pose risk of clinical safety. This area of
study is referred to Structure Activity Toxicology and represents a holistic approach
to safety science. The presentation will include strategies of de-risking molecules
with potential adverse structural moieties and metabolites and successful means of
risk mitigation that have been applied in the course of identifying promising clinical
lead candidates.
1379 MITIGATION STRATEGIES DURING DISCOVERY
LEAD OPTIMIZATION: MANAGEMENT OF A
PRECLINICAL OFF-TARGET ADRENAL FINDING.
B. L. Homer, M. T. Baratta, J. C. Davila, A. D. Burdick and J. W. Davis. Global
Research and Development, Pfizer, Chesterfield, MO.
Compound safety studies conducted in rats and dogs during Lead Optimization resulted
in an off-target dose dependent adrenal finding, characterized by increased
cortical vacuolation and adrenal weights. The finding did not appear to be development
limiting, but the absence of routine biomarkers for detection of adrenal toxicity
raised concerns. A team was created to develop and execute a plan to further
characterize this finding, understand the cause, and address the risk of bringing the
compound into clinical trials. The underlying hypothesis was that the lead compound
inhibited the adrenal steroidogenesis pathway, resulting in accumulation of
intermediate metabolites. Lipid stains (ORO and adipophilin) of adrenals of compound
treated animals revealed neutral lipids within the vacuoles. By electron microscopy,
membrane bound cytoplasmic vacuoles appeared empty or contained
variably granular to lucent substance, with acicular clefts and foci of membranous
material. There was no evidence of cytotoxicity. In rat, dog and human adrenal microsomal
assays and human H295R adrenal carcinoma cell line cultures, treatment
with compound or a positional isomer partially inhibited the 21-hydroxylase mediated
metabolism of progesterone to 11-deoxycorticosterone. Addition of the isomer
292 SOT 2010 ANNUAL MEETING