The Toxicologist - Society of Toxicology

2673 IMMUNE-MEDIATED VASCULAR INJURY IN NON-
HUMAN PRIMATES.
J. L. Bussiere 1 and C. Johnson 2 . 1 Toxicology, Amgen, Inc., Thousand Oaks, CA and
2 Pathology, Amgen, Inc., Thousand Oaks, CA.
Anti-drug antibody (ADA) responses can potentially affect the outcome and interpretation
of a toxicology study and assessing the relevance of toxicity that may be
ADA-mediated in nonhuman primates to clinical populations can be difficult.
During the development of a monoclonal antibody (MAb) drug which targets the
immune system, a vascular lesion was noted that was not immediately explainable
as drug or ADA-related. In a 6-week cynomolgus monkey study with weekly dosing
of 10, 75 or 300 mpk IV or 300 mpk SC, chronic periarteritis involving multiple
organs was observed in 2/6 animals given 300 mpk IV, and in 1 tissue in 1/6 animals
given 300 mpk IV, 1/6 animals given 75 mpk IV and in 1/6 animals given 300
mpk SC. The etiology of the vascular lesion was uncertain based on routine
histopathology evaluation. A vascular target was not anticipated based on literature
describing target-deficient humans or KO mice and was thus thought not to be related
to the mechanism of action of the MAb. Evidence of an immune response to
the MAb associated with enhanced clearance was noted in 3/5 animals with the lesion,
and these animals tended to develop ADA quicker than non-affected animals
that eventually became antibody positive. The safety margin at the NOAEL of 10
mpk was ~5x/20x based on AUC/Cmax, and FIH trials were initiated. In a follow
up 3-month study with weekly SC dosing of 5, 25, or 90 mpk, periarteritis was
noted in only 1 tissue of 1 animal at the mid dose. Immunohistochemical (IHC)
staining for antihuman IgG and antimonkey IgG and IgM revealed granular staining
in blood vessels with the vascular lesions of animals from both studies. This
staining pattern suggested that ADA/drug complex deposits might have a role in
the pathogenesis of the lesion. No periarteritis was seen in a 6 month study at similar
doses. These data supported the conclusion that ADA contributed to the toxicity
seen with this MAb and was not likely to be relevant to humans. Close monitoring
of ADA in the clinical trials, along with other endpoints allowed for
progression of single and multiple dosing.
2674 IMAGING AS A TRANSLATIONAL TOOL FOR
ASSESSING CLINICAL RELEVANCE OF DRUG-
INDUCED VASCULAR INJURY.
A. Lerman. Mayo Clinic, Rochester, MN. Sponsor: H. Smith.
There is a growing need to identify the potential cardiovascular effect of new therapeutic
options prior to launching large randomized clinical trials, and particularly
introducing the new therapy to clinical practice. The endothelium is strategically
located between the circulation and the vascular wall and regulates vascular tone,
growth and thrombosis. The vascular wall continues to undergo continuous vascular
injury and repair, and the role of the endothelium is to mediate this repair
process. An abnormality that impairs this process results in endothelial dysfunction
and progresses to more severe vascular injury that can mediate a cardiovascular
event and mortality. There are several methodologies to assess the effect of a specific
drug on the endothelial function. In vitro methods such as organ baths, to assess
the effect of a drug on the vascular function and specifically on the endothelium.
Further studies can be done in small and large animals to assess the effect of acutely
or chronically administered drug on the vascular endothelial function,. When the
studies with the new drug continue into a human investigation, there are several
methodologies that enable us to assess the specific effects of this new therapeutic
modality on endothelial function in humans. These methods include noninvasive
and methods to assess the specific effect on the coronary endothelial function.
Additionally, there are novel imaging modality to assess not only the effect on the
function, on the structure of the vascular wall. This imaging modality, particularly
of interest in the coronary circulation, can have a more accurate imaging of the effect
of the drug on the vascular wall. Thus, the application of these in vitro, nonclinical,
and clinical methodologies to the assessment of new therapeutic drugs on
vascular function and specifically on endothelial function may increase the safety of
the drug and prevent the clinical incidence of drug-induced cardiovascular morbidity
and mortality.
2675 ARE WE THERE YET? – ATTRITION IN THE
PHARMACEUTICAL INDUSTRY AND IMPACTFUL
STRATEGIES FOR REDUCING FAILURE.
J. Stevens 6 , C. Afshari 5 , B. Car 1 , I. Cotgreave 2 , K. Kolaja 3 and B. Pennie 4 .
1 Bristol-Myers Squibb, Lawrenceville, NJ, 2 Astra-Zeneca, Uppsala, Sweden, 3 Roche,
Nutley, NJ, 4 Pfizer, Groton, CT, 5 Amgen Inc., Thousand Oaks, CA and 6 Lilly,
Indianapolis, IN.
There have been many reports over the years that indicate a significant amount of
attrition of candidate molecules in the pharmaceutical industry is due to safety related
failures. In the recent years new approaches have been deployed to shift safety
related attrition earlier in the pipeline. The impact of these new strategies will not
be fully realized until they are in place for a number of years. In the meantime,
there is no way to objectively assess to what extent and in what manner we are improving
as an industry and what further changes and areas of research are needed.
Therefore it is important to begin dialogue that aims to provide a forum to discuss
contemporary views of the rate and causes of current safety related pharmaceutical
attrition. An analysis of the strategies that appear to be most useful (or least useful)
to drive this attrition earlier, i.e. fail fast will be included. Varying perspectives will
be provided on the primary reasons for safety related attrition within companies
and the current strategies deployed to address the problem. Special focus will be
given to the early stage portfolio work through the first in human trials. The strategies
that will be discussed will include the integration of in vitro and in vivo models
with technologies such as imaging platforms, genomics, and protein/biochemical
analyses. Gaps or areas for future research support will be highlighted as
appropriate.
2676 THE INTEGRATION OF MULTI-DISCIPLINARY
APPROACHES WITH DISCOVERY TOXICOLOGY IN
OPTIMIZING DRUG CANDIDATES.
B. D. Car. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb,
Princton, NJ.
Discovery Toxicology has been integral to the drug discovery and development
process at BMS and legacy companies for over 13 years. This department approaches
target and candidate selection with a multi-disciplinary team including
pathologists, cardiologists/safety pharmacologists, toxicologists, molecular and cell
biologists. DT has leveraged the integration of classic approaches such as in vivo
toxicology and pathology with new technologies including genomics and metabonomics
approaches and close partnerships with Discovery Metabolism and
Pharmacokinetics, Biotransformation, Bioanalytical and Pharmaceutics groups.
Focusing initially on in silico and in vitro technologies, the group moved to a more
integrated in vitro/vivo approach to addressing failures due to preventable developability
issues and avoidable target-associated safety issues. Collectively, this improved
target success and resulted in a lower compound attrition rate. Recognizing
that such an approach can create a checkbox mentality and reduce hypothesis testing,
the focus has shifted to more a risk-adjusted and therefore fiscally responsible
direction, which was achieved without compromising attrition. Key to the success
has been high level integration across associated disciplines and within the context
of expert chemistry and pharmacology groups, leveraging their expertise whenever
possible.
2677 POTENTIAL USES OF STEM CELL TECHNOLOGY IN
EARLY PIPELINE SAFETY SCREENING.
I. Cotgreave. Global Safety Assessment, Molecular Toxicology, AstraZeneca, Södertälje,
Sweden. Sponsor: C. Afshari.
Strategies to reduce late- stage attrition are associated with a need to develop and
explore novel systems for lead selection. One area that is under exploration is the
optimal use for stem cell models. Current attrition reasons and strategies to reduce
at Astra-Zeneca will be discussed. Strategies to produce safety screening techniques
based on human embryonic stem cells and induced pluripotency will be discussed,
focusing primarily on the need to predict human cadio- and hepatotoxicity. Several
collaborative initiatives will be high-lighted, including the Stem Cells for Safety of
Medicine (SC4SM) program, a UK-based public-private consortium. Results of
initial validation exercises will discussed and the expectations for the near future
debated.
2678 EFFECTIVE AND EMERGING PLATFORMS FOR
PREDICTIVE TOXICOLOGY.
K. L. Kolaja. Nonclinical Safety, F. Hoffmann-LaRoche, Nutley, NJ.
Attrition of drug candidates within the pharmaceutical industry occurs throughout
the entire development process. Ideal screening strategies identify liabilities early
and accurately to enable project teams to make lead optimization decisions that will
match the clinical goals for a given program. A combination of effective assays that
survey genetic toxicology, teratogenicity, cardioavascular toxicity, and target organ
SOT 2011 ANNUAL MEETING 573