The Toxicologist - Society of Toxicology

than genetic mutations which have long been the hallmark of cancer. Since cancer
is considered a disease of clonally expanded dedifferentiated cells with stem cell-like
properties, the genomic analysis of signaling pathways involved in stem cell maintenance
and renewal in vivo might provide a useful alternative for estimating cancer
risk following short term environmental chemical exposure. We have identified alterations
in the Wnt signaling pathway in target tissues as early as two weeks following
chemical carcinogen exposure while little or no change was observed in this
pathway following non-carcinogen exposure. The observed alterations in Wnt signaling
gene transcripts were also dose-dependent and correlated well with the relative
potency of the chemical carcinogen. Bioinformatic analysis of public gene expression
data from cancer studies reveals clustering of Wnt signaling genes into
receptor/ligand and second messenger gene families during stem cell growth. In this
talk we describe research that facilitates the genomic characterization of alterations
in these signaling pathways as predictors of the carcinogenic potential of environmental
chemicals.
fetal exposure during this developmental window). For compounds which are pharmacologically
active in non-human primates only a DART study in a single, i.e.
this species is sufficient. Fertility assessment may be covered in the repeated dose
toxicity test if functional assessment is not feasible (e.g. monkey). The revision of
the S6 will focus on the redundancy of a classical embryo-fetal developmental toxicity
study for monoclonal antibodies recommending a rather integral approach e.g.
with an enhanced peri-postnatal development study covering nearly the complete
period of gestation.
1436 PRECLINICAL STRATEGY CONSIDERATIONS FOR
ASSESSING THE REPRODUCTIVE AND
DEVELOPMENTAL TOXICITY POTENTIAL OF
BIOPHARMACEUTICALS.
J. Cavagnaro. Access BIO, Boyce, VA.
1434 CURRENT THINKING AND EXPERIENCES ON
DEVELOPMENTAL AND REPRODUCTIVE SAFETY
ASSESSMENT OF BIOTHERAPEUTICS.
C. J. Bowman 1 and T. E. White 2 . 1 Pfizer, Groton, CT and 2 GlaxoSmithKline, King
of Prussia, PA.
As scientific thinking and regulatory expectations around highly target-specific biotherapeutics
have evolved, it has become increasingly difficult to design meaningful
nonclinical strategies that reduce uncertainty around the risk of effects on human
reproduction and development. Importantly, these nonclinical studies are likely the
most reliable method available to prevent drug-induced birth defects and infertility
since clinical evaluation of these endpoints is unethical or rare. These studies should
generally be in compliance with ICH S5, which is designed primarily to detect toxicity
to reproduction and development (hazard identification). From ICH S5 relatively
standard nonclinical strategies for small molecules have evolved, but for practical,
technical, and sometimes ethical reasons may have limited value for large
molecules or vaccines (issues ranging from placental transfer to limited off-target
toxicity). Although most biological effects of biotherapeutics have an origin in
modification of a target or target signaling, it is not uncommon to have unexpected
effects on reproduction and/or development since regulation/function of the target
during these lifestages is often not well understood, particularly for novel drug targets.
As described in ICH S6, for biotherapeutics careful scrutiny of the nonclinical
strategy and conduct of specific studies is necessary to appropriately account for
many issues, particularly species specificity, immunogenicity, biological activity
and/or elimination half-life. In order to adhere to ever-changing regulatory expectations,
minimize the use of animals; and improve the performance of safety assessment/toxicology
around potential treatment-related effects on reproduction and
development; innovative strategies using a combination of animal models (e.g.,
transgenic) and study designs (e.g., use of homologues or combined pre/postnatal
development in nonhuman primate) are currently being developed and applied by
many companies.
1435 CURRENT REGULATORY EXPERIENCE AND
PROPOSED MODIFICATIONS TO ICH S6.
J. van der Laan. Centre for Biological Medicines and Medical Technology, National
Institute for Public Health and the Environment, Bilthoven, Netherlands. Sponsor: C.
Bowman.
The regulatory approach in the preclinical assessment of new biotechnology-derived
human pharmaceuticals in the ICH S6 Guideline is explicitly different from
the common approach for conventional small molecule, chemically-synthesized
pharmaceuticals. The development of a huge number of monoclonal antibodies for
a broad population including women of child-bearing potential revealed that the
minimal attention to this group of products in the present S6 Guideline merits an
update in the description of the regulatory approach. In preparing the revision of
the guideline we have evaluated the experience with respect to developmental and
reproductive toxicity (DART) testing for the products with a European marketing
authorization, with a further emphasis on the monoclonal antibodies and related
products. This evaluation has revealed that for protein hormones and other proteins
the classical DART approach of two species (mainly rats and rabbits) has been used
to test the reproductive safety. For 15/20 approved monoclonal antibodies DART
has been tested. The Cynomolgus monkey showed to be the species used in the majority
of the cases (10 out of 15). The human fetal risk of the exposure to monoclonal
antibodies is more associated with functional effects derived from influencing
development in the latter part in pregnancy rather than with malformations
resulting from interference with organogenesis in the first trimester (due to limited
The “principles” of DART testing for biopharmaceuticals are similar to those for
small molecule pharmaceuticals and in general follow the guidance outlined in
ICH S5 (R2). However, because many biopharmaceuticals are species-specific, alternate
approaches or “practices” are generally needed to evaluate DART potential
as outlined in the initial ICH S6 guidance. The need for this “case-by-case approach”
is dictated by differences in product attributes. This presentation provides
both a framework for developing DART testing strategies for biopharmaceuticals,
in the context of the overall clinical development strategy, as well as an overview of
the state of DART testing of biopharmaceuticals. The various strategies that have
been successfully implemented over the past two decades will be summarized based
upon regulatory reviews and the recently published BioSafe White Paper (Birth
Defects Res (Part B), 33:176-203, 2009). Lessons learned will be applied to future
strategies in the context of novel compounds now entering development. Current
challenges will be highlighted as well as the importance of communicating and
managing potential DART risks of biopharmaceuticals.
1437 CHALLENGES AND SOLUTIONS FOR EVALUATING
THE DEVELOPMENTAL TOXICITY POTENTIAL OF
BIOTHERAPEUTICS.
L. Andrews. Genzyme Corporation, Framingham, MA.
As the development of biotherapeutics becomes a more advanced science based
challenge, the selection of relevant animal models, utility of traditional species and
alternatives to traditional safety approaches are becoming more accepted and in
fact, necessary. The challenges of biotherapeutics become especially evident when
considering the most appropriate science based approach for the conduct of developmental
and reproductive studies.
Designing an informative developmental and reproductive toxicity study for a biotherapeutic
can be a challenge in light of the need to utilize alternative approaches
that may be divergent from a more traditional Segment I, II, III approach and include
utilization of two species. Alternatives to the traditional safety approach include
the use of homologous proteins, transgenic animals, animal models of disease
as well as state of the art non-invasive, non-terminal technologies such as high resolution
imaging and scanning methods. In addition, a science based approach to rationale
study design has allowed for a better use of animals through the development
process. Study design considerations must be addressed in order to most
effectively utilize animals and wherever possible reduce the need for large numbers
and multiple studies. The opportunities and challenges for these approaches with
respect to developmental and reproductive studies as well as the approach to implementing
these areas to help reduce animal use and advance the science of biotechnology
drugs will be discussed. A specific example of a monoclonal antibody in development
will be illustrated including a discussion of regulatory feedback and
alternatives to a traditional approach.
1438 CASE STUDIES: DEVELOPMENTAL AND
REPRODUCTIVE TOXICITY (DART) STRATEGIES
EMPLOYED TO SUPPORT THE REGISTRATION OF
GOLIMUMAB AND USTEKINUMAB.
C. Sachs, G. Treacy and P. Martin. Centocor R&D, Inc., Radnor, PA.
Golimumab and ustekinumab are fully human monoclonal antibodies to soluble
cytokines (tumor necrosis factor α and IL-12/23, respectively). Cynomolgus monkeys
were identified as biologically relevant species for toxicity studies for both antibodies.
Common goals of the developmental toxicity studies for both antibodies
304 SOT 2010 ANNUAL MEETING