Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations. Author, Reporter: Stephen J. Williams, Ph.D.
The fall 2012 Meeting of the Mid-Atlantic Society of Toxicology (MASOT) focused on the challenges and solutions in developing proper Development and Reproductive Toxicology (DART) studies with regards to the newer classes of bio-therapeutics such as vaccines, antibody-based therapies, and viral-based therapies. The full meeting and MASOT links can be found at http://www.masot.org. The overall synopsis of the meeting talks agreed, that although the general aim and design of DART studies for biological are very similar to DART studies for small molecule therapeutics, it is more necessary to take into consideration the pharmacodynamics, pharmacokinetic differences between biologics and small molecules. In addition it is imperative to use pharmacologically-relevant species, such as non-rodent (guinea pig and non-human primate). The meeting was highlighted by the keynote speaker, Dr. A. Wallace Hayes, renowned board-certified toxicologist, committee and expert panel member for National Academy of Sciences, NIEHS, EPA and Department of Defense, and editor of well-known textbooks including Principles and Methods of Toxicology. Dr. Hayes discussed a timeline of milestones in the field of toxicology.
The following are the meeting talk abstracts as well as notes for each presenter.
What’s So Different About DART Assessment of Biologics? Christopher Bowman Ph.D., DABT (Pfizer, Inc.)
Abstract: The aim of developmental and reproductive toxicity (DART) safety assessment of a biologic is no different from that of a small molecule. Both cases consist of evaluating the potential for maternal toxicity, pre- and postnatal development toxicity (including juvenile toxicity) and effects of fertility (reproduction). The differences lie in the in the product attributes of a specific biologic, the pharmacological response, the potential for undesirable toxicities and how these product attributes influence and are influenced by the biology. Thus the primary challenge for developing a DART strategy for a biologic are derived from the complexities of these biomolecules and how that dictates a case-by-case strategy for appropriately evaluating the potential for developmental and reproductive toxicity. Most protein biologics have very limited potential for off-target toxicities, but this is not necessarily the case for other modalities such as anti-sense oligonucleotides and antibody-drug-conjugates. In these cases, off-target toxicities can be a major feature of the DART safety assessment. The most noticeable difference in DART assessment of biologics is the need to conduct these studies in pharmacologically relevant species and how that can influence the overall nonclinical strategy (including DART). This has led to increased use of non-human primates as a model system and led to optimizations of this model for this purpose and revisions to international guidelines.
Notes: Dr. Bowman emphasized the need to understand the type of biological you are testing and to both devise DART studies based on this information, additional endpoint you may want, as well as carefully choosing the correct species most relevant to the biologic. He highlighted general differences between small molecules versus a biologic with respect to their pharmacology. These differences are summarized in the Table below:
| Small Molecule | Biologic-based therapy | |
| Species specificity | Low | High |
| Route of administration | Usually oral | Parental |
| ADME (PK, bio-distribution etc.) | Wide distribution | Low distribution |
He noted that clinical trials for biologics rarely include reproductive toxicity so the preclinical DART study is of utmost importance. He also emphasized that currently, the FDA requires two species for DART testing of small molecule therapies (usually one rodent and one non-rodent). However this is not possible with many biologics as species is to be taken in consideration when designing a meaningful DART study. Study designs can be like most DART studies but want to have a steady exposure during fetal organogenesis, use high doses (10 times the clinical dose) to achieve maximal pharmacology, confirm exposure to fetus and to F1 generation, and determine embryolethality. Some biologics like interferon and insulin-growth factor receptor (IGFR) antagonists are fetal abortifactants. In fact Lucentis (Ranibizumab) and Macugen (Pegaptanib) were approved with no or little DART studies, however these drugs showed reproductive toxicity, resulting in warning concerning pregnancy on the label. Also important is the effect on the immune system and reproductive system of offspring, as well as the pharmacodynamics profile in the offspring.
Species Selection for Reproductive and Developmental Toxicity Testing of Biologics; Elise M. Lewis, Ph.D. (Charles River Preclinical Services)
Abstract: Regulatory guidelines for developmental and reproductive toxicology studies require selection of “relevant” animal models as determined by kinetic, pharmacological, and preceding toxicological data. Rats, mice, and rabbits are the preferred animal models for these studies based on historical experience and well-established procedures and study protocols. However, due to species specificity and immunogenicity issues, developmental and reproductive toxicology testing for biologics is limited to a pharmacologically relevant animal model as described in the ICH s6 guideline.
Notes: Dr. Lewis notes that DART studies in guinea pigs and hamsters represent a cost effective alternative to large animal models as well as the benefit of shorter duration and ability to assess mating behavior. She also notes that reproductive toxicology of vaccines should be done in an animal model that can elicit an immune-response to the vaccine, especially to determine any maternal-fetal interaction. For example, a vaccine may be directed to a maternal protein which when suppressed, may negatively impact the developing fetus. However it is important to remember that guinea pigs can spontaneously abort so it is good to have proper control arms of a substantial size in order to statistically determine the impact of those spontaneous abortions.
Placental Transfer of an Adnectin Protein During Organogenesis in Guinea Pigs Using a Radiolabeled Methodology; Lakshmi Sivaraman, Ph.D. (Bristol-Myers Squibb)
Abstract: Knowledge regarding the placental transfer of large molecular weight therapeutics is important to support the enrollment of women of childbearing potential in clinical trials. There is limited information in the scientific literature that reports the extent to which the conceptus is exposed to these large molecules during organogenesis. Placental transfer of large therapeutics has been difficult to quantify, due to limited blood volumes that can be obtained from the embryo, as well as insufficient assay sensitivity. Thus, it is possible that embryos are exposed to pharmacologically active concentrations after maternal drug exposure. We have adopted a radiolabeled approach to quantitate embryo-fetal exposure of a novel protein therapeutic platform (adnectins). Adnectins are fibronectin-based proteins containing domains engineered to bind to targets of therapeutic interests.
Notes: Adnectins molecular weight is typically less than monoclonal antibodies and while IgG is not transferred in great quantity past the placental barrier there have been studies in human indicating maternal-fetal transfer of monoclonal antibodies. This is particularly important for two reasons: the monoclonal interacts with a target important in development, or the fetal immune system could be augmented. Their work will be published in Drug Metabolism and Disposition. In general Dr. Siveraman engineered a radiolabel on adnectin and used different detection methods to quantify the fetal exposure to a single maternal dose. Dr. Siverman was able to detect radiolabel in the fetus however it is not clear whether this is a significant amount.
Reproductive Toxicity Testing for Biological Products in Nonhuman Primates: Evolution and Current Perspectives: Gary J. Chellman, Ph.D., DABT (Charles River Preclinical Services)
Notes: Dr. Chellman gave a review of the current trends being driven by regulatory agencies with regard to nonhuman primate DART studies of biopharmaceuticals. He noted that an advantage using nonhuman primates were the close physiologic resemblance to humans and because a large animal could monitor pregnancy over time using ultrasound technology. In general, Dr. Chellman spoke about new study designs which not only reduce the number of animals required but also significantly reduce costs. For example, a DART study which cost upward of $750,000 now can be done for as little as $350,000. Dr. Kary Thompson of Bristol Myers Squibb then gave a talk about use of these new enhanced designs to determine reproductive toxicity issues with ipilimumab (Yervoy).
Other research papers on Pharmaceutical Intelligence and Reproductive Biology, Bio Insrumentation, Endocrinology Genetics were published on this Scientific Web site as follows
Non-small Cell Lung Cancer drugs – where does the Future lie?
Reboot evidence-based medicine and reconsider the randomized, placebo-controlled clinical trial
Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”
Leptin and Puberty
Gene Trap Mutagenesis in Reproductive Research
Genes involved in Male Fertility and Sperm-egg Binding
Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organization can cause reversible sterility in male mice
Pregnancy with a Leptin-Receptor Mutation
The contribution of comparative genomic hybridization in reproductive medicine
Sperm collide and crawl the walls in chaotic journey to the ovum
Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations
Biosimilars: CMC Issues and Regulatory Requirements
Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers
Assisted Reproductive Technology Cycles and Cumulative Birth Rates
Innovations in Bio instrumentation in Reproductive Clinical and Male Fertility Labs in the US
Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)
Guidelines for the welfare and use of animals in cancer research
Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”
2012pharmaceutical
sjwilliamspa