Continuing Education Courses

Session Chairs: Rana Samadfam, Charles River Laboratories, Montreal, QC, Canada;
and Alan Hoberman, Charles River Laboratories, Horsham, PA

Educational Support Provided by: Charles River and the American College of Toxicology
The human body is an ecosystem consisting of different communities including human cells with all the complexity of human cell biology, bacteriome, virome, and other microorganisims with both harmless and pathogenic members. There are interactions and competition for resources between members of each community. In this ecosystem, complex interfaces consolidate signals from hosts (bacteria and human) and microbiota (bacterial, phage, virus, etc.) and activate appropriate effector programs to maintain a delicate balance. Failure to maintain this balance contributes to inflammatory disorders, including arthritis, allergies, and colitis. This course will discuss new findings on cross talk between the immune system and the microbiome and how efficacious in treating inflammatory disorders the new therapeutic approaches with microbiome origin are compared with standard of care.

CE1-1 12:00 Noon–12:30 PM Human Ecosystem
Rana Samadfam, Charles River Laboratories, Montreal, QC, Canada

CE1-2 12:30 PM–1:30 PM Preclinical Studies in the Era of the Microbiome
Rodney R. Dietert, Cornell University, Ithaca, NY

1:30 PM–2:00 PM Break

CE1-3 2:00 PM–2:20 PM The Influence of Gut Virome (Phages) and the Immune System on Intestinal Health
Corinne Maurice, McGill University, Montreal, QC, Canada

CE1-4 2:20 PM–3:00 PM Efficacy of Live Therapeutics in Inflammatory and Autoimmune Conditions
Samantha Coulson, Coolum Beach, Australia

3:00 PM–4:00 PM Discussion

CE1-1

The microbiome has a great influence on human health and disease development and progression. It also has the potential to influence the safety and efficacy of therapeutics targeting different diseases, in particular those associated with chronic inflammation (obesity, diabetes, autoimmune, skin diseases, and IBD). A large part of the reciprocal cross talk between the microbiome and the human host occurs in GI system, as the majority of both microbiome and human immune system components reside in this organ. Immune cells, including lymphocytes and macrophages, are consistent occupants of the GI track. It is estimated that the number of lymphocytes is roughly equivalent to those in the spleen. This talk will focus on interactions between the microbiome and the immune system, including GALT (gut-associated lymphoid tissue).

CE1-2

Microbiomes are prevalent at the interface of the human body’s site exposure to the external environment. These locations (e.g., mouth, gut, skin, airways, urogenital tract) also happen to be the toxicological routes of exposure for most drugs, environmental chemicals, food, and food additives. As a result, human microbiomes are the first and arguably the foremost target of potential toxicological damage. Their reaction to environmental exposures drives the ultimate whole-body, benefit-risk determination. Degradation of microbiomes increases the risk of noncommunicable diseases and conditions via inflammation generating changes at barriers, while the same toxicant-induced microbial degradation also leads to reduced colonization resistance and increased risk of infectious diseases. This presentation will cover (1) the fundamental nature and importance of human and animal model microbiomes, (2) the prevalence and nature of recently identified microbiome toxicants, and (3) strategies for microbiome safety evaluation to enhance health risk analysis.

CE1-3

Familiar to many, the term “microbiome” represents the trillions of microorganisms we harbor inside our bodies. In the past 20 years, we’ve learned much about our resident bacteria and its role in our overall health, but relatively little is known about the viruses in this environment. New technologies have allowed us to identify not only that they exist, but also that native viruses, too, can affect the nature and progression of disease. We know the gut “virome” is significantly altered in patients with IBD, but does a change in viral composition influence gut inflammation? Are all viruses bad, or can they offer protection, as they do in mice? In this talk, we ponder these questions and explore the components of the human intestinal virome that shape our immune system in the context of health and IBD.

CE1-4

Ulcerative colitis (UC) is characterized by chronic digestive track inflammation and immune system malfunction. We investigated the efficacy of Lactobacillus (three strains combined) in an in vivo model of DSS colitis either alone or in combination with standard-of-care drugs, including Cyclosporin A (CsA). Treatment with both CsA and live bacteria significantly prevented colitis progression when compared with control, consistent with improvements in the colon length and composite histopathology score. The combination of live bacteria + CsA had a superior effect on in-life scoring and histopathology findings. Decreases in anti-inflammatory cytokines, including IL-2, Il-6, Il-17, KC/GRO, and TNF, were observed in the colon of animals receiving live bacteria formulation or CsA alone. Consistent with in-life scoring and histopathology, additive effects were observed for combined therapy (live bacteria + CsA). Fecal microbiome profiling indicated an apparent slight improvement, where a shift toward baseline microbiome composition was observed in treated animals compared with DSS control.

Session Chairs: Denis Roy, SciLucent Inc., Herndon, VA; and Sherrie Smith, Emmes, Rockville, MD

Clear, well-written documents are a crucial element to successfully advancing a pharmaceutical product to market. But what exactly does that mean in the context of regulatory writing? Regulatory writing is not only limited to submissions; it also includes meeting requests, supplemental information, annual reports, and more. A successful regulatory author must have a combination of scientific expertise, regulatory knowledge, and communication skills so as to write the story of the therapeutic product truthfully and accurately and convincingly build the case for regulatory approval. Nonregulatory scientists need at least a good understanding of the principles and processes to ensure smooth regulatory submissions. Because both the regulatory and the scientific landscapes are constantly changing, even the most experienced regulatory authors can learn from mistakes and emerging challenges encountered by others. The goal of this course is to provide a practical perspective on regulatory authoring, including practical tips and tricks for success, through recent case studies from an industry and agency perspective.

12:00 Noon–12:15 PM Welcome
Sherrie Smith, Emmes, Rockville, MD

CE3-1 12:15 PM–12:50 PM Introduction to Regulatory Writing and Types of Submissions
Dexter Sullivan, GAD Consulting, Raleigh, NC

CE3-2 12:50 PM–1:30 PM Pre-meeting Packages Document Authoring: Content, Regulatory Expectations, and Effective Writing
Tim Hummer, AstraZeneca, Gaithersburg, MD

1:30 PM–2:00 PM Break

CE3-3 2:00 PM–2:40 PM Practical Approaches on How to Successfully Plan and Execute CTD Regulatory Documents Authoring: 30 Years of Mistakes and Learnings
Denis Roy, SciLucent Inc., Herndon, VA

CE3-4 2:40 PM–3:20 PM Perspective from a Pharmacology/Toxicology Reviewer at US FDA: What Matters and What We Look for in Your Regulatory Submission
John Dubinion, US FDA, Silver Spring, MD

3:20 PM–4:00 PM Discussion

CE3-1

The approval of a new pharmaceutical is the culmination of many years of development. A large piece of the development process includes interactions with regulatory agencies. Although some of these interactions take place via face-to-face meetings or teleconferences, the large majority of interaction is through regulatory writing. Therefore, an effective regulatory writing program is key for the successful approval of a pharmaceutical. This presentation will cover the basics of regulatory writing and the types of documents that need to be prepared, including those for meeting requests, meetings, filings, and waivers. Examples will be included throughout the presentation.

CE3-2

The success of your pre-meeting submissions with regulatory agencies is critically linked to the quality of the technical and scientific authoring that goes into your meeting request and package. This presentation will provide a practical and effective overview of some of the most successful approaches to authoring pre-meeting packages to maximize your chances of success and will include concrete examples to avoid pitfalls and mistakes commonly made.

CE3-3

Authoring clinical- and marketing-enabling submissions can be challenging, especially when facing competing timelines or difficult/complex programs. Guidance documents and examples providing direction on the format and content of the CTD modules are readily available in the public domain, but each nonclinical development program is different and can be challenging. This presentation will provide hands-on and practical know-how information for authoring your CTD submissions (INDs and NDAs), including dos and don’ts for effective scientific and technical authoring, while navigating internal and external cross-functional stakeholders, review cycles, and corporate goals and timelines.

CE3-4

The success of a response, meeting, clinical trial, or marketing submission is ultimately defined by the quality and completeness of the regulatory documents submitted to US FDA. The US FDA pharmacology/toxicology reviewer plays a critical role in evaluating the technical and scientific information submitted and in determining if it is safe to proceed. Over the years, the review division personnel have reviewed numerous submissions and hence can provide a unique and broad perspective from a regulator point of view. This presentation will provide an agency’s perspective on the type and nature of regulatory documents encountered by US FDA reviewers, including tips on what they are looking for, advice based on real-life learnings, and common mistakes to avoid.

Session Chairs: Pallavi Limaye, Sekisui XenoTech, LLC, Kansas City, KS;
and Brian Ogilvie, Sekisui XenoTech, LLC, Kansas City, KS

Determination of potential drug-drug interactions (DDIs) is an important aspect of safety assessment. This course will focus on both conventional and nonconventional mechanisms of DDIs and how the in vitro and in vivo studies along with physiologically based pharmacokinetic (PBPK) modeling help in predicting DDIs. The course will begin with a talk outlining the conventional small molecule–related DDIs, in vitro methods, and regulatory requirements in such assessment. The second talk will discuss the drug interactions that are rather unconventional and involve indirect mechanisms such as altered physiology or genetics. The third talk will focus on the increasingly concerning unconventional DDI involving the growing trend of natural product usage. The fourth talk will discuss the regulatory insights and how the in vitro data can be used in PBPK modeling for accurate DDI prediction. The fifth talk will discuss the utility of PBPK modeling in predicting the systemic and organ-specific drug concentrations for repurposing drugs, using COVID-19 drugs as examples. Overall, the course will provide an in-depth look at this significant issue, which affects drug development both pre- and post-marketing.

CE5-1 12:00 Noon–12:05 PM Introduction
Pallavi Limaye, Sekisui XenoTech, LLC, Kansas City, KS

CE5-2 12:05 PM–12:30 PM Evaluation of “Conventional” Drug-Drug Interactions: In Vitro Approaches
Brian Ogilvie, Sekisui XenoTech, LLC, Kansas City, KS

CE5-3 12:30 PM–1:00 PM Mechanisms and Examples of Unconventional Drug-Drug Interactions
Leslie Dickmann, University of Wisconsin, Madison, WI

CE5-4 1:00 PM–1:30 PM Natural Product Drug Interactions: Weeding through the Complexities Using Translational Tools
Mary Paine, Washington State University, Spokane, WA

1:30 PM–2:00 PM Break

CE5-5 2:00 PM–2:30 PM The Role of PBPK Modeling in Drug Repurposing for COVID-19 Treatment
Kuan-Fu (Freddy) Chen, Certara, Seattle, WA

CE5-6 2:30 PM–3:00 PM Utility of In Vitro Metabolism Data for Drug-Drug Interaction Prediction in PBPK Modeling Submissions: Regulatory Considerations and Comparison of Approved NDA Applications
Yaning Wang, Createrna Science and Technology, Wuhan, China (Former Director, Division of Pharmacometrics, FDA)

3:00 PM–4:00 PM Discussion

CE5-1

This talk will introduce the scope of this CE course and set the stage for the following talks.

CE5-2

Conventional small molecule drugs (and other xenobiotics) may be viewed as direct victims or perpetrators causing DDIs. A drug whose clearance is largely determined by a single route of elimination, such as metabolism by a single CYP450 enzyme, is considered a victim drug. Such drugs have a high victim potential because inhibition or induction of that enzyme by a concomitantly administered drug may result in a large increase or decrease in victim drug exposure and may lead to overt toxicity or loss of efficacy of victim drug, respectively. Perpetrators are drugs that inhibit or induce the enzyme that is otherwise responsible for clearing a victim drug. Apart from CYP450 enzymes, drug disposition can also be largely dependent on uptake or efflux by a transporter or on metabolism by a drug-metabolizing enzyme other than CYP enzymes and need to be considered from the victim/perpetrator perspective. The major drug regulatory agencies (US FDA, EMA, and PMDA) have issued guidance documents for industry with requirements for in vitro studies to evaluate the victim and perpetrator potential for candidate drugs. In this presentation, clinically relevant examples of victim and perpetrator drugs, the current in vitro methods that can be used to assess such DDI potential, and regulatory requirements will be discussed.

CE5-3

Conventional DDIs are a result of direct alteration of CYP450s or transporters by one drug molecule that leads to altered pharmacokinetics of another drug molecule. Unconventional drug interactions tend to involve more indirect mechanisms and generally require altered physiology or genetics. For instance, certain inflammatory mediators are known to alter drug metabolism and transport activity. A well-studied example of this is IL-6 suppression of CYP3A4, one of the most important enzymes involved in drug clearance. Recent research efforts in this area have focused on improving predictions of inflammatory mediators on the extent of drug clearance. In addition, some DDIs are only observed in individuals with a certain genetic profile, and DDIs can be introduced or exacerbated because of genetically based gain or loss of enzyme or transporter function. This presentation will focus on these more nuanced and unconventional drug interactions, which can be difficult to predict using standard in vitro methods. Mechanisms of action of these interactions, suitable in vitro models to consider in research, in vitro to in vivo translation, and clinical case studies will all be discussed.

CE5-4

Humans have used botanical and other natural products for medicinal purposes since antiquity. The marketing and use of natural products continue to increase worldwide. Along with the rising sales are increasing concerns about patients supplementing their prescribed pharmacotherapeutic regimens with these perceived safe and effective products, increasing the risk for unwanted natural product-drug interactions. Like drug-drug interactions, common pharmacokinetic mechanisms underlying natural product-drug interactions include induction and inhibition of drug metabolizing enzymes and transporters by the natural product, leading to altered systemic or tissue drug concentrations and potentially, toxicity or reduced efficacy. However, unlike for drug-drug interactions, there are no harmonized recommendations for assessing natural product-drug interactions. Because natural products are inherently complex chemical mixtures, a multidisciplinary effort involving clinical pharmacologists, natural products chemists, biomedical informaticists, and health communications experts is needed for rigorous assessment and dissemination of the drug interaction liability of natural products. The National Center for Complementary and Integrative Health established the Center of Excellence for Natural Product Drug Interaction Research in September 2015. One deliverable of the center is a set of recommended approaches to guide researchers in the optimal conduct of natural product-drug interaction studies. Such approaches are based on results generated from a series of interaction projects examining methodically selected natural products as precipitants of potential clinically meaningful pharmacokinetic interactions, including cannabis, goldenseal, green tea, and kratom. These efforts will lead to improved design of future natural product-drug interaction research and, ultimately, evidenced-based information about how best to manage these complex interactions.

CE5-5

The key parameters necessary to predict DDIs are intrinsic clearance (CLint) and fractional contribution of the metabolizing enzyme toward total metabolism (fm). In vitro experiments provide important information about basic pharmacokinetic (PK) properties of new drugs and can serve as a starting point for building a PBPK model. However, key PBPK parameters such as CLint and fm still need to be optimized based on in vivo data. This presentation will discuss how the in vitro data with optimization can be used in PBPK models to assess drug metabolism and predict DDIs. As a case study, the presentation will summarize the accumulated knowledge from 53 approved New Drug Applications (NDAs) submitted to the Office of Clinical Pharmacology, US Food and Drug Administration, from 2016 to 2018 that contained PBPK models. The underprediction, overprediction, and modifications needed to accurately predict DDI will be discussed along with the regulatory considerations.

CE5-6

PBPK modeling has become an integral part of drug development from early to late stages to help understand and extrapolate drug absorption, distribution, metabolism, and excretion to predict DDIs and PK in specific patient populations. PBPK modeling has gained the spotlight during the COVID-19 pandemic and has been used to predict systemic and drug concentrations in the lung in an effort to repurpose existing drugs for COVID-19 treatment. In this presentation, we will provide an introduction to PBPK modeling (theory and application) and then describe some application case studies involving COVID-19 repurposing. Specifically, a mechanistic model of lung physiology will be described, and the application of this model to investigate drug candidate concentrations in the lung will be outlined. Use of the models to provide insight into clinically relevant questions regarding dose and optimal drug combinations for COVID-19 treatment will also be discussed.

Session Chairs: Mark Vezina, Charles River Laboratories, Senneville, QC, Canada;
and Pramila Singh, Charles River Laboratories, Lyon, France

Educational Support Provided by:
Biomere and American College of Toxicology

Eye disease and the loss or impairment of vision because of toxicities are serious conditions that affect health status and quality of life. This CE course will provide detailed information on how to design nonclinical studies for ocular therapies and for non-ocular therapies that may have unintentional, off-target ocular effects. Designing ocular development packages from proof of concept and efficacy studies to safety and translational studies will be discussed in detail by experienced CRO professionals specialized in nonclinical ocular testing methods, including current standards for evaluation of structure, function, and physiology of the eye. Specific studies to support the nonclinical development program for ocular therapies—including small molecules, biologics, novel gene therapies, and both permanent and refillable ocular devices—will be described by pharmaceutical and biotech professionals working on some of the latest and most novel ocular therapy products. Particular attention will be placed on pivotal nonclinical safety studies and points to consider about what is essential in a nonclinical data package for a range of ocular therapeutic modalities. A regulatory perspective will be provided on data requirements for ocular therapies and non-ocular drugs as well as expectations for 505(b)(2) applications. This course will cover approaches that can ensure translational benefits are realized and regulatory expectations are considered for the nonclinical program through to clinical trials. Actual case examples will be taken from current ocular therapeutic product development programs and what has proven to be essential to support clinical trials for these promising therapies.

12:00 Noon–12:05 PM Introduction
Pramila Singh, Charles River Laboratories, Lyon, France

CE2-1 12:05 PM–12:35 PM Designing Nonclinical Studies to Support Clinical Trials for Ocular Therapeutics
Margaret Collins, Charles River Laboratories, Reno, NV

CE2-2 12:35 PM–1:05 PM Strategies for Handling Expected and Unexpected Off-Target Ocular Effects with Non-ocular Therapies
Mark Vezina, Charles River Laboratories, Senneville, QC, Canada

CE2-3 1:05 PM–1:30 PM Regulatory Perspective of Nonclinical Expectations for Developing Ocular Therapies via 505(b)(2) Pathway
Aling Dong, US FDA/CDER, Silver Spring, MD

1:30 PM–2:00 PM Break

CE2-4 2:00 PM–2:40 PM Critical Success Factors When Working with Gene Therapy Products for Ocular Diseases
Kali Stasi, Novartis Institutes for BioMedical Research, Cambridge, MA
Christopher Thompson, Novartis Institutes for BioMedical Research, Cambridge, MA

CE2-5 2:40 PM–3:20 PM Points to Consider for Ocular Permanent and Refillable Slow-Release Devices: Nonclinical Toxicology Strategies
Vladimir Bantseev, Genentech, Inc., South San Francisco, CA

3:20 PM–4:00 PM Discussion

CE2-1

This talk will describe the various studies typically necessary to support an IND/NDA submission for an ocular therapeutic, including proof of concept/efficacy studies and IND-enabling ocular toxicology safety studies. The standard considerations for non-ocular compounds should be applied, but the nuances for ocular compounds will be discussed, including establishment of dose multiples and margin of safety. Animal models that are appropriate for the intended target, as well as the limitation of models, will be covered. The discussion of study designs will include species considerations, routes of administration, appropriate endpoints (need-to-have versus nice-to-have), inclusion of ocular sampling during the study, and regulatory expectations. Challenges include small dose volumes, increased sensitivity for endotoxin and toxicity in dose formulations, dose loss and/or sensitivity to the dosing procedure, risks of repeat ocular sampling, and appropriate ocular histology.

CE2-2

Numerous compound classes intended for systemic administration have the potential to cause adverse ocular effects. The manifestation of these effects can be inopportune and can cause delays and additional expense in a drug development program. This talk will cover strategies that will help in effectively managing how to deal with unexpected or known compound class-related ocular toxicity that can manifest during nonclinical studies in which the eye is not the intended, or anticipated, target. The discussion will include a summary of the compound classes currently known for the potential to cause off-target ocular effects, endpoints that can be useful for characterizing the effects, strategies for determining the timing and nature of the effects, and some case studies where off-target ocular changes occurred in various stages of compound progression.

CE2-3

The 505(b)(2) pathway is frequently used when developing ocular therapies for marketing authorization. However, during product development, the sponsor/applicant may often have questions regarding what data can be used in the application, how to use data that were not conducted by or for the sponsor and that they do not have a right to reference or use, and how to fill in the gap(s) for regulatory expectations. This talk will address these questions, focusing on the nonclinical expectations, and recommend strategies on how to establish a scientific bridge for using previously generated data to meet the regulatory nonclinical safety expectations when developing different types of ocular therapies via the 505(b)(2) pathway.

CE2-4

Gene therapy products require some special considerations during early development, especially since they frequently target rare and debilitating diseases without any available treatment. The need for delivery with an invasive method or surgery and through a device/injector also means that they are often expected to have long-term or even lifelong treatment effects from a single dose. The delivery of the specific treatment to the target cells; the evaluation of potential toxic and even detrimental, potentially permanent effects; the effects of inflammation; the effects of design and evaluation of toxicology studies to smooth translation to clinical trial time-efficient design; and the evaluation of risk-benefit approaches will be discussed. The preclinical work supporting two novel ophthalmological gene therapy drug programs, one currently in Phase I/II clinical trial and another already launched, will be discussed, with relevant background from other ocular gene therapy programs.

CE2-5

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous delivery of ranibizumab into the vitreous for extended durations. The PDS includes a surgically implanted, permanent, refillable, intraocular implant; a customized formulation of ranibizumab; and ancillary devices for the initial fill, surgical implantation, and in-office refill-exchange of the implant. A comprehensive nonclinical toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registration. Using the completed PDS nonclinical toxicology program as a case study, this presentation will discuss the advantages and challenges for nonclinical toxicology strategies related to a permanent and refillable ocular drug/device combination for the development of ocular therapeutics for retinal diseases.

Session Chairs: Ronee Baracani, Loxo Oncology at Lilly, Boulder, CO;
and Daniel Minck, US Food and Drug Administration, Silver Spring, MD

Educational Support Provided by: Experimur
The ICH S5 Guideline recommends standards for the conduct of nonclinical development and reproductive toxicity testing required to support human clinical trials and marketing authorization for pharmaceuticals. The most recent revision, ICH S5(R3), was recently adopted. The aim of this course is to focus on the pre- and postnatal development (PPND) study in the rodent, including relevant study design changes in ICH S5(R3). A key takeaway from this course will be why the study is important, including the value of its individual components, and how it fits into the new age of ICH S5(R3). This course will begin with an overview of the PPND study design and endpoint considerations, followed by an overview of developmental milestones and their evaluation, including considerations for selection, conduct, and interpretation, given that their assessment is now expected per ICH S5(R3). Considerations for neurobehavioral assessments that meet the recommendations outlined in ICH S5(R3) will then be presented, and the course will end with a regulatory perspective. The information presented will be beneficial to Sponsors and contract laboratories that conduct PPND studies to support nonclinical development and is timely given the recent ICH S5 revision.

12:00 Noon–12:05 PM Introduction
Ronee Baracani, Loxo Oncology at Lilly, Boulder, CO

CE4-1 12:05 PM–12:45 PM Overview of ICH S5(R3) and the Pre- and Postnatal Developmental Toxicity (PPND) Study in the Rodent
Curtis Grace, Merck & Co., Inc., Kenilworth, NJ

CE4-2 12:45 PM–1:30 PM Pre- and Postweaning Developmental Landmarks in the Rat Pre- and Postnatal Development (PPND) Study
Pragati Coder, Charles River Laboratories, Ashland, OH

1:30 PM–2:00 PM Break

CE4-3 2:00 PM–2:30 PM Postweaning Functional Assessments in the Rodent PPND: An Overview of Neurobehavioral Assessments
LaRonda Morford, Eli Lilly and Company, Indianapolis, IN

CE4-4 2:30 PM–3:05 PM Regulatory Considerations Regarding the Conduct and Interpretation of the Rodent PPND
Daniel Minck, US Food and Drug Administration, Silver Spring, MD

3:05 PM–4:00 PM Discussion

CE4-1

The most recent revision of ICH S5(R3) was adopted in 2020; thus, this presentation will provide a general overview of the Guideline and proceed with an overview of the strategy employed to test for effects on pre- and postnatal development through the conduct of a rodent PPND study. The purpose of the PPND study will be reviewed and will include a discussion of the advantages and challenges inherent in a study that covers a wide range of developmental stages from implantation through sexual maturation. Basic design elements will be described, including species selection, dosing regimens, and study endpoints.

CE4-2

In its most recent revision, ICH S5(R3) recommends that milestones of physical development, in addition to just measurements of body weight, are to be included in the rodent PPND toxicity study. Multiple preweaning landmarks of development and reflex ontogeny (such as eye opening, pinna unfolding, surface righting, air righting, auditory startle, and response to light) and postweaning landmarks of sexual development (vaginal patency and balanopreputial separation) will be discussed in detail within the context of rodent neonatal development. Furthermore, an overview of the assessment techniques as well as conduct considerations will be presented. Specific examples will be provided in the context of historical data and relevance.

CE4-3

One of the objectives of the PPND study is to evaluate potential effects on the functional development of the indirectly exposed offspring. Specifically, functional assessment of the central nervous system (CNS) is expected to include sensory functions, motor activity, and learning and memory. ICH S5(R3) notes that a complex learning task should be used to evaluate learning and memory. In addition, ICH S5(R3) states that habituation should be evaluated when assessing locomotor activity and startle. These details were not included in the previous Guideline. ICH S5(R2) simply stated that it was “not possible to recommend specific test methods.” It was up to the Sponsor and laboratory investigators to determine methods to assess CNS function. This presentation will provide an overview of neurobehavioral assessments, including complex learning tasks and methods to detect habituation in activity and startle. Considerations in the selection, conduct, and interpretation of the CNS assessments will also be covered. While the focus will be on CNS assessments in PPND studies, the principles discussed will also apply to CNS assessments in juvenile toxicity studies.

CE4-4

This talk will provide a regulatory perspective on the assessment of pre- and postnatal developmental toxicity, including the potential concerns regarding adverse findings. Topics to be covered in this presentation will include the concepts that should be considered when determining the need for or appropriate timing of a rodent PPND study, such as target patient population and therapeutic indication; the study design considerations, including endpoint selection and pharmacology considerations; the interpretation of the PPND study data; and the types of additional supportive data that can be utilized to aid in interpreting the results of the rodent PPND study.

Session Chairs: William O. Iverson, Consultant, Faber, VA;
and Nancy E. Everds, Seagen Inc., Bothell, WA

Educational Course Provided by: Society of Toxicologic Pathology
Antibody drug conjugates (ADCs), which use a specific antibody to deliver a toxic payload to target cells, hold great promise to increase efficacy and reduce adverse side effects, especially for oncology drugs. Six ADC molecules have received marketing approval in the US over the past 18 years. Nonclinical safety assessment has proven challenging as many ADCs still have steep dose-response curves and low therapeutic indices. Toxicities in many different organs and tissues have been seen, including bone marrow, skin, liver, kidney, eye, gastrointestinal tract, and nervous system. ADC-related toxicities may be more challenging to predict and manage than those seen with small molecules or unconjugated antibodies. This has led to more sophisticated engineering of antibodies, linkers, and drugs to increase internalization of drugs by target cells, decrease off-target toxicity, and decrease bystander effects. This course will give an overview of synthesis and mechanisms of representative ADCs, and the clinical and anatomic pathology findings associated with different classes of agents, including immunomodulatory molecules and PROTACs.

12:00 Noon–12:10 PM Introduction
William O. Iverson, Consultant, Faber, VA

CE6-1 12:10 PM–12:50 PM Immune-Modulatory Activity of Traditional and Nontraditional ADCs
Shyra J. Gardai, Seagen Inc., Bothell, WA

CE6-2 12:50 PM–1:30 PM Recent Progress in Antibody Drug Conjugates and PROTACs as New Modalities: Application to Oncology Drug Discovery
Lakshmaiah Gingipalli, AstraZeneca, Boston, MA

1:30 PM–2:00 PM Break

CE6-3 2:00 PM–2:40 PM Clinical Pathology Effects of Antibody Drug Conjugates in Toxicology Studies
Niraj K. Tripathi, Labcorp Drug Development, Madison, WI

CE6-4 2:40 PM–3:20 PM Anatomic Pathology Associated with Antibody Drug Conjugates
Matthew D. Smith, Charles River Laboratories, Reno, NV

3:20 PM–4:00 PM Discussion
Nancy E. Everds, Seagen Inc., Bothell, WA

CE6-1

Antitumor activity of monoclonal antibodies conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent, was thought to be primarily the result of intracellular payload release leading to mitotic arrest and apoptotic cell death. Recently the ADC community has realized that secondary mechanisms involving engagement of the immune system may play an important role in the antitumor response. We have determined that auristatin conjugated ADC drives apoptosis in a manner consistent with immunogenic cell death. The endoplasmic reticulum (ER) possesses elasticity to accommodate the proper environment to facilitate protein folding, and its flexibility is dependent on microtubule activity. Given the dependence on microtubule integrity on ER function, recent data have revealed that targeted disruption of microtubules can induce severe ER stress, which is associated with the exposure and release of immune-activating molecules. The release of these immune-targeted agents during the process of cell death is known as immunogenic cell death (ICD). ADC administration in vivo drives ER stress and ICD, resulting in improved immune cell infiltration and antigen processing that appears to improve the likelihood of T cell recognition of tumor-associated antigens. These observations have led the field to combine these targeted ADC therapeutics with T cell modulating checkpoint blockade antibodies. Multiple clinical trials are ongoing to evaluate the efficacy of this treatment pairing.

CE6-2

ADCs combine the specificity of antibodies with the potency of cytotoxic small molecule drugs. ADCs have the potential to provide “step-change” efficacy for the treatment of many types of human cancers. This lecture explores the following aspects of ADCs: background of ADCs; the role of the cytotoxic warhead, linker, and antibody in the design of the final molecule; and the mechanisms of ADCs internalization and release of warheads. Analysis of different known cytotoxic warheads and their synthesis and mechanisms of action will be discussed. In the case study, we will describe tubulysin warheads synthesis, design of payloads, and conjugation to the antibody to make the final ADCs. We will also discuss the newer payloads, such as PROTAC, that are not directly cytotoxic but act through other mechanisms. We will conclude with in vitro and in vivo biological data of various payloads and ADCs as anti-cancer agents.

CE6-3

The presentation will focus on commonly observed clinical pathology effects of ADCs, including expected cytotoxic effects of warheads as well as some unintended “off-target” effects. Specific case examples will be presented to elucidate the effects of two antimitotic agents’ commonly used warheads (MMAE and DM1), as well as newer noncytotoxic payloads. We will compare the clinical pathology effects of ADCs with those of the conventional small molecule cytotoxic compounds, using information from already approved/marketed drugs, and discuss the role of biomarkers in the development of these immunoconjugates.

CE6-4

ADCs have become an increasingly common platform encountered in safety assessment studies conducted at contract research organizations. The pathology associated with ADCs can be quite complex and is dependent upon numerous factors, including linker stability, mechanism of action of the payload, and drug target. This presentation will highlight common macroscopic and microscopic observations associated with ADC studies, with an emphasis on pathology associated with various ADC payloads and drug targets.