Monday, November 10

9:00 AM–12:00 Noon

From Mice to Men, Development of Human Drugs and Biologics Under the Animal Rule

Chair: John V. Wade, Battelle, Columbus, OH
Co-Chair: Owen McMaster, CDER/Food and Drug Administration, Silver Spring, MD

The animal efficacy rule was finalized in 2002 and applies to the development of drugs to reduce or prevent serious life-threatening conditions caused by exposure to lethal or permanently disabling toxic agents; including chemical, biological, radiological, or nuclear (CBRN) substances. The studies conducted under the animal rule are used to support approval of treatments, as human clinical trials are generally not feasible or unethical. The characterization and development of animal efficacy models is critical to the success of drugs or vaccines being developed under the animal rule. This session will provide an introduction to the animal rule, the qualification requirements for animal efficacy models development, and case studies of development programs for therapeutics and vaccines.

What the AEL is the NOAEL?

Chair: Joy Cavagnaro, Access BIO, Boyce, VA
Co-Chair: Lisa D. Beilke, Toxicology Solutions, Inc., San Diego, CA

Is the NOAEL different in the eyes of a pathologist vs. a toxicologist, a clinical reviewer/FIH clinical investigator—the animal? Does clinical indication impact NOAEL and/or application of a NOAEL to a clinical indication? The pharmacological activity that is outside the projected therapeutic profile of a new drug may include a spectrum of functional effects, which are not hazardous and are reversible. Minor, albeit undesirable effects should therefore be distinguished from unintended reactions that are pertinent to toxicity and that may lead to target organ effects. In this way, pharmacodynamic activity, which is integral to the therapeutic action of a drug may be viewed differently from activity which is not indispensable for efficacy. In this respect, structural (morphological) changes in organs or tissues of potentially irreversible nature are of particular concern. For that reason, histopathology has remained the most consistent criterion by which target organs are identified and NOAELS are set. This session will draw out the common points that scientists often debate on this subject, particularly as exemplified by case examples. There will also be an interactive session where data will be presented and the audience will have an opportunity to vote on whether a NOAEL has been demonstrated.

Systems Toxicology: The Future of Risk Assessment

Chair: John Michael Sauer, Predictive Safety Testing Consortium (PSTC), Tucson, AZ
Co-Chair: A. Wallace Hayes, Harvard School of Public Health, Andover, MA

Systems toxicology: the future of risk assessment. The vision of the National Research Council report on Toxicity Testing in the 21st Century is becoming a reality as modern high-content and high-throughput technologies are applied. The approach can improve the toxicological assessment of a wide range of substances including those developed for example by the pharmaceutical, chemical, cosmetic and tobacco industries. This symposium will share the results from leading researchers in the field, to underpin the revolution that is taking place in toxicology.

2:00 PM–5:00 PM

Anti-Drug Antibody-Independent Immune Responses to Biologics in Rodent Studies—Regulatory Success in Early Drug Development

Chair: Krishna P. Allamneni, Jazz Pharmaceuticals, Inc., Palo Alto, CA
Co-Chair: Joy Cavagnaro, Access BIO, Boyce, VA

Due to the advances in recombinant protein technologies and subsequent development of rodent-crossreactive biologic agents for therapeutic use in humans, a rising trend is noted for rodent toxicology studies for biologics. The development of binding, sustaining/neutralizing anti-drug antibodies and subsequent safety or efficacy liabilities are well recognized. This symposium highlights the emergence of immune reactions in rodents that cannot be definitively attributed to immunogenicity of the biotherapeutic agents. A high-level overview of the pathophysiology of immune system in rodents, clinical presentation of immune reactions and differential diagnosis are discussed as a framework to assess risk. Plausible mechanisms of anti-drug antibody-independent immune responses in rodents are explored. Available tools to evaluate, characterize, and/or confirm immune reactions specific to mice, rats, monkeys and their limitations are presented. Case examples of clinical development in the context of rodent-specific immune responses are presented. A comprehensive view of the regulatory perspective on such rodent-specific immune responses in the context of first-in-human risk assessment is presented.

Use of Humanized Mouse Models in DMPK and Safety Testing of Compounds

Chair: Alema Galijatovic Idrizbegovic, Merck & Co, West Point, PA
Co-Chair: Charles Roland Wolf, University of Dundee, Medical Research Institute, Ninewells, Dundee, United Kingdom

The use of traditional laboratory animals to predict human outcomes in pharmacokinetics, drug-drug interaction or toxicity of compounds is often limited by the significant differences, which exist between animals and man. In order to address this issue a lot of efforts have been made by various groups over the last years to generate humanized mouse models, which are more predictive for various aspects of drug responses in humans. One approach is the generation of genetically humanized mice expressing single or multiple human proteins involved in drug metabolism and disposition, such as xenobiotic receptors, drug metabolizing enzymes and transporters. Another strategy involves the replacement of mouse with human tissue, resulting, for example, in humanized mice for the liver and/or immune system.

This symposium provides the current status and discusses the future perspectives in the field of humanized mouse models from the user’s perspective. It will be of interest to scientists involved in commercial drug development, particularly working in drug metabolism and toxicology, academic researchers, as well as regulators evaluating data generated during safety testing. Furthermore, with potential applications for risk assessment of chemicals and food ingredients, it will provide relevant information to scientists in the chemical and consumer healthcare industries.

Targeted Cancer Therapeutics: Concepts and Strategies to Improve Oncology Drug Development

Chair: Vijayapal Reddy, Eli Lilly and Company, Indianapolis, IN
Co-Chair: Elaine Knight, National Cancer Institute, Bethesda, MD

Over the last decade, the focus for anticancer drug discovery has shifted from traditional cytotoxic agents (with significant and well characterized toxicities) to rationally designed, molecularly-targeted pharmaceuticals. Of the new anticancer drugs approved by the US Food and Drug Administration (FDA) since 2000, majority have been targeted therapies, compared with only few traditional chemotherapeutic agents. The safety data derived from studies of approved targeted pharmaceuticals provide a wealth of information on the nature of toxicities identified in both nonclinical species and in patients. In many cases, the toxicity profile of a targeted therapeutic is closely linked to the biological consequences of modulating the intended targets. Continued advancement in our understanding of mechanisms of toxicity should provide a better understanding of the relationships between drug efficacy and toxicity, and possibilities for better clinical management of toxicity. This symposium will provide an overview of the advances in cancer biology that have facilitated discovery of anticancer drug targets or improved candidates for drug development. The symposium will also include an overview of approaches to nonclinical safety evaluation and tailored clinical evaluation of anticancer agents. Last, the session will include a regulatory perspective and regulatory challenges for both small and biologic targeted cancer pharmaceuticals. This topic should be interested to a broad range of attendees including from industry, academia, government and clinical and healthcare professionals.

Tuesday, November 11

9:00 AM–12:00 Noon

Breathe In, Breathe Out, It's Easy: What You Need to Know about Developing Inhaled Drugs

Chair: Jeff Tepper, Tepper Nonclinical Consulting, San Carlos, CA
Co-Chair: Jim Blanchard, Aradigm, Hayward, CA

It's no surprise that toxicologists feel unprepared for their first development program using an inhaled drug. Understanding of the area requires knowledge of lung anatomy, cell biology, respiratory physiology, particle physics and plumbing. Although Paracelsus informed us that the dose makes the poison and thus is of paramount importance, in the context of an inhaled drug, the "dose" is not easily defined. This CE course will attempt to demystify and provide background information enabling you to understand the issues and challenges associated with the assessment of respiratory safety pharmacology and designing an inhalation toxicology program. First an overview examining ventilation, how to measure it, its influence on dose and the perturbations observed with inhalation exposure will be covered. The topic of dose will be further explored to better understand the assumptions and methods associated with determining drug deposition and clearance to arrive at lung dose. Next the techniques used to deliver aerosols to animals in a physiologically appropriate manner, as well as the devices used to conserve test article, will be examined. With dose and inhalation exposure covered, common background, species specific, as well as toxicologically significant histopathology lesions will be discussed. Finally, insight into how regulators synthesize and evaluate these complex findings to assess clinical safety risks will be presented.

Cardiovascular Safety Evaluation—In Vitro to Humans

Chair: Norman Kim, Biogen Idec, Cambridge, MA
Co-Chair: Chris Mathes, ChanTest Corporation, Cleveland, OH

A consortium sponsored by Cardiac Safety Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and the Food and Drug Administration (FDA) proposed a new scientific testing paradigm for drug-induced cardiac safety. The proposal instituted Comprehensive In vitro Proarrhythmia Assay (CiPA) that provided a framework of a shift from the current testing guidelines as outlined in ICH S7B (nonclinical) and ICH E14 (clinical) to include a novel assays in human cells and in silico models of cellular electrophysiological effects to evaluate proarrhythmic drugs. Additional concepts besides CiPA have also been proposed. This symposium will review the most current cardiovascular testing paradigm of potential therapeutics in consideration of the regulatory guidelines. The current ICH S7B discusses nonclinical testing strategy for cardiovascular safety. These include consideration of chemical/pharmacological class of the molecules, outcomes of in vitro assays (notably hERG inhibition), in vivo cardiovascular study, and other related toxicology studies where cardiovascular endpoints are evaluated. The ICH E14 provided clinical assessment of potential QTc prolongation. Nonclincial and available clinical safety information provide the basis of an integrated cardiovascular risk assessment of molecules. The focus of the ICH guideline has been centered around QT/QTc intervals and potential arrhythmia. Based on the available information, it is apparent that cardiovascular testing paradigm should include more than the hERG inhibition assay and evaluation of other ion channels should be considered along with the newer novel assays such as induced pluropotent-derived human stem cells for a more comprehensive cardiovascular evaluation. The screening of molecules during early discovery and development phases could be better utilized and optimized for cardiovascular evaluation. This session will introduce and review these in vitro assays and nonclinical in vivo evaluation. Current pharmaceutical and regulatory thinking process of cardiovascular evaluation will be discussed, including a proposal of modification/elimination of ICH guidelines S7B and E14. A case study of venoxerine that ties the preclinical to clinical cardiovascular testing will also be discussed.

Centrally Administered Compounds in Small and Large Species—Dose Routes, Study Considerations, and Data Interpretation

Chair: Sven Korte, Covance Laboratories GmbH
Co-Chair: Teresa L. Wright, Shire, Lexington, MA

Many diseases affecting the central nervous system (CNS) are inadequately treated by traditional systemic delivery methods, partly because of the inability to bypass the blood-brain barrier. Delivery of large molecules, cells, and other novel therapies directly to the nervous system via intrathecal injection and/or implanted catheters overcomes this obstacle and administers the treatments close to the target region. Clinical experience using direct CNS administration of compounds for pain relief and chemotherapy has grown over the past decades, suggesting the same technologies can be applied to the treatment of degenerative and inherited disorders. Administration of drugs directly into the CSF may involve some risk, including reaction of the spinal cord or brain tissue adjacent to the device. The preclinical studies used to evaluate the safety of CNS administered compounds must differentiate between the effects of the delivery method, the therapy, and the combination. Reliable, well-characterized animal models for CNS administration of test articles have been developed which enable nonclinical development of these potential therapeutics. This CE course will discuss the technical challenges of preclinical intrathecal studies, design of studies and nonclinical programs, evaluation of results, and considerations for special endpoints in the studies.

2:00 PM–5:00 PM

Cytokines: The Good, the Bad, and the Deadly

Chair: Thulasi Ramani, Huntingdon Life Sciences, Somerset, NJ
Co-Chair: Carol S. Auletta, Huntingdon Life Sciences
, East Millstone, NJ

Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. This symposium presents an overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be “good” when stimulating the immune system to fight a foreign pathogen or attack tumors. Other “good” cytokine effects include reduction of an immune response, for example Interferon beta reduction of neuron inflammation in patients with multiple sclerosis. They may be “bad” when their expression causes inflammatory diseases, such as the role of TNF-alpha in rheumatoid arthritis or asthma and Crohn’s disease. Therapeutic modulation of cytokine expression can help the “good” cytokines to generate or quench the immune system, and block the “bad” cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause “ugly” cytokine release, which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discusses lessons learned in cytokine toxicology using case studies and suggests future directions.

Differentiating Adverse from Adaptive Changes in Toxicology

Chair: Anthony L. Kiorpes, River Bluff Associates, LLC, Bloomington, MN
Co-Chair: Arun R. Pandiri, Experimental Pathology Laboratories, Inc., RTP, NC

An important question in the practice of toxicology is, “what is an adverse finding”? Central to what every toxicologist does is the interpretation of a large experimental data set to arrive at a no adverse effect level (NOAEL). In many cases, the difference between an adverse (pathological) finding from one that is adaptive (physiological) is not obvious. Specifically, this symposium will explore what are adverse findings and what differentiates them from normal physiological or adaptive changes from whole-animal, organ, molecular, and regulatory perspectives. The topic is timely as recent meetings, working groups, and papers have attempted to address this issue. The intended audience is the general toxicologist regardless of industry segment.

In Silico Methods for Mutagenicity Prediction vis a vis ICH M7 Guidance

Chair: Joel Bercu, Amgen, Inc., Thousand Oaks, CA
Co-Chair: Vijay K. Gombar, Eli Lilly and Co., Indianapolis, IN

The manufacture of the active pharmaceutical ingredient (API) of a drug involves a number of starting materials, reagents, and intermediates. Many of these chemicals could be potentially genotoxic and may end up as impurities in an API. It is the responsibility of the sponsor pharmaceutical company (Pharma) to identify, control, and assess risk posed by these potential genotoxic impurities (GTIs). Given that a GTI meets regulation on its limits, the ICH M7 draft guidance (Guidance) permits use of in silico approaches in contrast to experimental assessment of mutagenicity.

Now that more than two years have passed since the Guidance was issued, the present symposium seems timely and important to share and learn about (1) what are regulatory expectations around use of in silico methods, (2) which in silico methods Pharma companies are using, and why, for compliance, (3) what developments have since taken place by developers of in silico tools and methods, and most importantly (4) case studies on risk assessment by Pharmas highlighting their experience in the use of their chosen in silico methods. There could not be a more suitable forum than the ACT annual meeting, which brings together important stakeholders, for discussion and shared learning around these salient topics.

Wednesday, November 12

9:00 AM–12:00 Noon

Novel Therapeutics in Oncology: Recent Advances and Considerations for Nonclinical Safety Evaluation

Chair: Hadi Falahatpisheh, Pfizer, Pearl River, NY
Paul Moore, MacroGenics, Rockville, MD

In the early 1980s, monoclonal antibodies were considered to have the potential to revolutionize cancer therapy through selective and specific targeting of tumor-associated antigen-positive cells. However, this concept has met with limited clinical success in oncology at this stage.

These limitations led to the development of novel therapeutics such as antibody-drug conjugates, bispecific mAbs and cancer vaccines. ADCs combine the specificity of a mAb for a tumor-associated antigen with the potency of a novel generation cytotoxic agent and ensure selective tumor cell killing while reducing toxicity. Bispecific antibodies are designed to bind simultaneously to two different epitopes, such as a tumor antigen and a receptor on an immune effector cell with the objective to redirect effector cells to cancer cell killing. Therapeutic cancer vaccines take advantage of the individual's immune system to target tumor cells.

This symposium will review the recent advancements for these emerging modalities and will also highlight specific considerations and challenges associated with the nonclinical safety evaluation of these molecules.

Applied Nanotoxicology

Chair: Dave Hobson, LoneStar PharmTox LLC, Bergheim, TX
Co-Chair: Robin Guy, Robin Guy Consulting LLC, Lake Forest, IL

Nanomaterials, including nanoparticles and nanoobjects, are being incorporated into everyday products at an increasing rate. These products include consumer products of interest to toxicologists such as pharmaceuticals, cosmetics, food, food packaging, household products, etc. The manufacturing of products containing or utilizing nanomaterials in their composition may also present potential toxicologic concerns in the workplace. The molecular complexity and composition of these nanomaterials is ever increasing and the means and methods being applied to characterize and perform useful toxicologic assessments are rapidly advancing. This session will include presentations by experienced toxicologists in the nanotoxicology community that are focused on the applied aspect of the discipline toward supporting state of the art toxicologic assessments for food products and packaging, pharmaceuticals and medical devices, inhaled nanoparticle and gastrointestinal exposures and addressing occupational safety and health issues and concerns.

Stem Cells Research

Chair: Kathleen A. Funk, Experimental Pathology Laboratories, Inc., Sterling, VA
Co-Chair: Maralee McVean, Pre-Clinical Research Services, Inc., Fort Collins, CO

Stem cells have great potential in basic research and are being slowly integrated into toxicological research. This symposium will provide an overview of the state of the field, stem cell models, describe allogeneic stem cell treatments and issues of immunogenicity associated with protein therapeutics, and then concentrate on stems cell uses in regenerative medicine focusing on lung and testing strategies on engineered tissues from a pathologist’s’ perspective.

Safety Assessment Updates for Preventive Vaccines and Vaccine Adjuvants

Chair: David W. Clarke, Pfizer, Pearl River, NY
Jayanthi Wolf, Merck, West Point, PA

With the development of more refined vaccine antigens there has been a need to help boost the immune response through the addition of adjuvants into the formulation. The objective of this session is to review the rationale for the inclusion of adjuvants in a vaccine and some of the unique challenges that the inclusion of an adjuvant brings to the nonclinical evaluation of the final vaccine product. The session will include both the industry perspective on the nonclinical development of vaccines, but also the regulatory framework under which the work is conducted.

1:30 PM–4:30 PM

Hot Topics

Chair: Timothy J. McGovern, US FDA, Silver Spring, MD
Co-Chair: Melissa C. Rhodes, GlaxoSmithKline, Research Triangle Park, NC

(Hot Topics are subject to change)

  • FDA Tobacco/eCig Initiatives
    Michael Orr, US Food and Drug Administration

  • Update on Biosimiliars
    Barbara J. Mounho-Zamora, ToxStrategies Inc.

  • Animal Rights Extremists
    John Sancenito, INA Security

  • Update on FDA/CDER Guidances, Initiatives; ICH Activities
    Timothy J. McGovern, US Food and Drug Administration

  • PETA Questions the Value of AAALAC Accreditation—What Is Going on Here?
    David G. Serota, MPI Research

  • Update on Activities around the Ebola Outbreak
    Beth Leffel, Leffel Consulting Group

  • FDA Perspectives on Ebola Issues
    Christopher Ellis, US FDA/CDER