Symposia sessions are three hours each and are held Monday through Wednesday.

Monday, November 6, 2017

9:00 AM–12:00 Noon

Session Chairs: Thomas J. Steinbach, Experimental Pathology Laboratories, Inc., Research Triangle Park, NC; and Umesh Shanghvi, Sun Pharmaceutical Industries Ltd, Mumbai, India

In the hands of an experienced pathologist, the traditional microscope has been established as the best practice for diagnosis of cancer and other diseases for over a century. Major advances in the capabilities of digital imaging hardware and software now allow pathologists the possibility of moving to a new level of practice, using whole slide digital images for diagnosis, education, and research in morphologic pathology. Digital images can be used to make primary diagnoses and for consultation, telepathology and quality assurance, archiving and sharing, education and conferencing, image analysis, research and publications, and marketing and business purposes. Adoption of digital pathology has been hindered not only by cost and technical factors, but also largely by the mindset of technophobic pathologists and the acceptance by regulatory authorities. Potential efficiencies in work flow and diagnostic integration, coupled with the use of powerful new analytic methods, promise to radically change the future shape of toxicologic pathology.

Session Chairs: Jennifer L. Ingram-Ross, Janssen R&D, Raritan, NJ; and Mark Kao, Janssen R&D, Raritan, NJ

In addition to the challenges faced in the drug development for common diseases, drug development for rare diseases encounters numerous unique issues, such as lack of natural history data for the disease, small size in patient population, early onset of a disease in children, and limited resources and findings. Despite these challenges, efforts from pharmaceutical scientists, medical doctors, basic researchers, patient advocate groups, and regulatory agencies have made a great impact on the progress of drug development for rare and neglected diseases. The first presentation will provide an update on the National Center for Advancing Translational Sciences (NCATS) Therapeutics for Rare and Neglected Diseases (TRND) program. The next two presentations will focus on nonclinical case studies, giant axonal neuropathy (GAN) and Niemann-Pick disease type C (NPC), which include nontraditional novel approaches, such as parent involvement, in developing treatment programs and initiating INDs. The final talk will review regulatory pathways for rare and neglected diseases and will highlight recommendations in the 2015 Draft Rare Disease Guidance, expanded patient access, and patient-directed INDs.

Session Chairs: Patricia C. Ryan, MedImmune, Inc., Gaithersburg, MD; and Russette Lyons, Novartis, Cambridge, MA

The concept of this symposium is to highlight unique approaches required for advancing viral vectors as novel therapeutic modalities into the clinic. This session will cover therapeutic viral vectors, including both nonreplicating viral vectors and selectively replicating oncolytic viruses. The overall focus will be on regulatory pharm/tox preclinical considerations as well as translational safety. The first speaker will give the CBER perspective on preclinical considerations for development of viral vector gene therapy products and set the stage for future case examples to be presented. Each case example will cover some basic background and the unique pharm/tox aspects, regulatory pathway to clinical development, and lessons learned. The four cases include AAV gene transfer programs, adenoviral vector in development for hearing loss, two cases of selectively replicating oncolytic viruses, one in preclinical development; and FDA-approved melanoma treatment. These types of products are rapidly advancing in the R&D pipeline of a number of pharma companies, and it is timely to offer an in- depth and comprehensive review of these unique products.

2:00 PM–5:00 PM

Session Chairs: Matthew Holdren, Genentech, South San Francisco, CA; and Jennifer Sasaki, Genentech, South San Francisco, CA

Although technological advances continue to improve our ability to synthesize novel active pharmaceutical drugs, our ability to fully purify these drugs remains a challenge. Because of the presence of potential impurities, guidance documents such as ICH Q3A (Impurities in New Drug Substances) were implemented to specify limits for individual impurities. Additionally, the recently adopted ICH M7 (Assessment and Control of DNA Reactive [Mutagenic] Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk) guidance provides phase appropriate limits and strategies for assessing the potential mutagenicity of compounds. Taken together, these guidance documents provide an outline for assessing the potential mutagenicity and provide limits to ensure the safety of potential impurities. This session will review the strategies outlined in ICH M7, with a specific focus on the use of expert chemical reasoning to supplement in-silico assessments from both Regulatory and Industry perspectives and discuss the ongoing effort by the IQ DruSafe working group to evaluate the implementation of ICH M7. Lastly, case studies applying the principles outlined in ICH Q3A and M7 to conjugated biopharmaceuticals will be presented.

Session Chairs: Norman Kim, Roivant Sciences, Westford, MA; and Paul Baldrick, Covance Laboratories Limited, North Yorkshire, UK

Given the uncertainty of safety for new investigational medicines in humans, mitigating potential risks is paramount. In the absence of human data, nonclinical studies provide a basis for safety information and to extrapolate the starting dose in the first in human (FIH) study. Based on the nonclinical safety information required to support the initial clinical study, a potential safe starting dose and exposure in humans can be extrapolated in consideration of available toxicology, pharmacology and pharmacokinetic information. Occasionally, uncertainties in human doses have led to tragedies of marked adverse events and serious consequences. Classic examples included TGN1412 (Tegenero) and recently BIA10-2474 (Bial); both have led to a major modification in regulatory guidance documents from Europe. US FDA provides guidance on estimating the maximum recommended starting dose in the FIH studies (2005). EMA’s CHMP provides guidance on strategies to mitigate potential risks for FIH studies (2007 and 2016). Unforeseen incidences during the FIH trials have highlighted the need for clear thinking around what information may be needed and how best to select starting dose levels in clinical testing. This session will examine current and proposed processes in minimizing potential risks in FIH trials from the US, EU and Japan.

Session Chairs: Thulasi Ramani, Envigo, Somerset, NJ; and Patricia C. Ryan, MedImmune, Inc., Gaithersburg, MD

The objective of the session is to highlight novel methodologies, or investigative topics, in toxicology presented by early career professionals. The range of topics will be quite broad and will center around PharmTox aspects common to pharmaceutical development of small or large molecules, or specialty biologics.

Tuesday, November 7, 2017

9:00 AM–12:00 Noon

Session Chairs: Gary R. Burleson, Burleson Research Technologies, Inc., Morrisville, NC; and Kristina E. Howard, US FDA/CDER, Silver Spring, MD

This session will introduce the role that immune system responses can play in the development of hepatic injury/toxicity or immunity. This series of presentations will introduce the components of the immune system present in the liver followed by the impact of viral and bacterial infections on the liver. Specific types of hepatic toxicity mediated by the immune system will be presented.

Session Chairs: Joshua Bartoe, MPI Research, Mattawan, MI; and Dave Serota, Seventh Inning Stretch Consulting, LLC, Kalamazoo, MI

Three of the top four leading causes of blindness in developed nation—diabetic retinopathy, glaucoma, and age-related macular degeneration—persist without definitive cure. The prevalence of each of these diseases is projected to double, causing an increase in government, patient, and private insurer expenses by 376% in the United States over the next 30 years. The first commercially available ocular gene therapy product for a rare genetic disorder, Leber congenital amaurosis, will be approved for marketing in 2017. A myriad of sustained release technologies and routes for established ocular therapies are also becoming successful ocular products. Small biotechnology firms to large pharmaceutics companies are aggressively investing resources into developing the next line of molecules to combat ophthalmic diseases. It is an exciting time to be an ocular toxicologist! This session is designed to inform toxicologists, at all levels of experience, on critical considerations when designing today's cutting-edge preclinical safety studies for ocular-targeted test articles.

Session Chairs: Francis Wolenski, Takeda Pharmaceuticals, Cambridge, MA; and Rob Stachlewitz, Charles River, Reno, NV

This session will provide case examples of issues that may arise for early career toxicologists. Six early career professionals from across a variety of fields (industry, contract lab, regulatory, and academia) will state the issue they experienced, how they responded, and how the situation was resolved (either positively or not). After each speaker, a small panel of preeminent toxicologists (Ilona Bebenek, Denis Roy, and Rob Stachlewitz) will provide their perspectives about alternative approaches. Two question and answer sessions will give the audience an opportunity to comment and share their experiences. This format is designed to promote an interactive discussion between speakers, panelists, and the audience.

2:00 PM–5:00 PM

Session Chairs: Nicola Stagg, Genentech, South San Francisco, CA; and Hanan Ghantous, US FDA/CDER, Silver Spring, MD

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases when there is a lack of translatability/predictivity that lead to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. The objective of this session is to better understand safety findings that are translatable versus safety findings that are not and why. Case examples on anti-drug antibodies, drug-induced liver injury, bone marrow toxicity and peripheral neuropathy will be highlighted. The outcome of this session on is to better inform the future of nonclinical safety assessments for field pharmaceutical drug development.

Session Chairs: Ilona Bebenek, US FDA/CDER, Silver Spring, MD; and Timothy Hart, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA

Epigenetic modifiers affect cellular processes by modulating gene expression. This session will review the concepts of epigenetic control mechanisms and how these are being targeted for therapeutic benefit. While manipulation of these targets has the potential for controlling or modifying devastating disease processes, it may also lead to unintended effects, such as physiologic alterations, neoplasms, or transgenerational effects. Because of these potential adverse effects, many of the drugs targeting epigenetic modifiers are being initially investigated in cancer patients with few therapeutic options. While they are effective anti-cancer agents, histone deacetylase (HDAC) inhibitors can cause alterations in cardiac electrophysiology in animals and humans. Results of mechanistic evaluations for these changes will be reviewed. The nonclinical toxicity assessment of some of the newer epigenetic targeting agents, such as those targeting EZH2, BET, LSD1, and PRMT, will be reviewed along with early clinical activity. Finally, as pharmaceutical agents targeting novel pathways move from the bench to the clinic, regulatory review and perspective of nonclinical toxicology results supporting their progression will continue to evolve as more agents targeting the epigenome enter drug development.

Session Chairs: Florence G. Burleson, Burleson Research Technologies, Inc., Morrisville, NC; and Sean M. Jeffrey, University of Connecticut, Storrs, CT

With declining birth rates and increasing lifespan, seniors are a rapidly growing segment of the population. They represent about 13% of the population, yet consume 40% of prescription drugs and 35% of over-the-counter drugs. It is projected that the proportion of older adults in developing countries is also expected to increase, and that the proportion of individuals over the age of 60 will reach 22%. Even in the absence of disease, there are age-related changes in organs that result in pharmacokinetics and pharmacodynamics changes, and decreases in immunity. Polypharmacy, common in older adults, further increases drug-drug and drug-disease interactions, can contribute to adverse drug events, and is associated with functional status decline and increased morbidity and mortality. One in six hospital admissions in older adults is due to an adverse drug event, and three-fourths of these hospitalizations are due to adverse drug reactions. Given the significant use of drugs in older adults and ongoing exposures to environmental toxicants, a better understanding of these age-related changes and their impact on this sensitive population is timely and should be of broad interest to the various sectors of the ACT membership.

Wednesday, November 8, 2017

9:00 AM–12:00 Noon

Session Chairs: Mike Moore, AZ-Pharma Consulting LLC, Phoenix, AZ; and Alan Hoberman, Charles River, Horsham, PA

Development of pharmaceuticals for pediatric indications presents unique challenges. Documented safe doses for adults can not be simply extrapolated to children based solely on body weight. Data from nonclinical studies in mature animals and clinical data in adults can provide an initial safety assessment for pediatrics including conduct of a pediatric clinical trial. However, often safety effects can not be adequately or ethically assessed in pediatric clinical trials, necessitating the conduct of toxicity studies using juvenile animals. Factors unique to design of a juvenile animal study (JAS) include species and age-related organ and metabolic development, PK/ADME, pharmacology, and practical considerations such as dosing formulation, limitations for administration route and biological sample collection, as well as litter effects, unique husbandry requirements, etc. Additionally, regulatory agencies differ as to the timing of JAS to support a pediatric study. Session presentations include industry and regulatory agency assessments of JAS data bases as to lessons learned and optimal study designs, global harmonization efforts regarding the timing and conduct of JAS studies for pediactric drug development, and unique study design aspects and considerations for each of the three most common laboratory animal species used in juvenile animals studies.

Session Chairs: Jorg Blumel, Genentech, South San Francisco, CA; and Rodney Prell, Genentech, South San Francisco, CA

The field of cancer immunotherapy around checkpoint inhibitors targeting the PD-1/PD-L1 pathway has made tremendous progress in recent years and changed the paradigm of cancer therapy. More recently, the attention has shifted toward exploring the potential of various other pathways involved in regulating cancer immunity beyond checkpoint inhibition as potential targets for therapeutic intervention. A diverse portfolio of novel modalities employing various modes of action is currently considered for development. These modalities include biotherapeutics targeting less explored immune regulatory pathways like DLL-1, T-cell redirecting bi-specific antibodies, soluble T cell receptors targeting intracellular antigens presented by major histocompatibility complex I, adoptive T-cell therapy with chimeric antigen receptor expressing T cells (CAR-T cells), or personalized therapeutic cancer vaccines. In contrast to the established checkpoint inhibitors, which have a very consistent safety profile, these highly innovative approaches possess very unique toxicities and multiple challenges for nonclinical and clinical development. These challenges include but are not limited to severe dose-limiting acute toxicities or lack of relevant animal species. The session will introduce these novel approaches and review current nonclinical data, highlight their unique safety profiles and challenges in nonclinical safety assessment, and discuss the translational relevance and challenges using recent case examples.

Session Chairs: Jennifer Burkey, Critical Path Institute, Tucson, AZ; and Dina Andrews, Amgen, Inc, Thousand Oaks, CA

The Critical Path Institute's Predictive Safety Testing Consortium (PSTC) formed the Pancreas Injury Working Group (PIWG) to develop translational biomarkers of drug-induced pancreatic injury (DIPI) and propose them for formal regulatory qualification. The team has conducted thorough literature reviews and data sharing exercises to prioritize types of pancreatic injury where translational biomarkers are most critically needed, as well as created a list of candidate biomarkers. This session will focus on the issues of drug-induced nonclinical and clinical drug-induced pancreatic injury, including comparisons and distinctions between the two. Discussion will include review of the drugs and drug classes associated with DIPI, purported mechanisms, useful animal models, and ongoing PSTC work and successes toward development of predictive, diagnostic, and monitoring translational DIPI biomarkers. Topics will center on exocrine pancreas injury, with some discussion of endocrine/islet-specific DIPI cases as well. The session will bring together safety researchers from the pharmaceutical industry and government, and participants will have the chance to join in discussion of practices and experiences in a noncompetitive information session.

1:30 PM–4:30 PM

Session Chairs: Tim McGovern, US FDA/CDER/OND; and Melissa Rhodes, Roivant Sciences, Raleigh, NC

  • What Is New in the Final US FDA Guidance on the Abuse Potential of Drugs
  • Health Effects from Wildfire Smoke: Epidemiology and a Case Study from a Large San Diego Wildfire
  • CAR T-Cell Products
  • Update on ICH S1 Activities: Challenges in Predicting the Carcinogenic Potential of Human Pharmaceuticals
  • Bia 10-0274: Overview on Preclinical Toxicology

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