SUNDAY, SEPTEMBER 30
AM1: CiPA Components in Early Cardiovascular Safety Assessment
Implementation of the Comprehensive in vitro Proarrhythmia Assessment (CiPA) is the focus of a Monday afternoon session at this year's Safety Pharmacology Society meeting (see "CiPA Real Life Implementation"). This continuing education course will provide background on the technologies that form the foundation of CiPA, including; 1) Cardiac ion channel biology and standard in vitro techniques for examining the effects and consequences of drug-induced block, 2) A discussion and hands-on demonstration of in silico techniques for predicting cardiovascular ion channel effects, 3) The use of human stem cell-derived cardiomyocytes as an integrated biological system for examining the potential for mixed ion-channel effects, and 4) Interpretation of clinical ECG data for distinguishing selective hERG channel effects from mixed ion channel effects. Each of these topics will include translational examples and the course will wrap up with an open panel discussion where speakers and session co-chairs will field questions from course participants. Attendees will leave this course understanding the principles underlying each element of CiPA, practical knowledge of the advantages and limitations of each element, and the foundation necessary for critical evaluation and implementation of the new paradigm.
AM2: SENDing Safety Pharmacology into the Future
The deadline for submitting cardiovascular and respiratory data electronically using the Standard for Exchange of Nonclinical Data (SEND) is rapidly approaching. This course will focus on how the CDISC SEND v3.1 standard applies to vital core battery safety pharmacology data sets, specifically how to prepare and work with data sets, FDA's expectations about safety pharmacology data and the challenges frequently faced when implementing SEND in an organization. An interactive and practical exercise will be conducted for a typical study data set that will permit those who attend to follow progression of data derived from a study report to complete SEND format. In addition, an advanced data visualization and analysis capabilities presentation will be given to highlight the nonclinical study data in SEND format. Upon completing this course, you will have a better understanding of how SEND can be integrated into the conduct of safety pharmacology and related studies.
AM3: Diurnal/Circadian Rhythm and Female vs Male Preclinical Assessment in Drug Development
This course will focus on diurnal/circadian rhythm effects as well as sex effects in in vivo studies during preclinical drug development. The participant will learn about study design and data interpretation to address these two factors that can impact the overall risk:benefit assessment of a novel drug. Data will be presented that will address cardiovascular respiratory and even CNS interpretation and safety prediction. Each talk will include practical details of how to conduct evaluations as well as interpretation, and current knowledge of translation to the clinical use of new drugs.
How I Survived the Ever-Changing Landscape of Safety Pharmacology!
Join us for a panel discussion with several or your colleagues as we discuss the ever-changing landscape of Safety Pharmacology over the past 17+ years. How have those with various backgrounds ended up as contributing scientists in the Safety Pharmacology Society? How do you start with a background in toxicology, environmental sciences, clinical research, physiology, etc. and become an integral member of the Safety Pharmacology community? We will address various topics and encourage attendees to also share their stories including the benefits of receiving a DSP (as applicable). Some of these topics/questions include:
1. Describe your current responsibilities.
2. Do you do any drug evaluations or are the Safety Pharmacology studies contracted?
3. What training or experience helped you get this job?
4. What additional training would have been helpful?
5. What would the ideal Safety Pharmacology job look like?
6. How will you keep up with the business?
PM1: Advanced Topics in Safety Pharmacology: Clinical Translation Case Studies in Central Nervous System, Cardiovascular, and Respiratory
This course will cover a range of organ systems within safety pharmacology, with case studies demonstrating the translatability of preclinical models to clinical effects. We will have four presentations with case studies on myocardial infarction, retinal function, cardiac contractility/cardiomyopathy and respiratory safety findings, and a final interactive session to talk about any case studies the attendees may have to share from their experiences and discuss the predictive value of CNS effects.
PM2: Safety Assessment of Oligonucleotides and Gene therapy: The Success Stories and Set-Backs Over the Past 10 Years
This course will address the history and the advances made in oligonucleotide therapy gene including the preclinical requirements as well as translatability to clinical trials as surmised by Dr. Xuan Chi, from CDER, FDA. We will also address how oligo therapies are designed (e.g. targeting), determination of efficacy in the discovery stage, and safety in the IND-enabling preclinical studies. What have been the challenges and achievements that are brought oligonucleotides to the forefront in drug development. We will discuss the advancements and successes in gene therapy (“after the storm”) as well as begin the conversation of gene editing as a research tool and therapeutic method.
PM3: Advanced Central Nervous System Models: Issue Resolution and Clinical Translation
This course will focus on CNS assessment that is not included in the typical core evaluations but used for advanced issue resolution in safety pharmacology. The participant will learn about generation of data for evaluation of cognition, drug dependence, EEG variations across species, and the importance of age in evaluation. Each talk will include practical details of how to conduct evaluations, when to use the models for issue resolution in drug development, and current knowledge of translation to the clinical use of new drugs.
Evening Welcome Reception
MONDAY, OCTOBER 1
Exhibits and Posters Open
Title: Science=Solutions for the US Opioid Crisis
The current US opioid crisis is an intersecting and overlapping set of issues related to both licit (i.e. prescription opioids) and illicit (i.e. heroin and fentanyl-related synthetics) substances. In addition to the increasing numbers of deaths related to these drugs, multiple other indicators of harms from opioid use have been increasing: infectious disease outbreaks (e.g. Hepatitis C and HIV), neonatal opioid withdrawal, need for addiction treatment, and non-fatal overdoses. Opioids are the major cause of harm but interactions with benzodiazepines and some antidepressants are implicated in morbidity and mortality as well. While the problems are national in scope, different areas of the country have been impacted in distinct ways. Thus, efforts must be geared toward the specific issues facing particular communities (or regions). A notable issue is that prescription drug misuse can affect both patients to whom medications are dispensed as well as the broader network of persons interacting with these patients. The implication is that both patients and non-patients must be considered in developing policies and practices to address the opioid crisis. Key responses include primary prevention, reducing excess prescribing of opioids, saving lives acutely with naloxone, improved treatment of the underlying addiction, and research to inform prevention and treatment efforts. Fundamentally, prescription and illicit opioids are each elements of a larger epidemic of opioid-related disorders and death. Viewing them from a unified perspective is essential to improving public health. The perniciousness of these epidemics requires a multipronged interventional approach that engages all sectors of society.
Wilson Compton, MD, MPE
National Institute of Drug Abuse
National Institutes of Health
Rockville, MD, United States
Date: Monday, October 1, 2018
Track A (am) Secondary Pharmacology: From the Test Tube to the Clinic
Assessing the off-target pharmacology of a chemical series is a primary component in drug discovery safety strategies and comprises screening lead molecules against a broad range of targets (receptors, transporters, enzymes, and ion channels) that have a known linkage to a safety related event (Bowes et al). General prevalence of activity across a chemical series can be a useful warning flag for potential safety concerns, and identification of specific off-target liabilities can highlight areas for mitigation and influence on chemical design. As PK/PD modelling establishes a predicted dose and exposure for man, the importance of in vitro selectivity diminishes, and the quantitative relationship between exposure and off-target engagement becomes the focus for safety risk assessment. Understanding the quantitative translation of off-target in vitro pharmacology to preclinical and clinical effect is important to enable contextualization, risk assessment and mitigation planning for the patient. The session will look at the achievements and advancements in the application of secondary pharmacology to identify assess and mitigate off-target liabilities of molecules and reduce safety related drug attrition.
Track B (am) Next Generation Non-Opiate Pain Management
The focus of this session will be on the debilitating and overwhelming crisis in the public’s abuse of opiates. Shockingly, the rapid upswing in deaths due to opiate overdose has not plateaued but is altering pain treatment and the life expectancy demographics. Although opiates are exceptional drugs for reducing pain, their side-effects associated with respiratory depression, euphoria, and drug abuse have an integral role in the current epidemic. This session will provide information on current knowledge of opiate effects and begin the discussion on development of new drugs without opiate-like abuse potential. Identification of the desirable profile for more acceptable pain treatment will be the core discussion in the session.
Lunch Break, Poster Presentations, Exhibits
Track A (pm) Safety Pharmacology/FDA Discussion on the Gastrointestinal System
Drug-induced side effects on the gastrointestinal (GI) system are a relatively common occurrence which can have a significant impact. Particularly during clinical development, it can often lead to issues of poor toleration and in some cases drug attrition. Furthermore, these side effects can have an impact on adherence and compliance to therapies, as well as quality of life when the drug is on the market. From a nonclinical perspective, regulatory guidelines state that safety pharmacology studies on the GI system are considered supplemental and/or conducted when there is information about the compound (or drug target) which indicates a cause for concern regarding GI function. This session will provide background and overview of the GI system, various strategies, in vitro and in vivo tools for assessing GI function in a nonclinical setting, safety evaluation, hazard identification, risk mitigation from a regulatory perspective, and issues associated with adverse GI effects during clinical drug development, including nonclinical-clinical translation. Collectively, this information will enable the safety pharmacologist to identify and manage GI side effects to better provide predictive, integrated risk assessment during drug development.
Track B (pm) CiPA Real-Life Implementation
This is a critical year for CiPA-related activities and sharing the knowledge and experience of CiPA as extensively as possible among the safety pharmacology community. The CiPA Steering Group will update the community on the validation status of CiPA assays at a public meeting in the first half of 2018. The current version of the in silico model is already available to download and a series of publications describe its use. In 2018 interested groups will have the opportunity, after the protocols and validation data are known, to run the CiPA assays on proprietary and reference compounds gaining valuable experience with modern drug discovery molecules. This experience will be shared during this session.
TUESDAY, OCTOBER 2
Exhibits and Posters Open
Title: The Promise and Perils of Heart Failure Gene Therapy
Gene therapy trials for many diseases have recently been progressing and that includes trials for heart failure. Existing trials and planned trials use adenovirus as well as adeno-associated vectors (AAVs). Several targets appear valid but several hurdles exist including efficient myocardial delivery and immune-reactivity concerns. Although AAVs are considered less inflammatory they still can elicit responses and pre-existing antibodies can also limit effective gene delivery to the target organ. This lecture will discuss therapeutic advances for heart failure gene therapy and continued safety issues with both vectors and transgenes.
Walter Koch, PhD
Temple University Lewis Katz School of Medicine
Philadelphia, PA, United States
Date: Tuesday, October 2, 2018
Track A (am) Cardio-Oncology
Safety pharmacology has traditionally focused on the potential effects on the cardiovascular and other systems in patients or volunteers taking their first dose of the compound. Cardio-Oncology side effects are now recognized as an important consideration during selection of therapies for cancer patients as they impact a number of functional cardiac endpoints. However, realization and incorporation of these side effects into standard safety packages presents a unique challenge as the phenotypic manifestation of cardiac side effects in the treated population can be delayed (sometimes for years) after the conclusion of treatment. However, safety pharmacology often has unique expertise in assessing cardiac function in preclinical studies across a variety of models. Studies and paradigms that look beyond the first dose and provide data that can be translated to the clinic will be a requirement for supporting future oncology projects. To that end, this session will cover aspects of the cardio-oncology field that extend the traditional objectives of safety pharmacology assessment.
Track B (am) Central Nervous System and Sensory Assessments: Established and Emerging Nonclinical Drug Safety Testing Strategies
Undesired central nervous system (CNS)-related effects of medications contribute to a substantial amount of attrition in Phase II and III studies. While CNS and sensory adverse effects are prevalent with oncology and neurology drug candidates, the predictive value of preclinical models remains a challenge. This session will investigate the issues and methods that can be employed to better predict this class of effects going forward. For example, cognitive impairment can occur following administration of any agent with brain penetration. Addressing this becomes difficult when considering the complexity of cognition: attention, memory (and its various sub-types), sensation, perception, executive function, etc. While preclinical and clinical methods exist to address each of these facets of cognition, prioritization of which to employ becomes important. Other areas of unmet need include ocular toxicity, which is often noted at ophthalmology examination or histopathologically whereas ocular function is only rarely measured preclinically. Finally, neuropathies are increasingly being noted in clinic with novel oncology, immunology, and pain therapies. The predictive and translational value of established and emerging non-clinical CNS and sensory testing methods will be discussed.
Lunch Break, Poster Presentations, Exhibits
Track A (pm) Advanced Imaging Techniques in Preclinical Safety
This session will explore advanced imaging techniques used in preclinical safety studies. Our goal is to present real-world case studies where imaging has been used for advanced issue resolution in the drug safety and development process. We hope to expand our focus beyond the cardiovascular sector, including aspects of central nervous system (CNS) imaging, receptor occupancy, and drug distribution using non-standard techniques, such as magnetic resonance imaging (MRI), fluorescence, and positron emission tomography (PET). Further, this session will include a regulatory component addressing the issues and concerns with incorporating this data into investigational new drug submissions.
Track B (pm) In Silico Approaches
In recent years in silico modelling has become a mainstream part of safety pharmacology, and we have heard much about its role in cardiac safety and the CiPA initiative. In this session, the wider applications of mathematical modelling, machine learning, and bioinformatics approaches to other areas of interest to safety pharmacologists will be discussed. This series of talks will focus on different techniques and application areas including the central nervous system (CNS) and developmental toxicology. The session will also include a FDA CDRH Reviewer perspective on the role of in silico approaches to support regulatory decision making on medical device evaluation, an area where modeling and simulation is often used to support regulatory submissions..
WEDNESDAY, OCTOBER 3
Annual Members’ Meeting and Awards Ceremony
SPS Distinguished Service Award Presentation
Plenary Session: From Bench to Bedside—Translational Clinical Pharmacology Designs
The focus of this session will be on the use of secondary pharmacology and preclinical studies to impact clinical trial interpretation and design. While lead-optimization strategies have historically influenced the design of potential clinical drug candidates, there has been a recent emphasis to conduct more translative assays to predict potential adverse events in humans. The advent of stem cell-derived tissues including organs-on-chips, advances in mathematical modeling and greater emphasis on concentration-response analysis in the clinic have modernized the paradigm for drug development. The session will provide information on current knowledge of clinical trial design, the use of preclinical data to augment endpoints and biomarkers and the future of clinical safety trials.
Plenary Session: Interactive Case Studies
Pharmaceutical products typically undergo a variety of preclinical evaluations prior to use in clinical settings to help ensure the safety of patients. These evaluations allow the assessment of various types of hazards via in vitro and in vivo assays. As part of this assessment, scientists determine the clinical relevance of the hazards identified. Findings on clinically relevant hazards inform scientists when estimating safe clinical exposures and recommending adequate clinical safety monitoring and inclusion/exclusion criteria. The cases presented in this session provide insights on determining clinically relevant hazards across multiple physiological systems (i.e., central nervous system, gastrointestinal system, and cardiovascular system), as well as approaches to managing these toxicities in clinical settings.