Monday, September 23
AM1: Variability, Uncertainty and Probability in Safety Pharmacology Decision Making
In nonclinical safety assessment, including safety pharmacology, making decisions on the progression of compounds or on appropriate risk management is a key part of the role. Published data suggest that many of the safety-related failures in drug development are due to a breakdown in the decision-making and data integration process rather than an absence of critical safety data. The related topics of variability, uncertainty, and probability all play a role in that decision-making process. This course will illustrate how to deal with variability and uncertainty in decision-making. It will also provide a more quantitative framework for integrated or weight-of-evidence assessments to improve decision-making and communication. Specific examples of using a Bayesian assessment framework in assessing cardiovascular safety pharmacology will be presented. In addition, an example of how the data across a nonclinical safety package could be used quantitatively will be presented.
AM2: Advanced therapy medicinal products (ATMPs); Real World Approaches and Safety Concerns
As the Therapeutic universe continues to expand beyond small molecule approaches, Toxicologists and Safety Pharmacologists are faced with assessing the safety of cutting edge therapeutic approaches. The topics in this course will cover the development of advanced therapy medicinal products (ATMPs), their safety concerns, and Regulatory expectations. Specifically, material will cover stem cell based cardiac regeneration, ATMP approaches for Parkinson’s Disease, CAR-T, and Regulatory perspective(s). Course participants will leave with an understanding of the science underlying these approaches as well as potential safety concerns and mitigation strategies.
This Course is organized jointly by the Safety Pharmacology Society (SPS) and the German Society of Pharmacology (DGP).
AM3: Insights on Secondary Pharmacology in Drug Development
Secondary pharmacology has gained increasing attention and scrutiny by both the scientific community and regulatory agencies over the last few years. Although not part of the safety pharmacology per se, this is an important discipline aiming at identifying off-target liabilities of new chemical entities. The course will cover the following aspects:
- An overview of secondary pharmacology screening strategies applied by the pharmaceutical industry,
- Considerations when designing secondary pharmacology profiling (types of assays with pros and cons, panels of targets, hit rates and go/no go criteria, issues with translations, etc.),
- Computational tools to predict off-target liabilities
Time has been allocated to work in small groups on different real-life case studies directed by experts in which off-target safety issues were encountered.
Introduction and Overview to the Field of Safety Pharmacology
This course will offer an overview to the field of safety pharmacology in a relaxed, fun and interactive environment. The content of the course will be designed to introduce the participants to the history of the field and the regulatory guidelines that impact the safety pharmacologist. Additionally, strategies and basic study designs for the commonly employed assays that meet the current regulatory expectations will be reviewed from both a small molecule and large molecule perspective. This course is especially recommended to new attendees to the Safety Pharmacology Society Annual Meeting, less experienced scientists in the field of safety pharmacology and scientists in allied disciplines of drug development. More experienced safety pharmacologists may also find this a great refresher and networking environment.
PM1: Current Topics in Central Nervous System Assessment
It’s not just the Functional Observational Battery (FOB) and convulsions any more, central nervous system (CNS) safety pharmacology is a rapidly expanding area of concern and research. This need for more CNS de-risking capabilities has been brought about by the pharmaceutical and biotech industries’ growing focus on pain, abuse liability, psychological disorders, and rare diseases. This course will present a range of CNS assessments that go beyond the traditional core battery. Using case studies and experts in the fields, a variety of topics will be discussed including theories of addiction, translation of nonclinical models of pain, early de-risking, and the importance of drug-induced sleep/circadian disruption. Time will be allotted for interactive discussion of each topic.
PM2: Cardiovascular Translation from Animals to Man
You may believe you have a solid understanding of the translation of key safety pharmacology cardiovascular effects from animals to man. This is after all a topic which has been addressed before. New techniques and the application of rigorous comparison continue to shed light in this important aspect of safety pharmacology. This course will start with a consideration of what might be best practice in performing translation analysis and may challenge some of our established beliefs about the translation. This will be further explored by a consideration of examples more broadly than cardiovascular but illustrating how to effectively deal with areas where animals are known to be different from man and further focusing the need to make ‘apples to apples’ comparisons. Cardiovascular hemodynamics translation from small to large animal and large animal to man will be presented to cover the range of cardiovascular evaluations from early rodent studies to GLP safety pharmacology studies. The use of concentration-effect modeling which has been key in replacing the need for standalone TQT studies, and in silico prediction, will be presented to illustrate their utility in translation and prediction of effects in man.
PM3: Safety Assessment of New Therapeutic Modalities
Novel non-NCE therapeutic modalities represent an increasing part of the therapeutic tools, in oncology and immunology areas. Safety assessment programs should be adapted to enable the safe development of these novel modalities. The course intends to cover the safety pharmacology and toxicology assessment for New Biological Entities (NBEs), oligonucleotides, gene or cell therapies, protein-protein interactions (PPIs) and/or protein degradation products, with practical examples whenever possible.
Evening Welcome Reception
Tuesday, September 24
Exhibits and Posters Open
Title: The Utility of Human Stem Cell Models of Nervous System Disorders: Progress and Clinical Proof of Concept
Since the first derivation of patient specific induced pluripotent stem cells (iPSCs) more than 10 years ago, impressive progress has been made in developing their utility as a preclinical model system for drug discovery research. Dr. Eggan will share insights into the development of robust and reproducible model systems for the study of several nervous system disorders and deployed them in discovery research. This will include discussion of successful clinical results from a phase 2a clinical trial in ALS with a candidate therapeutic nominated by preclinical work using iPSC-derived neurons.
Kevin Eggan, PhD
Harvard Stem Cell Institute
Department of Stem Cell and Regenerative Biology
Cambridge, Massachusetts, United States
Date: Tuesday, September 24, 2019
Track A (morning) Emerging In Vitro Models and Their Application in Safety
The pharmaceutical industry is under pressure to introduce novel therapies at a faster rate and lower cost. One way to achieve this could be the implementation of in vitro models with greater predictivity to detect safety issues early in the pipeline. Indeed, introducing human biology early in the in the discovery process ensuring suitable efficacy and safety could potentially reduce late stage attrition.
Over the years, a number of predictive in vitro models for drug safety have been developed to address safety risks. In this session, we will introduce emerging innovative in vitro models for cardiac, neuro, vascular, hepato, and respiratory safety testing, discuss their translational value and how they could be implemented in the drug safety assessment strategy to facilitate decision making in compound selection.
Track B (morning) Hot Topics in Central Nervous System
As the central nervous system (CNS) is a complex organ and for which most of the readouts are indirect, CNS assessments are one of the most complicated evaluations done in safety pharmacology. In this session the following emerging topics in CNS safety assessment are presented: What is the most sensitive species for seizure assessment, what are upcoming methods for monitoring general behavioral change, best practices for the assessment of pain, and recent updates from the recent Cross Company Abuse Liability Council (CCALC) meeting on Advancements and Challenges in Abuse Potential Evaluation.
Lunch Break, Poster Presentations, Exhibits
Track A (afternoon) Can Safety Pharmacology Studies Support the Assessment of Immune-Related Adverse Events?
The nonclinical safety pharmacology testing of both biological and new chemical entities is designed to identify potential undesirable pharmacologic activity in appropriate animal models. These studies aim to evaluate functional effects on vital core battery systems and characterize the profile and severity of adverse events likely to develop in humans. The use of complementary in vitro and in vivo assays should be optimized as species differences may complicate study design and data interpretation. Preclinical testing concerns involving novel drugs, particularly biologicals, include their immunogenicity, tissue cross-reactivity, and effector function. This symposium will overview the applicability of safety pharmacology methods in the development of drugs with a risk for onset of acute immune-mediated drug reactions. Topics include an overview of the immune system and adverse events that can develop during development, acute organ system effects of immunostimulation, cytokine assays and associated functional assessment and translation of acute immunotoxicology findings to the clinic. This symposium will provide rationale regarding study designs and approaches taken if drug-related immune system effects develop and how application of safety pharmacology studies can assist based on individual drug properties and intended use in the clinic.
Track B (afternoon) Thoughts on Translation
A major objective within safety pharmacology as a discipline and a Society is to aid in the development and safe medical use of biologically active molecular entities. As such, it is vitally important that we develop and implement nonclinical assays or tools that are highly predictive for the presence and/or absence of clinical outcomes e.g. cardiovascular and neurological effects. As such, we strive to understand the translation between nonclinical results and clinical findings, and we also attempt to characterize or define the translation between nonclinical in vitro data and in vivo results. In this session we will expand on the concepts of translation to include a range of diverse topics such as: 1) the use of disease models, 2) the utility of imaging techniques in cardio-oncology, 3) safety-related compound attrition, and 4) proteomics/genomics (or precision medicine) that are relevant to safety pharmacology in our quest to support drug discovery and development.
Wednesday, September 25
Exhibits and Posters Open
Title: Leveraging the In Silico World of Data to Identify Personalized Medicine Approaches for Novel Drug Targets
Michael Burczynski, PhD
University of Pennsylvania
Perelman School of Medicine
Philadelphia, Pennsylvania, United States
Date: Wednesday, September 25, 2019
Track A (morning) How Clinicians and Clinical Pharmacologists View Safety Pharmacology Data
The main objective of the safety pharmacology studies during preclinical development is to ensure safety of clinical trial participants participating in Phase I studies and beyond. Often these early clinical studies can also include adaptive designs with patients included for efficacy, and so safety pharmacology studies may be the only comprehensive systems safety assessment data conducted prior to this exposure. Thus, the additional value of these preclinical studies includes translational insight into safety of not only healthy normal volunteers but also patients with a variety of health impairments, making them significantly more vulnerable. The use of this data spans the range from protocol design to feasibility assessments at the facilities entrusted to execute the clinical trial. During the drug development translation from preclinical into human subjects and patients, this presentation will evaluate the use of such safety pharmacological data:
- How do clinicians and clinical pharmacologists use these preclinical results?
- Which results are most useful in the design of First in Human (FIH) and early patient study protocols?
- How do the results from safety pharmacology studies inform the protocol endpoints and medical monitoring of studies?
- What improvements in these studies could be made to make them more useful?
During this session, these questions will be discussed for seizures, cardiovascular/contractility, gastro-intestinal disorders as well as for biomarkers bench-to-bedside translation.
Track B (morning) Recent Trends in High Performance Computing for Safety Pharmacology
Lunch Break, Poster Presentations, Exhibits
Track A (afternoon) What Do Biomarkers Mark? A Safety Pharmacology Perspective
This session will focus on providing an overview of the current state of biomarkers across a variety of safety related disciplines (i.e. cardiovascular, renal, and CNS), with the intention of capturing how these biomarkers could potentially be integrated into safety pharmacology and toxicology studies. Further, this session will explore new technologies or methodologies used to identify new biomarkers across disciplines.
Track B (afternoon) Impact of Early Safety Pharmacology Derisking Strategies and Technique
The integration of safety pharmacology assessments early in drug discovery programs can significantly impact the design, selection, and progression of compounds and the viability of pharmacological targets for new medicines to help avoid undesired safety concerns later in development. Covering both central nervous system and cardiovascular topics, this session will provide examples of in vitro and in vivo safety pharmacology studies or screening assays that can influence decision making prior to candidate selection and/or the conduct of first-in-human (FIH)-enabling safety studies. Speakers will discuss the rationale, timing, and overall strategies used for incorporating the various assays and whether any work has been conducted to demonstrate whether these assays predict related effects either in animals or humans. Potentially novel or underused techniques that could be incorporated as early derisking strategies may also be presented.
Thursday, September 26
Annual Members’ Meeting and Awards Ceremony
SPS Distinguished Service Award Presentation
Strategies for Getting to FIH and Beyond Efficiently and Safely
It has been nearly 20 years since ICH S7A added safety pharmacology evaluations to help protect volunteers in Phase 1 studies. During that time, safety pharmacology has evolved from an “outsider” to an integral part of early drug development and beyond. A broad range of strategies are used to advance candidate compounds through safety pharmacology studies and new ways to evaluate data and its role in supporting the Phase 1 trial. In addition to reviewing these topics, this session will offer a chance to discuss the role of safety pharmacology studies in impacting drug development with regulators from PMDA, EMA, and FDA along with representatives from large and small companies, CROs and consultants. This session offers a chance to appreciate how far we have come and how we can continue to make an impact in the years to come.
Revisiting ICH S7A and S7B
Safety pharmacology assessments span the drug development pipeline from early investigative screening studies to mitigation of clinical adverse effects. Whilst any in silico, in vitro, or in vivo model may be utilized where appropriate, a major proportion of the work revolves around the studies outlined within ICH S7A and S7B guidelines for first-in-human regulatory submission. These guidelines are 19 and 14 years old respectively The availability of new and evolving technologies, as well as a wish to streamline packages and animal use, has led to many organizations successfully implementing fit-for-purpose testing approaches (for small molecules, biologics and new modalities) which complement the established studies outlined within ICHS7A/B. The aim of this session is to initiate discussions into guideline revisions in the future, to ensure continuation of their relevance for the current industry and protection of human volunteers and patients, by introducing additional flexibility for tailored-approaches. The session will begin with an overview of informative data compiled from survey results and opinions from the SPS membership. We will also discuss how this should be collected (as per current stand-alone studies, within other studies or via non-animal methods). The ‘core-battery’ systems will each be addressed, discussing the translation of respiratory effects, CNS assessments within and beyond the FOB/Irwin multiparameter screen, and changes to cardiovascular requirements following the CiPA initiative.
President’s Summary/Meeting adjourned