Educational Co-Support Provided by: Charles River and American College of Toxicology
Our understanding of basic embryology is fundamental in the development of New Approach Methods (NAMs) intended to be used to identify and assess the hazard and risk of exposing pregnant women to a new drug/chemical/gene therapy. This symposium will focus on cutting edge technologies in NAM-based evaluation and predictive biology underlying drug/chemical induced neural tube defects (NTDs). The topics covered start with the basic cell biology of neurulation and pathophysiology of drug/chemical effects and will be followed by presentations covering synthetic reconstruction of the neural tube in an in vitro microsystems that utilizes human pluripotent stem cells and bioengineering; bioengineered in vitro platform as an off-the-shelf assay scalable to high throughput screening of various molecular libraries; in silico systems model for dynamical reconstruction of complex genetic networks underlying neurulation; and pathways to regulatory acceptance of NAMs. The development of the neural tube involves a complex of dynamic cell signaling and mechanical forces. Understanding these complex interactions is integral in the developing any generalized model to predict how a drug/chemical/gene therapy might cause disruption of cell function leading to an adverse outcome. The generalized models that translate our knowledge of a biological process allow for screening/prioritization of new drug/chemical and will lead to regulatory approval of NAMs that will replace animal testing for in case neurodevelopmental defects. The invited speakers represent academia, government, industry, and cover a wide geographical perspective. Their presentations will be followed by a moderated roundtable discussion with the panelists and session attendees.
Targeted protein degraders (TPDs) are rapidly evolving classes of drugs with great promise to address difficult drug targets in oncologic and non-oncologic disease. However, there is limited scientific consensus on the application of rigorous, consistent, and effective methods for assessment of their clinical safety. TPDs - including molecular glues and heterobifunctional degraders – use endogenous protein degradation processes to target previously ‘undruggable’ sites and diverse therapeutic protein targets. The goal of this CE course is to discuss the nonclinical and translational safety assessment of heterobifunctional degraders (often called proteolysis targeting chimeras or PROTACS) and molecular glues, focusing on the key challenges of early de-risking, nonclinical species selection and clinical translation. The first speaker will provide an introduction as well as discuss approaches to TPD safety assessments, illustrated by functional genomic profiling of molecular glues and PROTACs. The second speaker will address early de-risking strategies, focusing on a novel proteomic platform to identify off-target proteins. The third speaker will discuss strategies for assessing TPD safety in drug discovery, including the discussion of in vitro assays to inform in vivo studies. The fourth speaker will address the challenge of selecting pharmacologically relevant species to address the toxicity of TPDs, and will present some case studies. Our final speaker will present the regulatory perspective on the challenges and opportunities of protein degradation therapies. Overall, this course will address TPD safety assessment and how approaches may differ from those used for ‘traditional’ small molecule development.
Educational Co-Support Provided by: Eli Lilly and Company, Inc. and American College of Toxicology
Although the ICH S7A guideline on safety pharmacology (SP) largely achieved its objective, a proportion of remaining adverse events and attrition can be attributed in part to SP. Whilst in recent years, ACT sessions were dedicated to the development and implementation of the ICH S7B Q&As the current proposal focuses on safety and secondary pharmacology in a broad sense, across all organ systems, methodologies and general principles. Considering the scientific and technological advancements, the shift of the drug development paradigm towards novel modalities, and the evolving regulatory landscape, it has been proposed to revisit, adapt, and evolve the ICH-S7A (Valentin & Leishman, 2023). The constructive feedback received from customers, practitioners and stakeholders encouraged developing a concept paper, as the initial step in the process for revisiting an ICH guidance. Such concept paper would aim to clarify via a questions and answers (Q&As) process key features of ICHS7A, such as the use of adversity in the SP context, the emphasis on human based in vitro and in silico test systems, the in vivo assessment of critical endpoints using the latest validated technology platforms, the development of general principles for validation and qualification of models, and the refinement of the above points to make the guideline modality agnostic and sustainable over time, whilst refining the integrated risk assessment and margin of safety concepts. The development of Q&As might offer opportunities to select and progress optimized drug candidates, to refine and adapt the clinical monitoring, to increase likelihood of regulatory acceptance, and to avoid the unnecessary use of animals and encourage alternative approaches. The symposium will discuss such concept paper with perspectives from regulators, and subject matter experts for in vitro and in vivo SP.
A panel discussion at the end of the session will include participation from Dr. Jufeng Wang, President, Chinese Safety Pharmacology Society and Dr. Todd Bourcier, Director, Division of Pharm/Tox for Cardiology, Hematology, Endocrinology, and Nephrology, CDER, US FDA.
Across the globe, safety assessment of chemicals is done by many regulatory bodies and legislators potentially leading to divergent views on their human safety. In this session, this will be illustrated by discussing safety assessments of 2 excipients (iron oxide and titanium dioxide) and on one preservative (parabens). Parabens are used in food and drugs in the US and considered GRAS by FDA, however, in the US, individual States are attempting to prohibit the material. Unlike the US, iron oxide and titanium dioxide are only allowed in medicinal products in the EU on the basis that they are registered as a food color additive. As such, a potential ban of a food color additive has immediate consequences for its’ use in medicinal products. This is exemplified by TiO2 where the European Food Safety Authority (EFSA) concluded that due to potential genotoxicity concerns TiO2 could no longer be considered safe as a food additive. Extending this exclusion to pharmaceuticals could potentially result in patients in the EU being withheld from effective therapies. We will discuss the various regulator’s evaluations of the TiO2 case based on facts and science. This session will also highlight the EU initiative on One Substance One Assessment (OSOA) that should prevent potential divergent safety assessment of chemicals in the EU, preventing cases like the one with TiO2. The latest information OSOA will also be presented.
FDA concern over carcinogens in drugs has been highlighted at recent workshops, guidance documents, publications and research projects focused on this topic but the issue of carcinogens in foods have received less attention. The European Food Safety Authority Panel on Contaminants in the Food Chain recently provided a scientific opinion on the risks to public health related to the presence of nitrosamines in food. They concluded that ‘Meat and meat products' were the main food category contributing to 10 carcinogenic N-nitrosamines occurring in food. Although exhaustive, the report lamented the lack of data on important food categories and noted the increased presence of nitrosamines in foods after baking, frying, grilling, microwaving, indicate that cooking generates nitrosamines, with and without the addition of nitrate and nitrite. Nitrosamines represent only one of the many classes of carcinogens in foods. This session will explore the various types of carcinogens in foods including nitrosamines, colors, sweeteners, adulterants, pesticides and those generated during food preparation by the end user. There will also be a discussion of potential approaches to mitigate this global problem.
A traditional part of the final afternoon of the ACT Annual Meeting is the Hot Topics Symposium. Each year this session includes a variety of topics from leading experts focusing on late-breaking regulatory or scientific advances related to toxicology.
Educational Co-Support Provided by: Charles River and American College of Toxicology
The tide is turning in nonclinical safety assessment, driven by a powerful duo: virtual control groups (VCGs) and advanced analytics. These innovative tools are poised to revolutionize the field, dramatically reducing animal usage while upholding scientific rigor. VCGs unlock the power of historical control data. By meticulously analyzing existing datasets from past studies, we can reuse these data to create virtual control animals pools, reducing the need for concurrent control groups (CCGs). But this isn't mere data magic; sophisticated statistical and machine learning techniques come into play. We build robust models, meticulously validated, to predict how control data from these animals would respond to various study conditions. This mini-symposium throws open the doors to this exciting frontier. We'll delve into the fundamental principles of VCGs, explore the arsenal of advanced analytics at our disposal, and critically examine the ongoing quest for regulatory acceptance and widespread adoption. But theory isn't enough. We'll showcase real-world case studies where VCGs have been successfully implemented in diverse safety studies, demonstrating their potential for dramatic animal reduction.
This session will explore the opportunity to reduce the use of animals in late-stage clinical development for biotherapeutics by conducting sub chronic toxicity studies instead of chronic. Both industry and health authorities will provide their perspectives on this matter. The usefulness of chronic toxicity studies for biotherapeutics is being questioned because it is believed that most anticipated toxicity findings can be identified through exaggerated pharmacology and/or immunogenicity, which should be evident in sub chronic studies. Despite this, the industry continues to conduct chronic studies due to concerns about program delays caused by potential lack of regulatory acceptance. Therefore, the question remains: are sub chronic studies sufficient to evaluate the safety of biotherapeutics? This session will present case studies from industry (Pfizer and Roche), as well as health authority (Medicines Evaluation Board), offering evidence-based justifications to determine if sub chronic toxicity studies are adequate to support late-stage clinical development and registration.