Educational Co-Support Provided by: Health and Environmental Sciences Institute and Instem
Nitrosamines (NA) are chemicals found as impurities in drugs and food, associated with genotoxicity risks, but their toxicity varies based on structure, bioavailability, and potency, which can further categorize them into sub-classes of molecules that are either deemed to be a cohort of concern (CoC), weak acting mutagens (non-CoC), or non-mutagens. Despite the significant experimental and regulatory progress to date, there remains a need to implement robust and sustainable safety assessment methods that protect public health from NA risks while ensuring uninterrupted access to essential medications. Mechanism-based genotoxicity risk assessment (MGRA) is being applied to evaluate nitrosamine risk in drug development, following adverse outcome pathways (AOPs) to incorporate new scientific understandings and technologies. MGRA enables the evaluation of diverse genomic damage endpoints to inform on nitrosamine-related genotoxicity both in vitro and in vivo. The symposium will discuss various MGRA approaches, including optimized 1.) Optimized Ames testing, 2.) error-corrected next-generation sequencing (ecNGS) for mutagenicity, 3.) alternative in vitro cellular models, advanced in vivo genotoxicity strategies,4.) (Q)SAR and quantitative mechanics-based modeling, and 5.) regulatory perspectives on nitrosamine risk assessment. A 15 min panel discussion at the end of the session will enable a Q&A discussion between the speakers and the audience members. The session targets professionals, trainees, and students in toxicological research, drug development, and regulatory risk assessment, including of impurities and nitrosamines.
Educational Co-Support Provided by: Charles River and American College of Toxicology
Oligonucleotide-based therapeutics (ONTs) are a rapidly growing class of RNA-based therapies that have the potential to treat a diverse range of diseases through a variety of mechanisms (e.g. mRNA degradation, splicing, inhibition of protein translation, etc.). Two common classes of ONTs leading to degradation of target messenger (m)RNA include small-interfering (si)RNAs and antisense oligonucleotides (ASOs). While each has a distinct mechanism of action, they both have the potential for hybridization-dependent off-target silencing. In the case of siRNAs this can occur through full or partial hybridization-dependent RISC-mediated silencing or seed-region binding resulting in micro (mi)RNA-like effects. On the other hand, ASOs are generally limited to full or partial hybridization-dependent RNase H1 silencing. In either case the off-target profile of the clinical candidate will likely differ in the nonclinical species (i.e. rodent or non-rodent) compared to that of the human. Therefore, a challenge often encountered during development of these ONTs is how to manage toxicities in nonclinical safety studies that may be specific to the model species and of unknown relevance to the human. In this session we aim to 1) provide an overview of hybridization-dependent off-target mechanisms and risk assessment opportunities, 2) rodent specific hybridization-dependent off-target associated toxicities and derisking strategies, 3) a pathology perspective of off-target associated lesions, and 4) regulatory perspective on hybridization-dependent off-target assessment.
The International Conference on Harmonization (ICH) guidance documents outline nonclinical safety study requirements in pharmaceutical development. Waivers or modifications to these guidance documents may be granted in specific cases, such as substantial data from similar compounds, established clinical use, or well-understood mechanisms of action. Waivers must be scientifically justified and involve regulatory engagement assessed on a case-by-case basis to balance risk with safety and efficacy data. This symposium will discuss the nuances of waivers under ICH M3(R2), S6(R1), S9, S5(R3), and S1B(R1) and present case studies on submission approaches to health authorities. The first speaker will discuss strategies and case studies for waiving the requirement to perform in vivo embryofetal development (EFD) or enhanced pre-and postnatal development (ePPND) studies. The second will provide an overview of the carcinogenicity waiver industry experience to date, including case studies, best practices, and challenges encountered. The third will address the nonclinical safety strategy for T cell engaging bispecific (TCB) molecules, including case studies, and highlight the rationale for not conducting chronic toxicity studies and supporting first-in-human (FIH) studies. The final speaker will outline the pursuit of regulatory agreement on an unconventional in vitro safety package to support FIH trials within an oncology framework. Experts will share insights on interactions with regulatory bodies and submission strategies for modality-agnostic waivers, providing advanced guidance for toxicologists.
The requirement by FDA for the generation and submission of standardized CDISC-SEND-formatted toxicology study data has enabled the construction of large databases of toxicology study data that can be used to build predictive models. The Nonclinical Topics Working Group of the Pharmaceutical Users Software Exchange (PHUSE) has initiated a project to facilitate collaboration among regulators, pharmaceutical companies, contract research organizations, and software vendors to collaboratively develop open source software solutions to improve the fidelity and accessibility of these methods. More specifically, supervised machine learning models will be trained to detect and characterize patterns in toxicology study endpoints that are associated with the documented conclusions of expert toxicologists, e.g. target organs of toxicity, and then applied to streamline the interpretation of newly generated toxicology study data. Additional study interpretations, e.g. adversity of findings, NOAEL determination, clinical translatability, structure activity relationship – will be explored for development of predictive models. This symposium will provide an update on the progress of this project as well as perspective on the applicability of its deliverables from a diverse set of stakeholders.
Educational Co-Support Provided by: Altasciences and American College of Toxicology
Cell and gene therapies represent revolutionary advancements in modern medicine, offering the potential to treat diseases that were previously intractable. These therapies utilize complex techniques such as genetic modification, cell reprogramming, and targeted delivery systems. This allows for highly personalized and precision treatments across a wide spectrum of conditions, from genetic disorders to cancers, and beyond. Despite their promising potential, the intricate nature of these therapies introduces significant challenges and risks, particularly in predicting and managing adverse events. Adverse events can range from immunogenic reactions to unintended genetic consequences, highlighting the necessity for rigorous preclinical and clinical evaluations. Understanding and mitigating these adverse effects is essential for the safe and successful translation of these treatments from research to clinical application. The goal of this symposium is to highlight the lessons learned from both clinical and preclinical studies in the field of cell and gene therapies, to identify strategies to optimize the safety and efficacy of these cutting-edge modalities. Topics will include understanding the mechanisms of adverse events in gene therapy, emphasizing critical insights into safety profiles and efficacy assessments; preclinical development of a novel gene therapy using an AAV-delivered zinc finger transcriptional repressor to target and treat prion diseases via epigenetic mechanisms; latest methodologies to enhance T-cell receptor potency and safety, leveraging both in vitro and in silico techniques to prevent adverse effect in cell therapy; development and utilization of advanced mouse models to better evaluate new therapeutics, focusing on enhancing drug evaluation processes and accurate toxicity assessments.
Drug-drug interactions (DDIs) are common in patients undergoing polypharmacy and may result in reduced therapeutic efficacy or enhanced toxicity. Although DDIs are largely preventable, they currently increase the number of outpatient visits and hospitalizations, increase the economic burden to healthcare systems globally, and some are responsible for patient deaths. Over the past 20 years, our understanding of drug disposition and the mechanisms by which coadministered drugs cause clinically relevant pharmacokinetic (PK) DDIs has markedly advanced. Due to the global nature of drug development, different expectations from various regulatory agencies can increase drug development cost, delay patient access to medications, and lead to inconsistent recommendations for healthcare providers. Following a succession of regional guidelines released over the past 28 years since the first DDI guidance was issued by the US Food and Drug Administration (FDA) in 1997, the International Council for Harmonisation (ICH) adopted its M12 guideline in May 2024. ICH M12 promotes a harmonized approach in conducting and interpreting enzyme- and transporter-mediated in vitro and clinical DDI studies during drug development. This session aims to : 1) summarize the in vitro tools and methods that are used to assess the potential for DDIs in light of ICH M12, 2) highlight how ICH M12 was developed and summarize its scope and where challenges remain, and 3) provide insight on the implications of ICH M12 in the design of successful clinical trials in the complex area of oncology drug development.