Educational Co-Support Provided by: Charles River and SciLucent, Inc.
This session will present interactive case studies from pharmaceutical development across the toxicology testing continuum. The aspects that will be presented will include CMC (i.e. formulation preparation), excipients, impurities/degradants, analytical chemistry/bioanalysis stability, study designs (species, exposure, metabolites, duration, route of administration, etc.), safety margins, novel modalities (e.g. cell and gene therapy), unexpected toxicity, regulatory meetings, in the context of the targeted patient population/indication and regulatory jurisdiction. The moderators in this session include representation from pharmaceutical industry, CRO, consultants, and regulatory agency toxicologists. Moderators will interact and discuss with participants for each case study presented as the various perspectives are considered.
Educational Co-Support Provided by: EPL, Inc. and American College of Toxicology
Pathology is one of the most critical pieces in a toxicology report and so communicating with the pathologist is essential to understanding a toxicology study. The pathology report is the primary means by which the study pathologist communicates the histopathological findings and how those findings relate to other data from the study including organ weights, clinical pathology findings, macroscopic (gross) and in-life observations. In addition, the pathology peer review and a pathology working group are additional steps that can be taken to improve or clarify the findings in a toxicology study. This session will cover how a toxicologist should approach the pathology report to be able to critically review the data and the narrative. It will also cover the peer review process, how it is performed, and when best to perform a peer review and then introduce the concepts of a pathology working group and what problems a PWG can and cannot address. Finally, the session will end with a regulatory perspective on the pathology report, the peer review, and the pathology working group.
Educational Support Provided by: AstraZeneca
Rapid advancements in science and technology have led to the emergence of novel tools in nonclinical drug safety assessment, and considerable excitement about the potential of these tools to improve human risk prediction. However, there are no regulatory guidance or a uniform industry-wide strategy for using these promising novel tools. The session will include transparent discussion regarding the use of these novel tools by biotech/pharma in nonclinical safety to advance drug discovery and development. The session will feature a global pharmaceutical company’s overview of their overall strategy in using these tools (such as microphysiologic systems, omics, AI, cell painting, imaging) and an FDA speaker discussing the regulatory perspectives on integrating these novels tools into nonclinical safety assessment. The session will also feature examples of how these novel tools are used successfully by several pharmaceutical companies to advance drug discovery and development, by supplementing and/or enhancing current testing methods. This session will be impactful in enabling productive discussions among regulatory, government, and pharmaceutical stakeholders. The session will inspire progress towards the development of consistent industry practices and regulatory guidances for implementing these novel tools in nonclinical safety assessment, and lead to meaningful reduction in animal use.
Educational Co-Support Provided by: Aclairo Pharmaceutical Development Group, Inc. and American College of Toxicology
One of the challenges when developing safe and efficacious pharmaceuticals is finding a way to deliver these molecules to target tissues or cells in a safe and effective manner. Lipid-based nanoparticle formulations can serve as carrier systems to transport and deliver diverse therapeutic agents including biotechnology products and small drug molecules. These drug delivery systems are an area of intense research because they can facilitate a payload’s penetration of cell membranes, improve drug stability, aid in resisting proteolytic degradation, control drug release, and target drugs to specific tissues based on their biochemical composition. Drug formulations containing lipid-based nanoparticles have been investigated in products with a variety of indications and routes of administration; but nanomaterials present unique challenges during safety evaluation. This session will provide an introduction to the latest developments in lipid-based nanoparticle technology, describe safety considerations during evaluation of these delivery systems from a regulatory perspective and provide case studies describing how evaluation of lipid-based nanoparticle formulations have been approached.
Drug discovery and development is a complex, lengthy and expensive process that takes on average 10–15 years and approximately $1–2 billion for the approval of a new drug. While the studies needed to support clinical development are generally outlined in guidance documents, there is much less guidance on how to translate the nonclinical data into clinical designs. Nonclinical studies are performed to conduct the First‐in‐human (FIH) clinical trial which is the first major milestone to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Resolving how to move forward and even whether to move forward requires significant cross‐functional collaboration with pathologists, ADME scientists, biologists, and clinical staff. There are many reasons why drug candidates might fail, these could be as simple as insufficient understanding of the nature of the translational process, failure to effective integrate the data coming from different pharmacologically relevant species or erosion of margin of safety during chronic toxicology studies. This continuing education (CE) course is aimed to help participants improve their skills at “Managing translational challenges from nonclinical to clinical program” encountered during drug development by providing case study examples for various modalities. Speakers will briefly review the key principles of translation development and will provide case studies from multiple therapeutic areas and involving several types of toxicology challenges.
Educational Support Provided by: Society of Toxicologic Pathology
We will present an overview of the mechanisms of action, toxicologic liabilities, and safety risk assessment approaches for novel biotherapeutics for use in treating nervous system disorders and neuromuscular diseases. These modalities include vector-based therapies such as lentiviral and adeno-associated viral vectors (AAVs), cell-based therapies such as stem cells and CAR-T cells, nucleic acid-based therapies such as antisense oligonucleotides (ASOs) and mRNAs, and novel antibody-based therapeutics. The session will begin with an overview of the mechanisms of action for each of these therapeutics, how they can specifically target the nervous system and the unique aspects of safety risk assessment for these novel biotherapeutics. Additionally, there will be a presentation on the methods for investigating biodistribution, pharmacokinetics and pharmacodynamics to enable clinical/human dose prediction of these novel therapeutics. Finally, there will be 2–4 short case studies to demonstrate the importance of an informed safety assessment for novel biotherapeutics that target the nervous system. The goal of this session is to provide a well-rounded overview of the rapidly emerging biopharmaceutical research that is focused on developing novel therapeutics for the treatment of nervous system disorders and neuromuscular diseases.
Educational Co-Support Provided by: Burleson Research Technologies and American College of Toxicology
The last several years have witnessed several advancements within the field of immunotoxicology. These include, but are not limited to, a greater understanding of the mechanisms underlying various immune-mediated diseases including cancer, new therapeutic options to treat inflammatory and autoimmune diseases, and the development of new immunotoxicity assays (including in vitro alternatives for the evaluation of dermal sensitization). This past year also saw the publication of the revised FDA guidance, “Nonclinical Evaluation of the Immunotoxic Potential of Pharmaceuticals”, which covers several aspects of immunotoxicology that have arisen since the publication of ICH S8, “Immunotoxicity Studies for Human Pharmaceuticals”. This session will provide an overview of the new guidance and address three areas that are key to this guidance and of increasing interest within the immunotoxicology community – dermal sensitization, immunostimulation/immunomodulation, and developmental immunotoxicity.
Educational Support Provided by: SciLucent, Inc.
Toxicology assessment is an important part of the manufacturing process of pharmaceuticals to ensure that impurities are managed to acceptable levels. Impurity management is multi-disciplinary requiring interaction of the toxicologist with different parts of the Chemistry, Manufacturing and Control (CMC) organization. Several ICH Quality and Multidisciplinary guidelines are set up to guide pharmaceutical sponsors in ensuring high quality and safe medicines for patients. This session will discuss how toxicological principles are used to ensure that impurities are controlled to safe levels for patients. The ICH Q3A/B guidelines discuss when impurities need to be qualified, which is done by generating biological data (clinical or nonclinical) to understand the safety of the impurity. DNA-reactive (i.e., mutagenic impurities), require specific control, often- times lower than the ICH Q3A/B thresholds because of their innate hazards. Biological drugs involve different syntheses than traditional “small molecules” and require some alternative approaches to toxicological assessment of impurities. Finally, information generated by the toxicologist in incorporated into a CMC regulatory submission to demonstrate the hazards and control strategies of impurities. This course will outline and discuss the basic strategies for toxicological assessment of impurities as well as showcase practical case studies.
Educational Co-Support Provided by: Takeda and American College of Toxicology
Drug-induced kidney injury (DIKI) is among the most frequently reported adverse events across drug development and can result in dose-limiting toxicities and the discontinuation of treatment in patients. Further, with the advent of many new modality therapeutics, kidney-related adverse events continue to increase, warranting additional investment into translational models of DIKI and improved mechanistic understanding. Addressing various limitations including species-specific differences, biomarker sensitivity and specificity, as well as relevant in silico, in vitro, and in vivo models for nephrotoxicity can aid in advancing safety strategy surrounding DIKI outcomes throughout drug development and improve predictivity in the early drug discovery space. This symposium will present novel research pertaining to DIKI and highlight approaches to better evaluate safety liabilities. In addition, the utility of kidney injury biomarkers and in vitro models in the regulatory framework for pharmaceuticals will be explored. Our first speaker will explore the utility of advanced human in vitro models (e.g., microphysiological systems) for de-risking nephrotoxicity throughout drug development. Next, speaker two will discuss the implementation of translational biomarkers for DIKI to provide early detection and inform critical drug development decisions. Speaker three will detail the advancement of preclinical in vivo models for assessment of immune-mediated DIKI following exposure to immunotherapies. The final speaker will conclude the course by discussing safety-by-design strategies for prevention/mitigation of DIKI across modality agnostic programs and related regulatory aspects. As experts in their field, the speakers offer key insights into kidney physiology and toxicological parameters that are essential for successful implementation of kidney model platforms and safety strategy approaches, which will aid in accelerating drugs from bench to bedside to provide patient populations with effective treatment.
Educational Support Provided by: Preclinical GPS
Nonclinical development programs for therapeutic peptides often fall somewhere between that of small molecule and biologics programs, with aspects of both ICH M3(R2) and ICHS6 (R1) being applicable. Peptides can range from simple synthetic polypeptides with natural amino acids to more complex molecules with non-natural amino acids and/or conjugated moieties. The types of toxicology studies needed often differ depending on the type of peptide modification. Because of this complexity, current guidance documents often lack sufficient advice for peptide development. In 2020, FDA codified the definition of a protein as any alpha amino acid polymer with a specific, defined sequence greater than 40 amino acids. For these molecules, a Biologics License Application regulatory route is used. For polypeptides of < 40 amino acids, regardless of manufacturing method, a New Drug Application regulatory route is used. Although this provides clarity for US marketing applications, this definition is not necessarily followed by other global regulatory agencies. The EFPIA peptide safety working group has conducted an industry-wide survey to capture the standard approaches companies are using for the development of therapeutic peptides and recommendations on what guidance documents could be updated to provide additional advice. In this symposium, results of the survey will be presented in an effort to harmonize toxicology programs implemented across pharmaceutical companies and the expectations from regulators. Case studies will be presented to describe successful approaches that have been taken for various peptide programs, with an emphasis on adhering to 3Rs principles. Additionally, general considerations for peptide development based on current FDA policy will be presented.
Immunogenicity risk remains a concern for all therapeutic protein products, regardless of regulatory pathway. There is increased interest in in vitro assay methodologies for all aspects of drug development, and particular interest with respect to immunogenicity due to the inability of most non-clinical models to inform human immunogenicity risk. This symposium will present results from a collaboration between industry, CRO & regulatory laboratories to evaluate potential positive and negative controls for in vitro immunogenicity assays completed with a range of assay formats. Speakers from each sector will present in vitro assay methods ranging from innate to adaptive immune function that could be used for immunogenicity risk assessment. In vitro assay methodologies will be followed by a presentation of humanized mouse study data asking if it could also be informative for immunogenicity risk assessment. The session concludes with a Q&A/panel discussion.
Educational Co-Support Provided by: Charles River and DSI
Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements, followed up with a nonclinical EEG study. Thus, it would be preferable to have earlier prediction of seizurogenic risk that could be used to eliminate liabilities early in discovery while there are options for medicinal chemists making potential new drugs. Attrition due to cardiac adverse events has benefited from routine early screening; could we reduce attrition due to seizure using a similar approach? Specifically, microelectrode arrays (MEA) could be used to detect potential seizurogenic signals in stem-cell-derived neurons. In addition, there is clear evidence implicating neuronal voltage-gated and ligand-gated ion channels, GPCRs and transporters in seizure. Recent data provide evidence that we can detect seizure in MEA in linked to a panel of ion channel assays that predict seizure, with the aim of influencing structure activity relationship at the design stage and eliminating compounds predicted to be associated with pro-seizurogenic state. This session will be of great interest to attendees looking to have a better understanding of cutting-edge science in MEA and ion channel and how to apply these to identify and to mitigate seizure risk.
The developing antimicrobial resistance crisis has prompted a re-evaluation of the use of bacteriophage (phage) for treatment of serious bacterial infections. Phage therapy has been widely used in Eastern bloc countries for over a century to treat serious, antibiotic resistant infections. Given the extensive diversity of phage, specificity for their target strains and apparent safety profile, Phage therapy holds significant potential for treatment of serious bacterial infections and as novel vectors for gene therapy. What are phage and how are they currently being used in clinical practice? What are some of the key challenges and safety concerns associated with phage therapy? How do the body and the immune system more specifically respond to phage therapy? This session seeks to inform on the current state and utility of phage therapy. An introductory talk will address how phage are identified and properly formulated and standardized. Subsequent speakers will address interaction of phage with the microbiome and host immune system as well as recent clinical successes with phage therapy. Speakers will also discuss other potential uses for phage and how recent advances in molecular biology and genomics have enabled a resurgence in phage-based therapies. Finally, an FDA speaker will share a regulatory perspective on Phage therapies, what the regulators look for and key clinical expectations for both natural and engineered phage products. This session will serve as an introduction to the use of phage as therapies for significant bacterial infections, some of their development challenges and well as their future promise.
The CAR T cell therapy landscape has evolved considerably since the approval of the first CD19 CAR T- cell therapy for the treatment of B cell malignancies in 2017. One of the biggest challenges facing this class of therapeutics is access to treatment. Despite many approved CAR T-cell therapies, only a small fraction of eligible patients can receive this transformative treatment. Approaches to improve access to CAR T therapies include the development of ‘off-the-shelf’ therapies using gene-editing approaches, and in vivo CAR T-cells, where viral vectors encoding CAR construct are directly administered to patients. This symposium will explore the unique safety, regulatory and translational challenges that novel CAR T-cell modalities present. The goals of this symposium are to 1) provide an overview of a nonclinical development package for a novel ex vivo CAR T-cell product, 2) discuss safety de-risking strategies for off-the-shelf, gene-edited CAR T-cells including assessing risk of oncogenic transformation associated with these new technologies, 3) discuss common regulatory challenges associated with CAR T-cell therapies, and 4) explore ways to leverage nonclinical and prior clinical information to project the FIH dose and discuss the impact of patient and product-specific attributes on the kinetics and efficacy of CAR T-cells. The audience will gain an understanding of nonclinical development strategies for CAR T cell products ranging from autologous to off-the-shelf CAR T-cells. Whenever possible, speakers will share their experiences or present case studies to enable a robust discussion on fringe cases or specific developmental, translational, or regulatory questions.
Educational Support Provided by: Roundtable of Toxicology Consultants
There is currently an urgent unmet medical need for newer, safer, and more effective medications to treat CNS disorders, thus emphasizing the need for continued attempts at advancing promising molecules into clinical testing. At present, the dearth of reliable biomarkers for CNS injury is impeding efforts to develop new drugs for neurological diseases. There is a need for more sensitive and specific biomarkers for neuronal or glial cell injury that can help detect and predict neuro-toxicities that are relevant across animal models and translational from nonclinical studies to the clinic. Better biomarkers may also provide improved understanding of on- and off-target effects that will be more informative for clinical development and, ultimately, regulatory approval. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) are urgently needed since biopsies of CNS tissues are not feasible. Non-invasive neuroimaging techniques, such as magnetic resonance imaging/spectroscopy and positron emission tomography, are also in great demand due to their non-invasiveness, high precision, and suitability for longitudinal analyses. Developing and using biomarkers through development from bench to bedside will require close cooperative interactions between sponsors and regulatory agencies. This symposium will address the current state of the art regarding biomarkers for CNS injury and toxicity. Speakers in this session will provide attendees with an overview of current approaches for detecting and monitoring CNS injury and toxicity with the aim of catalyzing interest and efforts to identify new biomarkers that can better facilitate efforts to bring therapies to patients with neurological diseases.
Novel nucleic acid-based therapeutics targeting specific tissues, including antibody-conjugated oligonucleotides have recently begun to revolutionize the field of genetic medicine. In addition to GalNac conjugated oligonucleotides, newer modalities such Antibody-conjugated oligonucleotides have the potential to improve selectivity targetability and overall safety by targeting specific cell/tissue types involved in the pathogenesis of difficult-to-treat diseases with high unmet medical needs such as neurodegenerative and neuromuscular diseases. These novel modalities are composed of innovative components and have unique mechanisms of action that often require specific considerations for the assessment of nonclinical safety and pharmacodynamic responses. This symposium aims to provide (A) the current-state-of-the-art for novel biologics-based oligonucleotide therapeutics, (B) present on considerations and best practices to assess putative toxicities, (C) and highlight nonclinical safety assessment strategies including, predictive safety and in vivo toxicology studies that serve to enable first-in-human clinical trials in patients. The speakers will share recent experiences with nonclinical development strategies for these novel modalities including regulatory risk assessment approaches and technical considerations that differ from more classical biologicals.
Educational Co-Support Provided by: IDEAYA Biosciences and American College of Toxicology
Artificial intelligence (AI) and machine learning (ML) play pivotal roles in revolutionizing how we conduct toxicology assessments and ultimately expediting the drug discovery and development process. By analyzing complex and potentially vast datasets with unprecedented speed and precision, AI algorithms can predict potential toxicity of compounds, enabling researchers to prioritize candidates early in the drug development pipeline. This accelerates decision-making by swiftly identifying promising drug candidates while minimizing risks. ML models can learn complex patterns from diverse biological datasets, offering insights into potential adverse effects and aiding in the design of safer therapeutics. The integration of AI in toxicology not only enables efficiency but can also reduce costs and resources associated with traditional assessments, thus streamlining the drug development process and delivering safer and more effective treatments for patients. In this symposium, we will provide specific examples as to 1) how AI and/or ML can be implemented in early safety screening during the drug discovery process, 2) the application of AI in digital pathology, 3), the development of a ML model that utilizes transcriptomic data to prioritize compounds based on DILI risk, and 4) the use of ML models to extract insights from SEND datasets.
This symposium is endorsed by the ACT Early Career Professional Subcommittee.
The promise of gene and cell therapy (G&CT) to provide cures for many diseases is slowly becoming a reality. This is particularly true for the AAV (adeno-associated virus) -based subcategory of G&CT since the approval of Glybera in 2012 and approvals by the US FDA and/or EU EMA of six additional in vivo therapies (Elevidys, Hemgenix, Upstaza, Roctavian, Luxturna, and Zolgensma) from 2017 through 2023. The first approvals boosted confidence in this approach and dramatically increased the number of products in development, as demonstrated by the fact that four of the six therapies were approved in 2022-2023. Despite successful approvals and years of experience, standardized global guidelines are limited. In addition, exponential growth in understanding of the therapies and associated safety risks, presents unique developmental challenges.
Targeting specialized compartments (such as the eye, ear, brain, cartilage, heart, muscle) is attractive due to the smaller amounts of product needed and the compartmentalized nature of the organs, limiting potential for systemic toxicities. In this Part 1 symposium, we will provide specific examples of preclinical development strategies for the eye, ear, and spinal cord and a regulatory perspective on the nonclinical expectations for the FIH safety packages for AAV therapies delivered to specialized compartments. The presentation will include general trends observed by FDA in IND submissions for gene therapies delivered to specialized compartments. The session will conclude with a Panel Discussion for Q&A from the audience.
Educational Co-Support Provided by: HESI and American College of Toxicology
Non-human primates (NHP) are an important, but limited resource to support safety assessment of new pharmaceuticals, in particular monoclonal antibodies. Use of sexually mature NHPs are even more limited, but can be used to inform risk of infertility and adverse pregnancy outcomes. Current examples of NHP use and alternatives to NHP use to inform developmental to reproductive toxicity (DART) risk will be presented and discussed. This will include a survey of marketed products over a 12-year span to understand how NHPs have been used to assess risk of infertility and how it was reflected in the label. Regarding future use of NHP in DART, we will also challenge industry and regulators that weight of evidence should be the default scenario to determine if experimental data are needed, considering non-NHP options (including standard species if appropriate) if that will inform the human risk assessment before considering use of NHPs only if they will address data gaps not available by other means. If NHPs are needed for DART because no other available test system will provide necessary data (e.g. pharmacological relevance) for the human risk assessment, we will offer some forward-looking considerations and recommendations for improvement. A short panel discussion will be included with the speakers (and other guests). This workshop is an outcome of a HESI DART working group whose members include health authority representatives from US, Europe, and Japan as well as industry.
Educational Support Provided by: QurAlis Corporation
Oligonucleotides and mRNA therapeutics have advanced over the past 20 years, as well as the number of drugs approved. With the advancement of this field, there has been an increase in novel targets and delivery mechanisms. While the field has advanced in targeted knockdown, the challenges have also increased such as local tolerability and off-target toxicity. This symposium will focus on these advancements and strategies for different modalities, including GalNAc siRNAs, ASOs, mRNA vaccines. Each talk will focus on the development strategy including type of studies performed, dose selection and the use of surrogate molecules if appropriate for an IND-enabling package and beyond.
The presence of impurities and degradation products in drugs is unavoidable and it is critical that control strategies are in place to ensure patient safety. A key piece to an appropriate control strategy understanding the possible toxic effects of impurities present at low levels in drugs. ICH Q3A/B address the quality and safety aspects of impurities in pharmaceuticals at product registration and include guidance on a qualification threshold dependent on the amount of drug administered, above which safety studies may be needed to establish the biological safety of an impurity. Although general study design considerations are discussed in the guidance, an IQ DruSafe Impurities Working Group survey identified some aspects of the qualification process that could benefit from harmonization, such as aspects of study design, as well as a defined approach for calculating a safe limit based on qualification data. Additionally, although it is recognized that higher qualification thresholds may be appropriate during clinical development or for short duration commercial products, data-driven safety-based limits are lacking. Finally, current qualification approaches do not consider 3R approaches for hazard assessment. This symposium will discuss recent recommendations for a harmonized approach that includes a 3R-based study design. A recent data analysis effort to identify classes of compounds that may require a lower qualification threshold will be discussed, as well as an analysis of nonclinical toxicology studies to aid in setting safety-based qualification thresholds during clinical development. Finally, there will be a discussion of possible future directions for impurity qualification, including new approach methodologies.
It is estimated that over 70% of Americans take at least one dietary supplement, with the market estimated to be around $60 billion and projected to have an annual growth rate of 5 to 10%. The products include vitamins, botanicals, minerals, protein & amino acids, fibers & specialty carbohydrates and omega fatty acids and many equate these “natural” products with “safe". Nonetheless, not only can the constituents in natural products themselves cause toxicity, but their interactions with non-prescription or prescription drugs can also alter the latter's efficacy or potentiate adverse reactions. With the passage of the 1994 Dietary Supplement Health and Education Act (DSHEA) FDA was authorized to oversee label requirements and promulgate good manufacturing practices, but not pre-market approval. This symposium will explore the regulations covering dietary supplements, and the toxicity of natural products alone and in combination with conventional drugs. An overview of the clinical history of supplement-associated hepatotoxicity will be accompanied by a mechanistic investigation of a food ingredient - drug interaction.
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.