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.