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.