Attendees will learn about:
Cardiovascular safety is a leading cause of drug attrition and often emerges too late, when the costs of failure are at their highest. For drug discovery scientists, identifying cardiac liabilities early in the development pipeline is not only a scientific imperative but also a strategic necessity. Early detection enables informed decision-making, more efficient use of resources, and the opportunity to refine or deprioritise candidates before significant investment in preclinical or clinical development.
Recent updates to FDA guidance on nonclinical cardiovascular safety testing highlight an important shift in regulatory expectations. In this changing environment, the use of robust, human-relevant in vitro models is becoming increasingly important for assessing cardiac risk and supporting the development of safer medicines.
This webinar will explore two key approaches to cardiovascular safety screening in discovery.
In Vitro Cardiovascular Screening: Overview and Case Studies of Early Antiviral Small Molecules in DiscoverySandra Chang PhD DABTProject Toxicologist, Aligos TherapeuticsIn vitro cardiovascular (CV) screening assays are critical components of the early toxicology assessment strategy particularly during small molecule pharmaceutical discovery. Early CV safety screening is often utilized to rank order compounds and elucidate risks in potential leads. The primary early in vitro CV safety screening assessment is to evaluate the inhibition of the human ether-a-go-go related gene (hERG) channel (Kv11.1), a voltage-gated K+ channel, associated with drug-induced QT prolongation which can lead to fatal arrhythmias (torsades de pointes). hERG assessment involves the determination of an inhibitory concentration (IC)50 often using the patch-clamp method where an IC50 of less than 10 μM may warrant further investigation or deprioitization of the molecule, functional group or scaffold. The strategy is often dependent on a number of factors including project timing, the chemical modality and the projected human efficacious exposure. While hERG inhibition evaluation is standard for small molecule discovery and ultimately recommended for clinical trials, subsequent steps when confronted with a hERG inhibitor during the early screening process can vary. In this presentation, case studies where routine patch clamp hERG screening resulted in inhibitory concentration IC50 values of less than 10 μM and next steps will be discussed. | Early In Vitro Cardiovascular Derisking Strategies to Reduce Compound AttritionRob Kirby PhD,Chief Operating Officer, MetrionA significant proportion of novel drug candidates fail in preclinical and early clinical development due to unforeseen cardiovascular risks that include arrhythmia potential, impacts on cardiac contractility or effects on blood pressure. Early screening focused on highlighting and eliminating such risks can not only focus early efforts to compound series that have a greater chance of success in the clinic but can also reduce the need for costly and resource intensive in vivo studies. Early profiling of ion channel activity (hERG, NaV1.5 and CaV1.2) can highlight key risks (including QTc prolongation), however, used in isolation these assays may not fully capture potential risks either mediated by compounds that show mixed ion channel activity or that have effects that may not be directly mediated by ion channel inhibition. Stem cell cardiomyocytes are a powerful tool to integrate such pharmacology and provide an integrated system that allows for the ability to look at the holistic response to a novel compound. Metrion’s validated clinically translatable assays are powerful early tools to highlight risk and put that risk into the context of free clinical exposure. Moreover, they can be used not only to examine acute effects of compounds but also longer-term effects that may be missed in acute ion channel studies. In this presentation we will highlight the utility of such assays and how they can be used effectively in a simple screening paradigm to efficiently select compounds with lower cardiovascular risk. |
Sandra Chang PhD DABT
Sandra Chang received her PhD in Pharmacology and Toxicology at UC Davis. She has over 10 years of industry experience in chemical, medical device and pharmaceutical toxicology. Sandra is currently a project toxicologist at Aligos Therapeutics overseeing nonclinical toxicology programs in discovery and development. She is a board-certified toxicologist. | Rob Kirby PhD
Dr Rob Kirby is the Chief Operating Officer at Metrion and an accomplished pharmacologist with nearly 20 years of experience in ion channel research and drug discovery. At Metrion, he is responsible for strategic planning, human resources, health and safety, GLP compliance, facilities and IT management, and resource planning. He has played a pivotal role in driving Metrion’s operational growth and in building the company’s international reputation as a leading ion channel contract research organisation (CRO). Before joining Metrion, Rob spent eight years at Xention Ltd (UK) as a Principal Scientist. There, he led multiple screening campaigns targeting a broad range of ion channels, including Nav1.x, Cav1.x, Cav2.x, Kv1.x, TRPx, Kirx, gIRK, ICrac, HCN, and hERG. His work made extensive use of automated patch clamp electrophysiology platforms (QPatch, PatchLiner) and fluorescence-based screening technologies (FLIPR, FLEXStation). Rob holds a PhD in Molecular Pharmacology and Electrophysiology from Sheffield Hallam University, where he researched a novel pharmacophore for BK potassium channel openers. He also earned a BSc (Hons) in Biomedical Sciences from the same institution, graduating with first-class honours and receiving two university awards. Over the course of his career, Rob has authored 15 peer-reviewed journal articles, 18 published conference abstracts, and holds two published patents. His research contributions include work on two compounds that advanced to Phase 1 and Phase 2 clinical trials during his time at Xention. He has led hit-to-lead ion channel screening campaigns for BK, Nav1.x, TRPA1, Kv1.x, and GIRK channels, and directed biology teams at both Xention and Metrion on multi-year drug discovery collaborations with Japanese pharmaceutical companies, focused on sodium channels for pain (over four years) and potassium channels for autoimmune disease (also over four years). He has also managed several externally funded grants, including the EU Framework 7 project ‘MAREX’ (Identification of sodium channel blockers from marine sources), the EUROSTARS project ‘E!5125 ICRAC’ (Identification of ICRAC channel blockers), and a Biomedical Catalyst grant from the UK Technology Strategy Board for ‘TRPA1 hit expansion and validation’. At Metrion, he implemented cardiac assay screening services and the development and expansion of GLP-compliant screening services. A founding member of Metrion, Rob is a recognised expert in the application of automated patch clamp electrophysiology to ion channel drug discovery and cardiac safety assessment. |
