Early In Vitro Preclinical Cardiovascular Safety Assessment for Smarter Drug Discovery

In Vitro Cardiovascular Screening: Overview and Case Studies of Early Antiviral Small Molecules in Discovery

Sandra Chang PhD DABT, Project Toxicologist, Aligos Therapeutics

In 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 Attrition

Steve Jenkinson, PhD, VP Drug Discovery and Safety Assessment,

Metrion

A 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, Na_V1.5 and Ca_V1.2) 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.

Steve Jenkinson PhD

Steve Jenkinson is VP of Drug Discovery and Safety Assessment at Metrion. He has over 25 years of experience in drug discovery and in vitro safety pharmacology within the pharmaceutical industry. Steve is a recognised thought leader in his field, with deep expertise in secondary pharmacology and a strong track record of managing drug discovery programmes across multiple therapeutic areas and stages—from target identification through to the nomination of preclinical development candidates.

At Metrion, Steve provides strategic scientific guidance to customers, helping them identify and manage potential safety liabilities in their drug discovery programmes. He also serves as the primary business development contact for customers based in the United States.

Prior to joining Metrion, Steve held senior drug discovery roles at GSK and Tanabe Research Laboratories, leading multidisciplinary teams focused on a range of therapeutic targets and modalities. He then joined Pfizer, where he served as Senior Director and established, developed, and led the in vitro secondary pharmacology team. During his tenure, he also led Pfizer’s Global In Vitro Safety Pharmacology team and played an active role in key cross-industry consortia, including serving as co-chair of the IQ DruSafe Secondary Pharmacology Working Group and as a member of the FDA’s HESI Pro-Arrhythmia Group.

Steve has provided critical in vitro safety pharmacology support to numerous drug discovery programmes, including those that have progressed to marketed therapies—most notably contributing to the development of Paxlovid. He has authored 55 peer-reviewed publications.

He holds a BSc (Hons) in Pharmacology from the University of Glasgow, a PhD in Pharmacology from the University of Leicester, and completed Postdoctoral research fellowships, at the Scripps Institute in La Jolla and the Neurosciences Institute in San Diego. Steve also holds a Master of Advanced Studies (MAS) in Clinical Research from the University of California, San Diego.