'Time Is a Critical Factor When Evaluating Oligonucleotide Therapeutics in Human Ether-a-Go-Go-Related Gene Assays’ (Nucleic Acid Therapeutics) receives ‘2024 Technology Innovation Publication Award’.
The rapidly activating delayed rectifier potassium current (IKr) is essential for regulating the action potential duration (APD) in ventricular cardiomyocytes, which is closely linked to the QT interval on an electrocardiogram. A rate-corrected QT interval longer than 440 ms is linked to an increased risk of Torsades de Pointes (TDP), a form of polymorphic ventricular tachycardia that can escalate to ventricular fibrillation and potentially cause sudden cardiac death. Several drugs have been removed from the market because of their propensity to prolong the QT interval and/or induce TDP. Most of these drugs have been reported to inhibit the human ether-à-go-go-related gene (hERG) potassium channel, which forms the pore forming subunit of IKr.
The International Council on Harmonization (ICH) S7B and E14 regulatory guidelines were introduced in 2005 in response to the discovery that hERG inhibition is associated with proarrhythmic liability. The guidelines utilise hERG inhibition and QT interval prolongation as surrogate markers of proarrhythmic liability. These have proven effective at preventing proarrhythmic drugs from reaching the market, which highlights the value in screening novel compounds early in the drug discovery process.
There is no requirement to perform early stage hERG profiling in compliance with Good Laboratory Procedures, although GLP hERG testing is offered . However, conducting experiments with optimised assays is essential to ensure an accurate assessment of a compound's half-maximal inhibitory concentration (IC₅₀) against hERG. It is essential to utilize high-quality screening platforms to ensure reliable potency assessments while maintaining efficiency in throughput, turnaround time, and cost-effectiveness. Metrion has developed a suite of non-GLP hERG screening assays across multiple platforms, offering various throughputs and assay formats to support different stages of the drug discovery process.
Metrion has configured a range of non-GLP hERG screening assays on the automated QPatch (48 well) and Qube (384 well) platforms. The assays are designed to enable the rapid evaluation of compounds in a cost-effective manner. Slower acting compounds can be tested with composite concentration-response assay formats to allow for longer drug equilibration periods. A positive control is also tested in each assay allowing the potency of test compounds to be benchmarked to a known reference.
Figure 1. A. Graph showing the peak hERG tail current (recorded at ambient temperature using the QPatch 48) plotted against time for a representative cell treated with 0.3, 1, 3 and 10 μM verapamil. The inset figure shows representative current traces in 0.1% DMSO, 0.3, 1, 3 and 10 μM verapamil. B. Graph showing the mean ± SD inhibition data (purple symbols), as well as individual inhibition values (grey symbols), plotted against concentration. The data were fitted with a Hill equation to yield the half-maximal inhibition concentration (IC50) and the 95% confidence bands (red dashed lines).
Metrion provides hERG screening services using the conventional manual patch clamp technique which, in addition to continuous compound perfusion, provides the most reliable and accurate potency assessments. Slower acting compounds can be tested with composite concentration-response assay formats to allow for longer drug equilibration periods. In addition, the experiments can be conducted at ambient or near physiological (36 ± 1 °C) temperature.
Figure 2. Graph showing the peak hERG tail current (recorded at 37 °C using the conventional manual patch clamp technique) plotted against time for a representative cell treated with 1 and 10 μM ondansetron followed by 1 μM E-4031. The inset figure shows representative current traces in 0.1% DMSO, ondansetron and E-4031. B.Graph showing the mean ± SD inhibition data (purple symbols), as well as individual inhibition values (grey symbols), plotted against concentration. The data were fitted with a Hill equation to yield the half-maximal inhibition concentration (IC50) and the 95% confidence bands (red dashed lines).
Early hERG screening provides significant benefits in the drug discovery and development process by enabling more informed decision-making and efficient use of resources. Early identification of potential cardiac liabilities helps to avoid costly late-stage failures, streamline development timelines, and improve the overall safety profile of drug candidates. By conducting hERG screening at an early, non-GLP (Good Laboratory Practice) stage, pharmaceutical companies can enhance the efficiency and success rate of their drug development pipelines. The key advantages of early hERG screening include:
Non-GLP hERG screening allows researchers to identify potential cardiac liabilities of drug candidates at an early stage of development. By detecting these issues early, problematic compounds can be eliminated before significant resources are allocated to their development. This early intervention minimises the risk of late-stage failures, which are often costly and time-consuming. Furthermore, early identification allows researchers to prioritise safer candidates and focus resources on optimising their profiles.
Conducting hERG screening in a non-GLP environment is considerably more cost-effective than GLP-compliant studies. Early-stage non-GLP screening helps manage research and development budgets more effectively by allowing companies to screen large numbers of compounds at a lower cost. Additionally, reducing the number of compounds that advance to expensive GLP studies reduces overall development costs.
Non-GLP hERG screening is typically faster than GLP studies, as it involves fewer regulatory requirements and procedural complexities. This rapid turnaround time is essential during the early stages of drug discovery, where quick decision-making can significantly impact the overall timeline. Quick feedback also provides medicinal chemists with valuable information for adjusting compound structures and improving safety profiles without causing delays.
Non-GLP hERG screening often relies on automated patch clamp systems and other high-throughput technologies, allowing for the simultaneous testing of large numbers of compounds. This high-throughput capacity enables researchers to screen hundreds to thousands of compounds within a short period, which is particularly beneficial during the early discovery phase when multiple candidates are being evaluated. The ability to rapidly assess the cardiac safety of numerous compounds increases the likelihood of identifying viable leads while reducing the time and cost associated with manual or lower-throughput methods. This approach also enables more comprehensive data generation, facilitating better-informed decision-making.
Early identification of hERG liabilities provides medicinal chemists with critical information for optimising lead compounds. If a compound exhibits hERG-related issues, researchers can modify its chemical structure to reduce or eliminate hERG inhibition while retaining its therapeutic activity. This iterative process of optimisation can be conducted more efficiently in a non-GLP setting due to lower costs and faster turnaround times. By refining compounds early, researchers can enhance the safety and efficacy of drug candidates before advancing them to more rigorous and expensive GLP studies. This targeted approach improves the chances of success in later stages of development.
Data generated from early non-GLP hERG screening informs strategic decisions about which compounds to advance to more costly and time-consuming GLP studies. By filtering out candidates with poor hERG profiles early, pharmaceutical companies can allocate resources more effectively and focus on the most promising drug candidates. This strategic selection process reduces the likelihood of late-stage failures and increases the overall efficiency of the drug development pipeline. Early screening data also enables more accurate risk-benefit assessments, helping companies align their development strategies with regulatory expectations and market needs.
'Time Is a Critical Factor When Evaluating Oligonucleotide Therapeutics in Human Ether-a-Go-Go-Related Gene Assays’ (Nucleic Acid Therapeutics) receives ‘2024 Technology Innovation Publication Award’.
Students learned about electrophysiology concepts, sodium channels in drug discovery and the commercial business-side of ion channels