Cardiac safety & early cardiac derisking
Cardiac safety in drug development is the process of assessing the potential of a drug to cause adverse effects on the heart. This involves assessing a drug’s potential to cause arrhythmias, prolonged QT interval, or other cardiac events.
Ion channel profiling remains central to assessing QT prolongation and the potential proarrhythmic risk (Torsade de Pointes; TdP) of a compound in early clinical development. High throughput ion channel screening is now integral to the development and safety profiling of most new chemical entities currently developed to address unmet medical needs (Bell and Fermini, 2021).
Historically, in vitro safety profiling has focused on assessing a compound’s ability to block the human ether-a-go-go-related gene (hERG; Kv11.1) potassium channel. hERG channel block is associated with a delay in cardiomyocyte repolarization and can be observed as prolongation of the QT interval on an electrocardiogram (ECG).
Inhibition of hERG alone may, however, overestimate the proarrhythmic risk of a compound and potentially prevent low-risk candidate molecules from clinical development. This may occur when a compound possesses mixed ion channel activity and modulation, particularly block of inward currents via calcium channels (CaV1.2) or sodium channels (NaV1.5), which may balance the hERG-mediated reduction in outward repolarizing current. Hence, compounds with a mixed ion channel profile may possess the delicate balance of outward repolarizing and inward depolarizing currents and may be devoid of TdP proarrhythmic risk.
The objective of the Comprehensive in vitro Proarrhythmia Assay (CiPA) consortium, headed by the US FDA and HESI, is to engineer an assay to assess the proarrhythmic potential of new drugs with improved specificity compared with the current hERG assay.
The CiPA proposal intends to increase the efficacy of the drug development process by:
- Moving the evaluation of proarrhythmic risk to an earlier stage in the drug development process
- Enabling compounds with properties that today are considered problematic to be further developed
- Providing a stronger scientific foundation for improved future drug labelling
Sophion Bioscience is a CiPA partner with long-standing interest and extensive experience in cardiac ion channels and cardiac safety assays.
QPatch has been used for in vitro safety screening by major pharmaceutical companies since 2005, as many researchers regard the Sophion QPatch series as the benchmark APC solution for cardiac safety. In recent years we have also seen an increasing interest in running cardiac safety assays in unattended HTS format on Qube 384. We, as well as CROs worldwide, are ready to assist you in setting up your CiPA assays.
CiPA cardiac ion channel assays
All standard CiPA-recommended assays are available on QPatch and Qube 384. Please ask your application scientist for help setting them up if they are not already installed.
Also, the challenging hERG kinetic Milnes protocol is available. This assay is recommended by the CiPA committee since it can detect changes in hERG amplitude and decay kinetics due to drug binding and trapping. The Milnes protocol can easily be run on QPatch, and the assay meets the FDA’s CiPA requirements for improved arrhythmia prediction. Data has a very good correlation with FDA’s manual patch clamp data. Read the application report ‘CiPA hERG Milnes kinetic assay on QPatch’ here.
Sophion CiPA publications and videos:
- Paper: A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm
- Paper: Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells
- You can also watch presentations by Clint Young (Xenon) and Lazlo Urban (Novartis) from one of our symposia at SPS.
- View Marc Rogers’ (Metrion Biosciences) take on CiPA or Arthur ‘Buzz’ Brown’s (MemChan Pharma) presentation; Predicting in vivo safety from in vitro tests from Sophions Ion Channel Modulation Symposium.