CiPA – Comprehensive In Vitro Proarrhythmia Assay

The objective of the CiPA consortium is to engineer an assay for assessment of the proarrhythmic potential of new drugs with improved specificity compared with the current hERG assay. Sophion Bioscience is a CiPA partner with long-standing interest and extensive experience in cardiac ion channels. Our instruments are used for in vitro safety screening by major pharmaceutical companies and CRO’s worldwide and we are ready to assist you in setting up your CiPA assays.

See publications related to Cardiac Ion Channels done on QPatch and Qube here

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a proposal by the FDA (Food and Drug Administration), the HESI (Health and Environmental Science Institute), the CSRC (Cardiac Safety Research Consortium) and the SPS (Safety Pharmacology Society) which is ultimately aimed at revising the non-clinical ICH-S7B and replacing the clinical ICH-E14 guidelines. The S7B and E14 guidelines were implemented 2005 in response to reports of certain drugs causing TdP (torsade de points) and these guidelines have been successful in that no drugs have been withdrawn from market for being proarrhythmic since 2005. However, the link between proarrhythmia and QTc prolongation is complex and depends on several other factors in addition to drugs blocking the hERG channel and while QTc prolongation is a sensitive marker for proarrhythmia it is also moderately specific because torsadogenic compounds prolong QTc, but not all QTc prolonging drugs are torsadogenic.

The intention of the CiPA proposal is to increase the efficacy of the drug development process by 1) moving the evaluation of proarrhythmic risk to an earlier stage in the drug development process, and 2) to enable compounds with properties that today are considered as problematic to be further developed and 3) provide a stronger scientific foundation for improved future drug labeling.

The CiPA proposal is based on a mechanistic understanding of proarrhythmic risk and is built around a three-component process:

1. candidate drugs are tested in multiple and standardized ion channels assays using overexpressing cell lines. This proposal includes Nav5 (peak and late currents), Kv4.3 (Ito), hERG (IKr), KvLTQ1/mink (IKs) and Kir2.1 (IK1),

2. the data from the ion channel assays are used in a computational model of a cardiomyocyte action potential model to see if the compound yields proarrhythmic markers. This model is calibrated using data from well characterized reference compounds,

3. the results from the in silico simulations are verified using iPS derived cardiomyocytes

The FDA has proposed a revision of the S7B in 2016 but there are still many questions regarding protocols, validation, translation and more still awaiting answers. It is difficult to say when the revision will be finally implemented.