The Non-invasive Translational Biomarker - Index of Cardiac Electrophysiological Balance (iCEB) Predicts Potential Risk of Cardiac Arrhythmias in Preclinical Models and in Patients: Superior to Current Biomarkers Such As QT?
Safety Pharmacology Society location:PRague date:28 September - 1 October 2015
Our biomarker “index of cardiac-electrophysiological balance” (iCEB = QT/QRS) was recently introduced/orally presented in SPS 2012/2013 and published (Lu et al., 2013). We investigated whether iCEB could predict potential cardiac risks in a better manner than the conventionally used QT-prolongation, in both pre-clinical models and patients. In pre-clinical models both in vitro and in vivo, iCEB predicted not only drug-induced long QT and –TdP-related arrhythmias, but also drug-induced cardiac arrhythmias related to slow conduction (i.e. QRS-prolongation) and QT-shortening. In patients with SCN5A mutated Brugada syndrome iCEB was significantly reduced, while it was significantly increased in the genotype positive patients with long QT syndrome (when compared to genotype negative-control subjects). Here we present two additional cases from drug discovery projects:
- iCEB is significantly increased in preclinical models for the clinical candidate-drug JNJ-859. It induced long QT in men in a Phase I study: JNJ-859 was stopped for further development.
- In a second case, the new drug JNJ-433 significantly prolonged QT-interval in preclinical models but did not significantly change iCEB. Supported by these data, JNJ-433 was moved forward since it was considered to be “safe” with respect to proarrhythmic liability, despite its noticeable QT-prolongation.
These data suggest that the new non-invasive and translational biomarker iCEB can be used in both preclinical animal models and in man and provide additional vital insights into a drug profile.