Mechanistic Understanding of Clinical Cardiotoxicity Associated with BMS-986094 using In Vitro Methods

The story of BMS-986094 is a classic tale of clinical stage failure, with cardiotoxicity being missed in preclinical testing. Tragically, failure to pick up this liability led to one death and eight patients being hospitalised with significantly reduced left ventricular ejection fraction (LVEF) during phase 3 clinical trials, and the drug was subsequently discontinued.  Retrospective analysis of the clinical data showed that 40% of patients dosed with BMS-986094 had some evidence of cardiac dysfunction.

In recent years, more sophisticated in vitro techniques have been developed including the use of functional human iPSC-derived cardiomyocytes in combination with microelectrode array; an approach currently being evaluated within CiPA (Comprehensive In Vitro Proarrhythmia Assay) for understanding proarrhythmic risk during preclinical testing. Using this combined approach, repeat dosing of BMS-986094 could be assessed over an extended time period, and the technique was found to be extremely sensitive with the detection of significant electrophysiological functional effects observed at low concentrations of BMS-986094.

To learn more about our research, which was presented at the Safety Pharmacology Society (SPS) Annual meeting in Berlin in September 2017, download our poster.

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