Late stage failure, as a consequence of drug toxicity, is a relatively common occurrence with over 10% of drug attrition attributed to safety in the clinic. It is apparent that the traditional preclinical models are not currently picking up these adverse events, and over recent years, there has been a push to develop human relevant models which are more predictive and can be used at an earlier stage to understand potential adverse effects. In fact, the Alliance for Human Relevant Science has been launched to specifically address this topic.
Research at Cyprotex is very much focused in this field. Our new developments involve some of the latest technologies in 3D models, MEA, HCS and stem cells. These models are proving successful at detecting organ-specific toxicity for investigational drugs which have failed in clinical trials. Cyprotex has performed a number of studies with clients who have observed elevated liver enzymes or cardiotoxicity during clinical trials who have subsequently investigated the mechanism of action in human in vitro models. This has allowed clients to then implement predictive human in vitro models as part of their preclinical strategy.
To demonstrate this, Cyprotex have been investigating BMS-986094, a guanosine nucleotide analogue being used to treat hepatitis C which was discontinued in Phase 2 clinical trials because of left ventricular dysfunction in over 40% of patients including a suspected death. Using stem-cell derived cardiomyocytes and microelectrode array (MEA), it was possible to detect the cardiotoxic liability at low concentrations indicating the sensitivity of this approach. The method also provides an insight into the mechanism of toxicity reflective of the clinical observations. This novel research will be presented through a poster at the SPS Annual Meeting in Berlin in September 2017.
Cyprotex have also been working in collaboration with DILIsym® Services to support their studies. Using Cyprotex’s expertise in cellular bioenergetics and mitochondrial toxicity in combination with the DILIsym® simulations, it has been possible to elucidate the mechanism behind TAK-875 hepatotoxicity, a GPR40 agonist which was terminated in Phase 3 trials. This research was presented at the SOT meeting in Baltimore in March 2017.