Benefits of Early In Vitro Screening for Seizure Liability in Problem Solving and Decision Making (P407)

Seizure liability remains a significant cause of attrition throughout drug development in pre-clinical and clinical studies. We have developed an approach utilizing hiPSC-neuronal cell microelectrode array (MEA) and ion channel screening for early seizure prediction. In our MEA assay, seizurogenic compounds were identified correctly with high predictivity, and correlations were observed between the in vitro and clinical exposures of many therapies known to cause seizure. In the early phase of nonclinical testing MEA studies can be used to derisk and prioritize a chemical series. E.g., after testing several compounds, one was identified with low seizure risk compared to the others in the series – this compound had distinct structural features. In another study of compounds undergoing nonclinical testing, exposures that caused no CNS signs or convulsions in rats, aligned with the results of the MEA study. Conversely, where convulsions were reported in rats, seizurogenic responses were present in the MEA study at comparable concentrations. These studies can also be used to determine the human relevance of seizures observed in nonclinical studies. E.g., nonclinical testing of a compound caused convulsions only in dogs. Testing metabolites in the MEA assay revealed only the dog-specific metabolite caused a seizurogenic phenotype. In addition, screening this metabolite against the seizure-related ion channel targets revealed a hit, providing mechanistic insight and also the opportunity for compound redesign. Collectively, these studies demonstrate the utility of this approach for early seizure prediction to provide mechanistic information, early de-risking, and support optimal drug design using human in vitro models.