Endurance Study: A retrospective non-interventional study to evaluate seizure liability using human cortical organoid technology

Seizure liability remains an important safety consideration identified during both clinical development and post-marketing use of small molecule drugs. Neurological adverse events, including both seizures occurring at therapeutic exposure levels and withdrawal-associated seizure phenomena, are often detected after initial human exposure, where they may influence dose selection, labeling, and risk mitigation strategies.

The present study is designed as a retrospective evaluation of drugs with previously characterized clinical outcomes, using a human iPSC-derived cortical organoid model that captures emergent neuronal network behavior and synaptic function (Marchetto et al., Cell 2010). Prior work has demonstrated that functional endpoints derived from this model may detect perturbations in neuronal activity at concentrations below those associated with overt cytotoxicity (Sirenko et al., Toxicol. Sci. 2019), supporting its utility in early hazard identification.

This protocol describes the planned evaluation of drug-induced changes in network-level activity following controlled exposure across pharmacokinetically anchored concentration ranges. The study is intended to assess whether assay-derived functional signatures are associated with known clinical seizure risk and to support future applications in prospective safety assessment (Wang et al., ALTEX 2022).