A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat

Soticlestat (TAK-935) is a potent and selective inhibitor of cholesterol 24-hydroxylase (CYP46A1), an enzyme primarily expressed in the brain that catabolizes cholesterol to 24S-hydroxycholesterol (24HC). In the ELEKTRA phase II clinical trial, soticlestat reduced seizure frequency in patients with developmental and epileptic encephalopathies, and two phase III studies evaluating the safety and efficacy of soticlestat in Dravet syndrome (SKYLINE) and Lennox-Gastaut syndrome (SKYWAY) have recently been completed. The exact mechanism of action by which soticlestat exerts pharmacological benefits remains undetermined. In this review, we assess the available preclinical evidence and present a working hypothesis for the antiseizure effects of soticlestat. The data support three potential mechanisms of action: (1) normalization of the seizure threshold via reduction of 24HC levels in the brain; as 24HC acts as a potent and selective positive allosteric modulator of glutamate N-methyl-D-aspartate receptors, reduction of 24HC levels by soticlestat may lead to decreased hyperexcitability and elevated seizure thresholds; (2) restoration of glutamate sequestration from the synaptic cleft; accumulation of glutamate in the synaptic cleft enhances neural excitation and can contribute to neurotoxicity; soticlestat may inhibit conversion of cholesterol to 24HC in the membrane lipid raft microdomain and help to preserve it, consequently reducing excessive glutamate excitation; and (3) suppression of neuroinflammation via reduction of inflammatory cytokine release. These potential mechanisms of action warrant further investigation.