The Complexity and Challenges of Developing Effective Epilepsy Therapies: Lessons to be Learned from Comparing Cenobamate, Carisbamate, and Padsevonil

receptor, presuming that effects at these two targets would lead to a synergistic increase in antiseizure activity. However, it failed in human trials. In contrast, cenobamate, which was discovered by a chemocentric approach and phenotypic screening, exerted impressive clinical efficacy with a high rate of seizure freedom. The amygdala kindled rat was the only preclinical model that correctly predicted the successful and unsuccessful outcomes of clinical development of cenobamate, carisbamate, and padsevonil. Hopefully, the present analysis of three ASM discovery programs with largely diverging clinical outcomes will help to better understand the complexity and challenges of ASM development.