Ranking of antiseizure medications in a panel of focal seizure models predicts their comparative efficacy in clinical add-on trials in drug-resistant focal epilepsy.

objectiveMost antiseizure medications (ASMs) have been discovered by testing in animal models, which are generally thought to predict antiseizure activity in patients. However, it is not known whether any of these models (or a combination of models) can predict whether a novel ASM exhibits higher clinical efficacy in focal drug-resistant epilepsy (DRE) than benchmark ASMs such as carbamazepine or levetiracetam. This important question has plagued epilepsy drug discovery for over three decades and serves as the basis of the present analysis.

methodsThe present analysis includes 23 ASMs that the U.S. Food and Drug Administration (FDA) approved for the treatment of focal-onset seizures. For assessing comparative preclinical activity, we used the median effective dose (ED

resultsExcept for the pilocarpine model, none of the seizure models predicted the comparative efficacy of add-on treatment with ASMs in focal DRE. However, when we combined the ED SIGNIFICANCE: The present study shows that ranking of ASMs across a panel of mechanistically complementary but agnostic models of focal-onset seizures yields greater translational accuracy and clinical predictivity for patients with focal DRE than rankings based on any single model. This novel finding can be used when defining a path forward that best identifies the most promising investigational compounds to advance to more expensive and time-consuming clinical investigations.