Pharmacological profile of the antiepileptic drug candidate padsevonil – characterization in rodent seizure and epilepsy models

The antiepileptic drug (AED) candidate, padsevonil, is the first in a novel class of drugs that bind to synaptic vesicle 2 (SV2) proteins, and to the GABAA receptor benzodiazepine site, allowing for pre- and postsynaptic activity, respectively. In acute seizure models, padsevonil provided potent, dose-dependent protection against seizures induced by administration of pilocarpine or 11-deoxycortisol, and those induced acoustically or through 6 Hz stimulation; it was less potent in the pentylenetetrazol, bicuculline, and maximal electroshock models. Padsevonil displayed dose-dependent protective effects in the intrahippocampal kainate and GAERS models that represent human mesial temporal lobe and absence epilepsy, respectively. In the amygdala kindling model, which is predictive of efficacy against focal to bilateral tonic-clonic seizures in the clinical setting, padsevonil provided significant protection in kindled rodents; in mice specifically, it was the most potent AED compared with nine others with different mechanisms of action. Its therapeutic index was also the highest, potentially translating into a favorable efficacy and tolerability profile in humans. Importantly, in contrast to diazepam, tolerance to padsevonil9s antiseizure effects was not observed in the pentylenetetrazol-induced clonic seizure threshold test. Further results from the 6 Hz model showed that padsevonil provided significantly greater protection than the combination of diazepam with either levetiracetam or brivaracetam, both selective SV2A ligands. This observation suggests that padsevonil9s unique mechanism of action confers antiseizure properties beyond the combination of compounds targeting SV2A and the benzodiazepine site. Overall, padsevonil displayed robust efficacy across validated seizure and epilepsy models, including those considered to represent drug-resistant epilepsy. SIGNIFICANCE STATEMENT Padsevonil, a first-in-class antiepileptic drug candidate, targets synaptic vesicle 2 (SV2) proteins and the benzodiazepine site of GABAA receptors. It demonstrated robust efficacy across a broad range of rodent seizure and epilepsy models, several representing drug-resistant epilepsy. Furthermore, in one rodent model, its efficacy extended beyond the combination of drugs interacting separately with SV2 or the benzodiazepine site. Padsevonil displayed a high therapeutic index, potentially translating into a favorable safety profile in humans; tolerance to antiseizure effects was not observed.