The
antiepileptic drug (AED) candidate, (4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one (
padsevonil), is the first in a novel class of drugs that bind to synaptic vesicle
protein 2 (SV2)
proteins and 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 chronic
epilepsy models, including the intrahippocampal
kainate and Genetic
Absence Epilepsy Rats from Strasbourg models, which 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,
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
padsevonil's antiseizure effects was not observed in the
pentylenetetrazol-induced clonic seizure threshold test. Further results in the 6 Hz model showed that
padsevonil provided significantly greater protection than the combination of
diazepam with either 2S-(2-oxo-1-pyrrolidinyl)butanamide (
levetiracetam) or 2S-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide (
brivaracetam), both selective SV2A
ligands. This observation suggests that
padsevonil's 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 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.