Abstract
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.
Highlights
Epilepsy is one of the most common neurologic diseases worldwide, and is associated with a significant healthcare burden (Devinsky et al, 2018; Thijs et al, 2019)
The antiepileptic drug (AED) candidate, (4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one, 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
Antiepileptic drugs approved in the last decade display good safety and pharmacokinetic profiles; far improved efficacy over first-generation AEDs has not been demonstrated in clinical studies (Chen et al, 2018), and approximately one-third of patients with epilepsy continue to experience poorly controlled seizures despite treatment, i.e., drug-resistant epilepsy (Kwan et al, 2010; Kalilani et al, 2018; Chen et al, 2018)
Summary
Epilepsy is one of the most common neurologic diseases worldwide, and is associated with a significant healthcare burden (Devinsky et al, 2018; Thijs et al, 2019). Antiepileptic drugs approved in the last decade display good safety and pharmacokinetic profiles; far improved efficacy over first-generation AEDs has not been demonstrated in clinical studies (Chen et al, 2018), and approximately one-third of patients with epilepsy continue to experience poorly controlled seizures despite treatment, i.e., drug-resistant epilepsy (Kwan et al, 2010; Kalilani et al, 2018; Chen et al, 2018). Polytherapy is a frequent treatment strategy for patients with drug-resistant epilepsy, since a substantial proportion will require more than one AED to reduce their seizure burden (French and Faught, 2009; Brodie and Sills, 2011). The combination of selected AEDs should allow for synergistic or additive efficacy without any detrimental impact on safety and tolerability (French and Faught, 2009; Brodie and Sills, 2011); a nonclinical mechanistic rationale for clinically used AED combinations is often lacking or has not yet translated into superior efficacy
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