Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Characterization in Rodent Seizure and Epilepsy Models

Abstract

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 (padsevonil), is the first in a novel class of drugs that bind to synaptic vesicle protein 2 (SV2) proteins and the GABA A 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 dosedependent 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 pentylenetetrazolinduced 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 STATEMENTPadsevonil, a first-in-class antiepileptic drug candidate, targets SV2 proteins and the benzodiazepine site of GABA A 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.All studies described in this report were funded by UCB Pharma. All authors are current or former employees of UCB Pharma.

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Interactions with Synaptic Vesicle 2 Proteins and the GABAA Receptor

“…In vivo binding data indicate 50% SV2A and BZD site occupancy at 0.2 and at 36 mg/kg, respectively, supporting in vitro results, with 100-fold lower PSL potency at the BZD site compared with SV2A. In the accompanying report, PSL is shown to be active in a variety of nonclinical seizure and epilepsy models in the 0.1-10 mg/kg dose range (Leclerq et al, 2019). This finding corroborates observations that moderateto-high SV2 occupancy is associated with antiseizure activity and that low-level BZD site occupancy potentiates this effect (Kaminski et al, 2009a).…”

“…The objectives of the studies reported here are to characterize the interactions of PSL with its intended therapeutic targets and to determine its selectivity for these targets using an array of validated in vitro and in vivo techniques. The pharmacological profile of PSL in nonclinical models of seizures and epilepsy is reported in the accompanying article (Leclerq et al, 2019).…”

Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAA receptors

“…23 With both acute and repeated (twice daily for 4 consecutive days) dosing, Padsevonil increased the threshold for PTZ-induced seizures to the same extent, indicating that tolerance was not developed. 22 In contrast, diazepam, a full agonist at the BZD site, showed a reduced ability to increase the PTZ threshold after repeated dosing. 22 Clinical evidence also supports the observation that partial agonists may be associated with a lower risk of tolerance.…”

“…22 In contrast, diazepam, a full agonist at the BZD site, showed a reduced ability to increase the PTZ threshold after repeated dosing. 22 Clinical evidence also supports the observation that partial agonists may be associated with a lower risk of tolerance. Clobazam, a partial agonist at the BZD site, has been used for the treatment of patients with Lennox-Gastaut syndrome for many years.…”

“…Although sufficient to contribute to antiseizure activity, the risk of developing side effects and tolerance could be reduced. Nonclinical studies have shown that Padsevonil is highly active in models of drug-resistant epilepsy 22 at doses that lead to >95% SV2A occupancy and <20% occupancy on GABA A Rs. 2 The potential of Padsevonil to induce tolerance was evaluated in the validated pentylenetetrazol (PTZ)-induced clonic seizure threshold test, where the ability of AEDs to increase the seizure threshold is evaluated after acute and repeated dosing.…”