Abstracts

Rationale: Padsevonil (PSL; UCB0942) is an antiepileptic drug (AED) candidate that exerts its anticonvulsant effects through pre- and post-synaptic mechanisms. It selectively binds with high affinity to the three isoforms of synaptic vesicle 2 proteins (SV2A, B, C) and with ~100-fold lower affinity to the benzodiazepine site of the GABA_A receptor, acting as partial agonist (Wood M, et al. AES 2017, abst 1.271; Wolff C, et al. AES 2017, abst 1.270). PSL displayed potent activity in a range of mouse models representing focal and generalized seizures (Leclercq K, et al. AES 2017, abst 1.272; Kaminski RM, et al. AES 2017, abst 1.273). We report on the protective effects of PSL in two chronic epilepsy models characterized by spontaneous recurrent seizures: 1) the mouse intrahippocampal kainate model of focal epilepsy and 2) the genetic model of absence epilepsy in rats (Genetic Absence Epilepsy Rat from Strasbourg; GAERS). Methods: Male C57BL/6J mice were surgically injected with kainate (1 nmol) in the right dorsal hippocampus. Bipolar EEG electrodes were implanted into the injected hippocampus, with additional monopolar surface electrodes placed over the frontoparietal cortex and cerebellum. After a 5-week period of epileptogenesis, mice (n=9) displaying hippocampal paroxysmal discharges (HPDs, =20/h) without any generalized seizures were selected for the study. Baseline EEG (20 min) was recorded before injection of vehicle or PSL (1–30 mg/kg; ip) and recording continued for additional 90 min. The number and duration of HPDs were measured. Male GAERS were surgically implanted with four bilateral cortical electrodes in frontal and occipital areas, and allowed a 2-week recovery period after surgery. After a 20 min baseline EEG assessment, rats (n=8) were injected with either vehicle or PSL (0.14–4.33 mg/kg; ip) and EEG recordings continued over consecutive 20 min epochs up to 120 min. The cumulative duration of spontaneous spike-and-wave discharges (SWDs) in each 20 min epoch was measured. Results: PSL at all tested doses induced a statistically significant and dose-dependent reduction of the number of HPDs in the kainate model. At 10–30 mg/kg doses, HPDs were almost completely abolished immediately after the injection. Consequently, similar effects of PSL were observed when cumulative duration of HPDs was calculated. PSL dose-dependently inhibited SWDs in GAERS and nearly complete suppression was observed at the dose of 4.33 mg/kg. These effects were already apparent in the first 20 min epoch and persisted throughout the recording period. The ED₅₀ of PSL (dose producing a 50% reduction in the total duration of SWDs) was 0.87 mg/kg. Conclusions: PSL displayed potent activity in the intrahippocampal kainate model of focal seizures that was reported to be resistant to several AEDs (Duveau V, et al. CNS Neurosci Ther 2016;22:497–506). Similarly, potent effects of PSL were observed in a genetic model of absence epilepsy. These data, together with previously reported effects of PSL in acute models, indicate potential efficacy against both focal and generalized seizures. Funding: UCB Pharma-sponsored