Pronounced antiseizure activity of the subtype‐selective <scp>GABA<sub>A</sub></scp> positive allosteric modulator darigabat in a mouse model of drug‐resistant focal epilepsy
Rachel Gurrell, Philip Iredale, Alexis Evrard, Venceslas Duveau, Céline Ruggiero, Corinne Roucard
Abstract
Abstract Aim Darigabat is an α2/3/5 subunit‐selective positive allosteric modulator of GABA A receptors that has demonstrated broad‐spectrum activity in several preclinical models of epilepsy as well as in a clinical photoepilepsy trial. The objective here was to assess the acute antiseizure effect of darigabat in the mesial temporal lobe epilepsy (MTLE) mouse model of drug‐resistant focal seizures. Methods The MTLE model is generated by single unilateral intrahippocampal injection of low dose (1 nmole) kainic acid in adult mice, and subsequent epileptiform activity is recorded following implantation of a bipolar electrode under general anesthesia. After a period of epileptogenesis (~4 weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) are recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3–10 mg kg −1 , PO), and positive control diazepam (2 mg kg −1 , IP). RESULTS Darigabat dose‐dependently reduced the expression of HPDs, demonstrating comparable efficacy profile to diazepam at doses of 3 and 10 mg kg −1 . CONCLUSIONS Darigabat exhibited a robust efficacy profile in the MTLE model, a preclinical model of drug‐resistant focal epilepsy. A Phase II proof‐of‐concept placebo‐controlled, adjunctive‐therapy trial (NCT04244175) is ongoing to evaluate efficacy and safety of darigabat in patients with drug‐resistant focal seizures.