Pronounced antiseizure activity of the subtype-selective GABAA positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy

Aim: Darigabat is an alpha 2/3/5 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 (MILE) 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 (similar to 4weeks), 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 MILE 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.