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

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.

Trial registration: ClinicalTrials.gov NCT04244175 NCT04686786.

Keywords: CVL-865; GABA; MTLE; darigabat; drug-resistant epilepsy; focal; gaba; seizure (total ≥5, ≤8).

FIGURE 1

Example of a typical HPD in an EEG recording in a MTLE mouse selected in the study prior to compound administration. The HPD occurs spontaneously, with an obvious start and well‐defined stop over the basal EEG.

FIGURE 2

Time course of the effect of compound over time on number of HPDs. Time course of the effect of vehicle, darigabat (0.3, 3, 10 mg kg⁻¹, PO), and diazepam (2 mg kg⁻¹, IP) on the number of hippocampal paroxysmal discharges (HPD; mean ± SEM, n = 10) during baseline and post‐administration periods. The arrow indicates the timing of compound administration. #, ##, ###, ####: p < 0.05, 0.01, 0.001, 0.0001, respectively, as compared to vehicle using a two‐way ANOVA.

FIGURE 3

Effect of darigabat on number of HPDs. Dot plot (individual rodent) of hippocampal paroxysmal discharges (HPDs) during the 30‐ to 90‐min period after administration was measured and expressed as a % of the baseline HPD frequency (mean ± SEM, n = 10). #, ##, ###: p < 0.05, 0.01, and 0.001, respectively, as compared to vehicle using a one‐way ANOVA. Diazepam was administered 2 mg kg⁻¹, IP.