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Abstract Details

Pronounced Antiepileptic Activity of Darigabat, a Subtype-Selective GABAA Receptor Positive Allosteric Modulator, in the Mesial Temporal Lobe Model of Drug-Resistant Focal Epilepsy
Epilepsy/Clinical Neurophysiology (EEG)
S13 - Epilepsy/Clinical Neurophysiology (EEG): Antiseizure Medications (1:12 PM-1:24 PM)
002

Mesial temporal lobe epilepsy (MTLE) is the most common form of drug-refractory epilepsy. Most of the morphological and electrophysiological features of human MTLE can be reproduced in mouse by unilateral intrahippocampal injection of kainate (MTLE mouse model). The MTLE model displays differential sensitivity to antiepileptic drugs and has a utility in the identification of new treatments for drug-resistant forms of focal epilepsy.

Darigabat is an α2/3/5 subunit-selective positive allosteric modulator of the GABAA receptor that has previously demonstrated broad spectrum activity in several preclinical models of epilepsy as well as in a clinical photosensitive epilepsy model. Here, we evaluated if selective enhancement of the inhibitory effect of GABA via this mechanism would suppress the aberrant overexcitation that underlies epileptic activity in a model of treatment-resistant focal seizures.

The objective of this study was to assess the acute antiepileptic effect of darigabat (CVL-865) in a preclinical model of drug-resistant focal seizures.

The MTLE mouse model is generated by unilateral intrahippocampal injection of a single low dose (1 nmole) of kainic acid in adult mice, and subsequent epileptic activity is recorded following implantation of a bipolar electrode under general anaesthesia. After a period of epileptogenesis (~4 weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) can be recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3-10 mg/kg, PO), and the positive control diazepam (2 mg/kg, IP).

Darigabat dose-dependently reduced the expression of HPDs, demonstrating comparable efficacy to diazepam at doses of 3 and 10 mg/kg.
Darigabat demonstrated robust efficacy in the MTLE model, a preclinical model of drug-resistant focal epilepsy. A Phase II proof-of-concept placebo-controlled, adjunctive-therapy trial (CVL-865-SZ-001, NCT04244175) has been initiated to evaluate efficacy and safety of darigabat in patients with drug-resistant focal seizures.
Authors/Disclosures
Rachel Gurrell (Cerevel Therapeutics)
PRESENTER
Dr. Gurrell has received personal compensation for serving as an employee of Cerevel Therapeutics. Dr. Gurrell has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Cerevel Therapeutics. Dr. Gurrell has stock in Pfizer Ltd.
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