AAN 2022 Presentation - Darigabat: pronounced antiepileptic activity in the mesial temporal lobe mouse model of drug-resistant focal epilepsy

Darigabat: pronounced antiepileptic activity in the mesial temporal lobe mouse model of drug-resistant focal epilepsy

Rachel Gurrell, PhD

Senior Program Director, Cerevel Therapeutics

American Academy of Neurology

4 April 2022

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Subtype selective GABAA receptor PAMs have therapeutic potential in epilepsy

PAM = Positive Allosteric Modulator

Program Goals:

• # Broad spectrum efficacy

• # Improved AE profile vs classical BZDs, even at high receptor occupancy

• # Chronic dosing

Darigabat: compelling translational data package supports clinical development program

Darigabat Profile

Novel mechanism: α2/3/5-selective GABAA receptor PAM

 including at doses achieving ~80%

Generally well-tolerated clinically, receptor occupancy

Antiepileptic activity in proof-of-principle photoepilepsy clinical trial - 6/7 subjects with complete suppression of response

Gurrell et al., Neurology 2019

An animal model of MTLE demonstrates key features of drug-resistant focal epilepsy

Pharmacoresistance in focal epilepsy

Patients with drug-resistant focal epilepsy need innovative novel antiseizure medications (ASMs)Investigate darigabat in a translationally relevant nonclinical model of drug- resistant focal epilepsy

 Mesial temporal lobe epilepsy model:

Chronic spontaneous seizures

Morphological features Pharmacoresistance

MTLE = mesial temporal lobe epilepsy

Intra-hippocampal kainate injection

Chronic spontaneous seizures

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