Abstracts

Clarification of the Mechanism of Action of Cenobamate

Abstract number : 1.437
Submission category : 7. Anti-seizure Medications / 7E. Other
Year : 2024
Submission ID : 995
Source : www.aesnet.org
Presentation date : 12/7/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Raman Sankar, MD, PhD – University of California, Los Angeles

Louis Ferrari, RPh, MBA – SK Life Science, Inc.

Rationale: Cenobamate is a novel antiseizure medication (ASM) approved for the treatment of focal seizures in adults. In phase 2 trials, cenobamate has demonstrated a robust antiseizure effect in patients with difficult-to-treat focal seizures, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic. Cenobamate is currently being studied in primarily generalized tonic-clonic seizures. Cenobamate’s mechanism of action (MOA) is unique and bi-modal, combining selective blockade of persistent sodium currents (INaP) and positive allosteric γ-aminobutyric acid type A (GABAA) receptor modulation.

Methods: We review the available evidence and provide further insight related to cenobamate’s MOA.

Results: Preclinical studies showed that cenobamate exerts effects on voltage-gated sodium channels (NaV) and GABAA receptors. The INaP contributes to the generation of a paroxysmal depolarization shift, which may serve as a basis for epileptic foci. There is an increase in INaP in spontaneously bursting hippocampal neurons after epileptogenic stimuli such as experimental status epilepticus. In preclinical studies, cenobamate modulated NaV by preferential blockade of the INaP, while sparing the transient sodium current (INaT). It is likely that by sparing the INaT, cenobamate does not interfere with fast-spiking GABAergic interneuron function, thus preserving network inhibition. The effect of cenobamate’s selective INaP block on the resting membrane potential is augmented by its positive allosteric modulation of GABAA receptor- mediated tonic currents. This enhances the INaT, presumably via preferential potentiation of the tonic (extrasynaptic) receptors. This potentiation was not reversed by flumazenil and cenobamate did not displace flunitrazepam binding, which suggests positive allosteric GABAA modulation via non-benzodiazepine binding sites. The combined effects of limiting the INaP while augmenting the INaT effectively suppresses the epileptiform activity of principal neurons. Cenobamate’s selectivity for the INaP over the INaT likely represents action on the NaV1.6 channel over the NaV1.1 channel and is a feature not shared by traditional ASMs like phenytoin or carbamazepine.

Conclusions: Cenobamate selectively inhibits the INaP, while sparing the INaT. Cenobamate’s selective inhibition of the INaP may involve preferential action at NaV1.6 over NaV1.1 channels. Sparing of the INaT is critical for preserving the inhibitory activity of fast-spiking interneurons. This effect may be enhanced by cenobamate’s positive allosteric modulation of tonic (extrasynaptic) GABAA receptors.


Funding: Funded by SK Life Science, Inc.


Anti-seizure Medications