XEN393 / Neurocrine Biosciences, Xenon - LARVOL DELTA

XEN393, A Novel Selective Dual Inhibitor of NaV1.2/NaV1.6 Channels Prevents Electrically-Induced Seizures in Mice and Rats (AES 2019) - "Xenon is currently developing a selective inhibitor of NaV1.6 (XEN901) for epilepsy based on the hypothesis that nonselective sodium channel inhibitors like carbamazepine and phenytoin would be better therapeutics if they inhibited action potential firing in excitatory neurons (primarily driven by NaV1.2 and NaV1.6 channels) without inhibiting firing of inhibitory interneurons (primarily NaV1.1 channels) and also avoiding potential cardiac liabilities by not inhibiting NaV1.5. Brain concentrations of XEN393 that block the target channels but spare off-target channels like NaV1.1 were well tolerated and prevented electrical induced seizures in mice and rats. This work enables the testing of the hypothesis that dual selective NaV1.2/NaV1.6 inhibitors, such as XEN393, that spare NaV1.1, NaV1.3, and NaV1.5 may provide a new class of more effective seizure prevention AEDs that may be better tolerated in clinical practice."

Preclinical