XEN901 for Epilepsy
XEN901, A Selective NaV1.6 Sodium Channel Inhibitor for the Treatment of Epilepsy
We are developing XEN901, a potent, highly selective NaV1.6 sodium channel inhibitor, for the treatment of epilepsy, including treatment resistant adult and pediatric focal seizures, as well as rare, pediatric forms of epilepsy, such as EIEE13, an early infantile epileptic encephalopathy associated with gain-of-function mutations in the SCN8A gene, which encodes the NaV1.6 sodium channel. By selectively targeting NaV1.6, it is anticipated that XEN901 may achieve efficacy conferred by this well-validated epilepsy target, but with a potentially improved therapeutic index compared with currently available non-selective sodium channel inhibitors.
There is strong human genetic validation supporting the rationale for treating epilepsy by blocking the NaV1.6 sodium channel. Nav1.6 is the most highly expressed sodium channel in the excitatory pathways in the CNS. When mutations in the SCN8A gene result in a gain of function in the NaV1.6 sodium channel, children can present with a very severe form of epilepsy. This early infantile epileptic encephalopathy is known as EIEE13. We have examined XEN901 in a pre-clinical model of genetically defined epilepsy as well as models representative of focal seizures. These studies showed that XEN901 is efficacious against seizures in both an SCN8A (NaV1.6) gain-of-function model, which is designed to be predictive of the pediatric genetic epilepsy EIEE13, and in the maximal electroshock seizure, or MES, model, which is designed to be predictive of adult focal seizures. When compared to phenytoin in both the SCN8A and MES models, XEN901 achieved the same degree of efficacy as phenytoin at one thousand fold lower brain exposures. XEN901 also was observed to have an improved therapeutic index relative to phenytoin as assessed by tests of rodent behavior and motor impairment.