XEN1101 is a positive allosteric modulator of Kv7 channels being developed for the treatment of epilepsy. Combination of anti-seizure drugs (ASD’s) is common in clinical practice. Hence we examined the potential for combination therapy with XEN1101 and other ASD’s. The efficacy of XEN1101 was evaluated in combination with valproic acid, phenytoin, or levetiracetam in the direct current maximum electroshock seizure assay (DC-MES). The combined efficacy of XEN1101 and levetiracetam was also evaluated in the 6 Hz psychomotor seizure assay (6Hz). 

We tested the efficacy of XEN1101 in combination with phenytoin in the DC-MES assay. A weakly efficacious dose of phenytoin (2 mg/kg protected 25% of mice) was combined with XEN1101 at 0.75, 1, 1.5, and 2.5 mg/kg in the DC-MES assay. XEN1101 was effective, with a total plasma EC50 of 0.154 µM when dosed alone and 0.04 µM when dosed in combination with phenytoin, a 3.85 fold increase in apparent potency. We next tested XEN1101 in the DC-MES assay in combination with valproic acid. A weakly efficacious dose of XEN1101 (1 mg/kg protected 30% of mice) was combined with valproic acid at 30, 56, and 100 mg/kg. Valproic acid showed a 50% effective total plasma concentration (EC50) of 1440 µM when dosed alone and 608 µM when dosed in combination with 1 mg/kg XEN1101, a 2.37 fold increase in apparent potency. Levetiracetam has been reported to be ineffective in the MES assay, but is effective in the 6Hz psychomotor seizure assay. To examine the combination of levetiracetam and XEN1101 we combined these compounds in both the DC-MES assay and the 6Hz assay. In the DC-MES assay adding levetiracetam (150 mg/kg, 25% protection) did not increase the effect of a modestly efficacious dose XEN1101 (1.5 mg/kg, 38% protection), with the combination protecting 50% of mice. In contrast, in the 6Hz assay, combining weakly efficacious doses of XEN1101 (4 mg/kg, 7% protection) and levetiracetam (300 mg/kg, 12% protection) did increase efficacy (67% protection). 

This data shows that of XEN1101 can improve seizure protection when combined with three anti-seizure drugs in rodent models.