Abstracts

Rationale:
Absence seizures occur in several epilepsy syndromes, most commonly in childhood absence epilepsy (CAE) and ethosuximide, valproic acid and lamotrigine are considered first line therapy. Absence seizures are characterized by sudden onset and offset, arrest of activity, staring and impairment of awareness with generalized 3 Hz spike wave discharges (SWD) on electroencephalogram (EEG). Oscillatory burst firing in the corticothalamic circuit is considered the underlying mechanism of absence seizures mediated in part through low threshold transient calcium channels (T calcium channels). The SWD on EEG associated with absence seizures are arrested when T channels and associated low voltage calcium currents are blocked. In a double blind, randomized clinical trial of ethosuximide, valproic acid and lamotrigine in 446 subjects with CAE, > 40% had not responded to treatment. Thus, there is a great need for additional medications to treat refractory absence seizures. Flunarizine is indicated for the prophylaxis of migraine and the treatment of vertigo including in children. In cultured rat cortical neurons flunarizine blocks both sodium and calcium currents in a concentration dependent manner with IC50vales of 0.94mM and 1.77mM respectively and demonstrates an approximate 10-fold selectivity for neuronal low-threshold calcium currents versus high-threshold calcium currents. Flunarizine has demonstrated efficacy in experimental models of absence seizures including both the pentylenetetrazole (PTZ) and gamma hydroxybutyrate (GHB) induced absence seizures in rats, when either administered independently or in combination with valproic acid or ethosuximide.
Method:
We are conducting an open-label, single-centre study to evaluate the clinical efficacy, safety and tolerability of XEN007 (containing flunarazine as the active pharmaceutical ingredient) administered as adjunctive treatment in 20 patients with treatment resistant absence epilepsy. Patients will undergo a screening visit and if they meet inclusion criteria, a baseline visit, three treatment phase visits and one follow-up visit. After one month baseline, patients receive 12 weeks of treatment. The initial dose of XEN007 to be initiated at Visit 2 will be 5mg/day and the dose can be escalated to 10mg/day at Visit 3. The primary outcome measure is median percent change in monthly absence seizure frequency in patients treated with XEN007 compared with the baseline period measured by evaluating patient seizure diaries at baseline and at the end of the treatment period. The secondary outcome measures include median percent change in the number of absence seizures on EEG, and bursts of SWD lasting 2 or more seconds in patients treated with XEN007 compared with the baseline period.
Results:
The study is ongoing and topline data from this open label study is expected by year end 2020.
Conclusion:
Supported by excellent clinical safety/tolerability in children, in-vitro mechanism of action against T calcium channels and in-vivo CAE pharmacology data, XEN007 is being tested as a potential treatment for CAE. Top line data is expected to be presented at the AES in 2020.
Funding:
:Grant from Xenon-Pharma to support research assistant, pharmacy costs and medication cost