Abstracts

Rationale: XEN1101 is a novel voltage-gated potassium (Kv7.2/3) channel opener currently in clinical development by Xenon Pharmaceuticals Inc. as a treatment for epilepsy. Transcranial magnetic stimulation (TMS), in combination with electromyography (EMG) and electroencephalography (EEG), allows measurement of resting motor threshold (RMT) and TMS-evoked EEG potentials (TEPs), which may indicate drug effects on corticospinal and cortical excitability, respectively. Several antiepileptic drugs (AEDs) have been shown to significantly increase RMT values and modulate TEPs, indicating a shift towards corticospinal/cortical inhibition. TMS was used to non-invasively determine whether XEN1101 (10, 15 and 20 mg) impacts cortical excitability. This TMS pilot study was designed to inform sample size calculation for a larger randomized, double-blind and placebo-controlled TMS cross-over study (N=20) with XEN1101. Methods: Eight healthy, right-handed male subjects (aged 21-35 years, 62.4 - 95.4 kg) were enrolled in this open-label TMS pilot study. RMT and TEPs were recorded prior to XEN1101 administration and at 2 and 4 hours post dose. Single-subject level analyses were performed via multiple independent sample t-tests to determine the effects of XEN1101 on TEP amplitudes. Multiple comparisons were accounted for using cluster-based permutation analysis. Results: At 4 hours post-dose, 20 mg of XEN1101 (plasma levels = 50 ±10 ng/mL) significantly suppressed TEP amplitudes occurring at late latencies (e.g., the peak at 180ms (P180) after TMS by 1.92 ± 0.03 µV, p<0.01) in each participant (N=3). The 10 mg (N=2) and 15 mg (N=3) XEN1101 dosages, with mean plasma levels of 23.1 and 36.3 ng/mL at 4 hours, did not show significant and robust TEP modulation. At the 20 mg dose level, RMT tended to increase (4.3 ± 0.6% increase (p=NS)). The 20 mg dose of XEN1101 was therefore selected to be taken forward into a larger TMS cross-over study and results from this placebo controlled, cross-over TMS study which is currently underway, will be presented at the meeting. Conclusions: This TMS pilot study provided compelling evidence of the biological effect of 20 mg dose of XEN1101 in the central nervous system suppressing cortical and corticospinal excitability. These results suggest that TMS can be useful in identification of a biologically active dose in healthy volunteers and support continued development of XEN1101 for epilepsy. Complete detailed results of the cross-over TMS study currently underway, will also be presented at the meeting. Funding: Xenon Pharmaceuticals Inc sponsored the study.