Abstracts

Rationale: XEN1101 is a novel chemical entity that enhances activation of neuronal Kv7.2-7.5 (KCNQ2-5) potassium channels and it is currently in clinical development by Xenon Pharmaceuticals as a treatment for epilepsy. XEN1101 is significantly differentiated from the first generation Kv7.2-7.5 opener retigabine, with greater in vitro potency on the Kv7.2 target, enhanced in vivo efficacy across multiple models, modest selectivity across Kv channels and reduced risk of pigmentation given lack of chemical dimer formation. The objectives of this first in human study were to evaluate the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending doses (SAD and MAD) of oral XEN1101. Methods: In the SAD Phase, 32 healthy volunteers were randomized (3:1) to XEN1101 (5, 15, 20, 25 or 30 mg) or placebo. The study featured an adaptive design. A crossover food effect cohort (N=10) was also completed with single doses of 20 mg. Repeat doses of XEN1101 (15 mg QD) were evaluated in a fasted and fed state (6 active and 2 placebo, per cohort) over 7 and 10 days, respectively. XEN1101 was formulated as an immediate release capsule. Serial plasma PK samples were collected for all cohorts. Safety evaluations throughout the study included adverse event (AE) monitoring, clinical laboratory tests, vital signs, ECGs, physical examinations and Columbia-Suicide Severity Rating Scale.  Results: XEN1101 displayed a PK profile suitable for once a day dosing with low peak to trough ratio. XEN1101 had less than dose-proportional exposure in the fasted state, with absorption enhanced by food (~1.8 fold for AUC_inf). Single and multiple doses of XEN1101 were well tolerated at C_max levels up to 104 ng/mL and 57 ng/mL, respectively. Apparent steady state was achieved by Day 6, based on the 90% CI for the ratio of Day 6 and Day 7 C_min being 0.820 - 1.120 (i.e., within the range 0.8 - 1.25). The majority of AEs were mild or moderate, resolved spontaneously and were consistent with antiepileptic drugs of this class (e.g., dizziness, sedation). There have been no SAEs, deaths, or clinically significant ECG or laboratory findings Conclusions: The current results suggest that XEN1101 is safe and well tolerated up to doses examined (single doses of up to 30 mg and multiple doses of 15 mg). The PK profile (including an effective half-life >24 hours), supports a once per day dosing schedule using an immediate release formulation, with attainment of steady state in 1 week without the need for titration. Complete, detailed study results will be presented at the meeting. Funding: Not applicable