Abstracts

Rationale: XEN1101 is a novel chemical entity that enhances activation of neuronal Kv7.2-7.5 (KCNQ2-5) potassium channels. XEN1101 is an investigational drug and 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 higher in vitro and in vivo potency and improved pharmacokinetics (PK) supporting once a day dosing. The objectives of this first Phase 2 clinical study are to evaluate the efficacy, safety, tolerability, and PK of oral XEN1101 in patients with refractory focal seizures. The doses for this study were selected based on XEN1101’s side effect profile in Phase 1 studies and surrogate pharmacodynamic endpoints obtained from transcranial magnetic stimulation (TMS) studies conducted in healthy subjects. Methods: This multicenter trial is being conducted at 90 sites in Europe and North America. Adult patients (~300) with focal epilepsy are planned to be randomized to 8 weeks of treatment with XEN1101 in one of three arms (25mg, 20mg, or 10 mg QD) or to placebo (randomized 2:1:1:2) in a double-blinded, parallel manner, stratified by background CYP inducer anti-epileptic drugs (AEDs). Significant effects on TMS measures present at 20 mg in a Phase 1 placebo-controlled trial (Beatch et al., AES 2018) were used to anchor the dose selection. Titration at initiation of dosing or tapering at termination of dosing are not required due to the PK characteristics of XEN1101. Eligibility criteria include ≥4 countable focal seizures per month recorded with an eDiary during an 8-week baseline period, while receiving stable treatment with 1-3 AEDs. Treatment with implanted neurostimulators and/or cannabinoids is permitted, as well as benzodiazepines as rescue medications for seizure clustering. Plasma PK samples will be collected at each visit. Safety evaluations include adverse event (AE) monitoring, clinical laboratory tests, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale assessment. Results: The primary endpoint is median percent change (MPC) in monthly (28 days) focal seizure frequency from baseline compared to the 8-week, double-blind treatment period versus placebo. Including a blinded sample-size reassessment, the study will have 90% power to detect a monotonic dose response assuming a -20% MPC in placebo and -25%, -30%, and -35% MPC at 10, 20, and 25 mg QD XEN1101, respectively. The Primary Analysis utilizes a closed, hierarchical testing procedure to control study-wide type I error to 0.05, and permits staged assessment of dose response followed by paired and grouped comparisons to placebo. Secondary endpoints include evaluation of responder rate compared to placebo, as well as evaluation of changes in weekly seizure frequency and quality of life assessments. Exploratory endpoints include evaluation of impact of XEN1101 on the number of seizure-free days, specific seizure types, time to pre-randomization monthly focal seizure count, and exploration of potential epilepsy-associated genes and biomarkers. The study is ongoing. Conclusions: Patients successfully completing the study may be eligible for enrollment in a long-term extension study. Incorporating TMS evidence of CNS activity in Phase 1 studies may be a useful adjunct in refining dose selection for Phase 2 epilepsy studies. Funding: The study is funded by Xenon Pharmaceuticals Inc