Abstracts

Rationale: XEN1101 is a novel, small molecule, selective KCNQ2/3 (Kv7.2/7.3) potassium channel positive allosteric modulator being developed for the treatment of focal onset seizures and major depressive disorder. Its pharmacokinetic properties support once daily oral dosing without the need for titration at initiation of dosing or tapering at termination of dosing. In vitro CYP experiments suggest a low potential for drug-drug interactions. XEN1101 demonstrates higher in vitro and in vivo potency compared to the first generation Kv7.2-7.5 opener, ezogabine, and lacks the chemical properties that could form pigmented dimers. 

XEN1101 has been evaluated in a Phase I clinical study and in a companion pharmacodynamic crossover study using transcranial magnetic stimulation. These data demonstrated that dosing up to 25 mg QD was generally well tolerated in healthy volunteers, reduced cortical excitability, and demonstrated a strong pharmacokinetic/pharmacodynamic relationship. We now report baseline and preliminary data from X-TOLE, a Phase 2b study that was recently completed.

Methods: X-TOLE is a Phase 2b randomized, double-blind, placebo-controlled, dose-ranging, multicenter study with an optional 3-year open-label extension (OLE). X-TOLE studied clinical efficacy, safety, and tolerability of XEN1101 administered as adjunctive treatment in adults with focal epilepsy. Additional 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 antiseizure medications (ASMs). Subjects were randomized to one of three active treatment groups or placebo in a 2:1:1:2 ratio (XEN1101 25 mg: 20 mg: 10 mg: placebo). The double-blind treatment period lasted 8 weeks. The primary endpoint is percent change in monthly focal seizure frequency from baseline to double-blind period. Secondary endpoints include 50% response rates and Clinical Global Impression of Change.

Results: A total of 530 patients were screened and 325 patients randomized and treated. The double-blind phase of the study has been completed but analysis of unblinded data is not yet available. Subjects had an average age of 39.8 ± 13 years, 50.5% were female, and 9%, 40%, or 51% took 1, 2, or 3 background ASMs, respectively. Median seizure frequency was ~13 per month (28-days) at baseline. During double blind, 10 subjects had a total of 14 SAEs, 8 of which were possibly related to the study drug in 6 subjects. There were no signals of concern from blinded review of safety labs, vital signs, and ECGs. The overall dropout was 12.3%; 96.5% of study completers rolled over into the OLE.

Conclusions: XEN1101 is a novel, selective KCNQ2/3 (Kv7.2/7.3) potassium channel positive allosteric modulator being developed for the treatment of focal onset seizures. The X-TOLE results are currently blinded but will be unblinded prior to presentation. Preliminary data reveal typical baseline demographics for a focal epilepsy study, a relatively low dropout rate and high conversion to OLE. All unblinded safety and efficacy data will be presented using a poster format.

Funding: Please list any funding that was received in support of this abstract.: The X-TOLE Phase 2b clinical trial was funded by Xenon Pharmaceuticals Inc.