Abstracts

Rationale:
XEN496 is a pediatric granular formulation of the neuronal KCNQ (Kv7) potassium channel modulator ezogabine (retigabine) being developed by Xenon Pharmaceuticals as a precision medicine treatment for KCNQ2-related neonatal developmental and epileptic encephalopathy (KCNQ2-DEE). Ezogabine was previously marketed as a tablet formulation (Potiga®/TrobaltTM, GlaxoSmithKline) for adjunctive treatment of focal seizures in adults. This tablet formulation was also historically used off-label in the KCNQ2-DEE pediatric population. A Phase 1 (PK) study was undertaken to (i) characterize the PK of ezogabine following a single oral dose administration of XEN496, (ii) guide the dosing regimen for an upcoming pediatric efficacy trial of XEN496 in KCNQ2-DEE in which XEN496 will be dosed with food and (iii) to conduct a retrospective PK and safety assessment to bridge between XEN496 and Potiga®.
Method:
XEN496 was packaged in single-dose sachets. An open label, randomized, single dose, two-treatment, two-period, two-sequence, crossover study was conducted in which 24 healthy adult subjects received a single dose of XEN496 (equivalent to 400 mg of ezogabine) under fasted or fed conditions for two 48-hour in-unit treatment periods, each separated by at least 6 days. PK samples were analyzed for ezogabine and its major N-acetyl metabolite (NAMR) using a validated bioanalytical method. PK parameters included maximum concentration (Cmax), time to Cmax (Tmax), and area under the curve from time zero to infinity (AUC0-inf).
Results:
In this study, XEN496 was safe and well-tolerated with a safety profile comparable to that of Potiga®. When compared to administration in the fasted state, administration of XEN496 under fed (high-fat meal) conditions slightly reduced and delayed ezogabine’s Cmax, but did not affect the extent of ezogabine’s systemic exposure. Although food slightly delayed the NAMR Tmax, total systemic exposure of NAMR was also not affected. In general, XEN496 exhibited comparable PK to Potiga® [geometric mean ratios XEN496:Potiga® 0.70 (fed), 1.32 (fasted) for Cmax and 0.82 (fed), 1.02 (fasted) for AUC0-inf] and performed as expected for an immediate-release dosage form. In this sachet presentation, XEN496 is chemically stable for at least 9 months under ICH long-term conditions with further stability studies ongoing.
Conclusion:
For XEN496, the fed and fasted states were bioequivalent (BE) (i.e., the 90% confidence intervals were within the reference range of 80-125%) for AUC0-inf and close to BE for Cmax.  For NAMR, the fed and fasted states were BE for both of these PK parameters. When compared to historical Potiga® data, XEN496 exhibited comparable biopharmaceutical and safety performance, suggesting that no formulation-related dose adjustments are indicated for future clinical studies. XEN496 is being progressed to a planned Phase 3 clinical trial to evaluate its clinical efficacy, safety, and tolerability in approximately 40 pediatric patients with KCNQ2-DEE.
Funding:
:This study was funded by Xenon Pharmaceuticals Inc.