XEN-1101: An Illuminating Prospect for Adults Afflicted by Focal Epilepsy

• XEN1101, marks a significant leap forward in the realm of precision medicine for drug-resistant epilepsy, as unlike current treatments that necessitate gradual dosage adjustments, XEN1101 offers the advantage of safe initiation at optimal dosage right from the start. 
• XEN1101 unveils compelling efficacy with a statistically significant reduction of at least 50% in seizure frequency for patients with focal epilepsy spanning a spectrum of disease severity, by regulating potassium channels to stabilize neuronal excitability

Focal-onset seizures (FOS), the predominant seizure type encountered in individuals with epilepsy, remain inadequately managed with existing anti-seizure medications (ASMs). While traditional medications fall short in stopping seizures for about one-third of patients and often come with significant side effects, Xenon Pharmaceuticals’ XEN1101, a potassium-channel opener, offers a promising solution. In cases where conventional treatments fail, XEN1101 enhances the release of potassium ions from neural tissues in the brain, effectively inhibiting neuronal firing and addressing a critical gap in epilepsy treatment.

At the recently concluded American Academy of Neurology Annual Meeting (AAN) 2024, the company presented abstracts of its lead drug candidate XEN1101. The interim data (NCT03796962) from the 18-month Phase IIb open-label extension study (X-TOLE) of XEN1101 (10, 20, and 25 mg once a day with food) in adults with focal onset seizures (FOS) were presented during the session. Of the 285 patients who completed the double-blind period (DBP), 96.5% (275 patients) enrolled in the open-label extension. Among them, 182 patients had received treatment for at least one year, and 170 for at least 18 months, with 57.8% (159 patients) continuing participation. The most commonly reported treatment-emergent adverse events (TEAEs) included dizziness, headache, fall, somnolence, and coronavirus infection. Overall, XEN1101 demonstrated a favorable safety profile similar to that observed in the DBP and other ASMs used for FOS treatment. No new safety concerns emerged, indicating the potential long-term efficacy of XEN1101 in this challenging patient population. 

Additionally, a presentation on the impact of disease severity on responder rates of XEN1101 in the Phase IIb study was made. The results highlighted that XEN1101 exhibited a significant, dose-dependent, and rapid reduction in focal onset seizure frequency among adults who had a median of 13.5 seizures per month and had previously tried six anti-seizure medications before stopping at baseline. A post hoc analysis suggested that the efficacy of XEN1101, as measured by the median percentage change in monthly FOS frequency might be most notable in patients with less severe disease. Consequently, an assessment of the potential impact of baseline disease severity on patients achieving a ≥50% reduction in seizure frequency (RR50), another commonly used endpoint for assessing ASMs, was conducted indicating XEN1101 effectiveness in patients with focal epilepsy in a range of disease severity. 

Research indicates that a significant portion of individuals with epilepsy fail to attain adequate seizure control using existing antiseizure medications (ASMs). Moreover, adults experiencing drug-resistant focal-onset seizures face considerable limitations in treatment options. XEN110, an innovative potassium channel opener, exhibits promising potential in reducing monthly seizure frequency among adults with refractory focal-onset seizures. By focusing on this demographic, XEN1101 holds promise for offering renewed prospects for enhanced seizure management and overall quality of life.