XEN1101 Reduces Monthly Frequency of Seizures in Adults With Focal Epilepsy

A novel potassium channel opener, XEN1101, reduced monthly seizure frequency in a dose-response manner in adults with focal epilepsy, according to the findings of a phase 2b randomized clinical trial published in JAMA Neurology.

In the trial, X-TOLE (ClinicalTrials.gov Identifier: NCT03796962), researchers sought to determine the safety and tolerability of XEN1101, and efficacy with respect to seizure frequency.

At 97 study sites, the researchers initiated treatment in 325 people, between the ages of 18 and 75, in Europe and North America, who experienced at least 4 focal-onset seizures (FOSs) per month, and who continued to take their current antiseizure medications during the study. During the 8-week blinded treatment phase, between June 2019, and August 2021, participants were allocated, in a 2:1:1:2 ratio, to receive either 25 mg, 20 mg, or 10 mg of XEN1101, or placebo, once daily, with food.

The primary efficacy analysis demonstrated that seizure frequency decreased in dose-dependent fashion during treatment.

Compared with placebo, the median decrease in seizure frequency among participants who received XEN1101 was:

• 52.8% of participants who received 25 mg (P <.001),
• 46.4% of participants who received 20 mg (P <.001), and
• 33.2% of participants who received 10 mg (P =.04).

The number of “responder” patients who achieved 50% reduction was similarly dose-dependent:

• 54.5% of participants who received 25 mg (P <.001),
• 43.1% of participants who received 20 mg (P <.001), and
• 28.3% of participants who received 10 mg (P =.04).

In 44–54% of patients, these responses occurred within the first treatment week.

Exploratory analyses, via the Clinical Global Impression–Change and Patient Global Impression–Change scales, indicated that overall health status also improved during the blinded treatment period, either statistically or numerically, at all dosage levels vs placebo.

The researchers noted that XEN1101 was generally well tolerated. The most common treatment-emergent adverse events included dizziness, somnolence, and fatigue, which occurred in dose-dependent frequency across groups, and were similar to those noted for other antiseizure drugs. No tissue discoloration events occurred, by contrast with a previously withdrawn drug in this class.

Discontinuation rates of XEN1101 and placebo were as follows:

• 15.8% of participants who received 25 mg,
• 13.7% of participants who received 20 mg,
• 2.2% of participants who received 10 mg,
• 3.5% of participants who received placebo.

The researchers noted that discontinuation was most often prompted by dizziness, followed by balance dysfunction, dysarthria, and gait disturbance.

Low rates of serious psychiatric and neurologic adverse events were noted, occurring in 7 participants across all XEN1101 doses, compared with 3 participants in the placebo group. No cardiovascular safety signals were noted, and no deaths occurred.

The study population was nearly 92% White, disallowing meaningful analyses of efficacy by race. In addition, the onset of the COVID-19 pandemic during the blinded treatment period could have introduced bias by limiting study enrollees to those with more clinically severe presentations.

“The findings of this study suggest that XEN1101 has the potential to address the unmet need for a treatment with a novel mechanism of action for patients for FOSs,” the researchers concluded.

A 5-year open-label extension of X-TOLE is ongoing.

Disclosures: Several study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures.