Xenon Pharmaceuticals (XENE) Study result summary

Study design and patient population

• X-TOLE2 was a multicenter, randomized, double-blind, placebo-controlled phase III study evaluating azetukalner (AZK) as adjunctive therapy in adults with focal onset seizures, using once-daily oral dosing with no titration required.

• 380 patients were randomized; 374 received treatment, with a mean age of 40, a median of five prior anti-seizure medications, and baseline seizure frequency of 12.75–13 per month, reflecting a highly refractory population.

• Over half of participants were on three concomitant ASMs.

• Doses tested were 15 mg and 25 mg once daily.

Efficacy results

• X-TOLE2 met its primary endpoint, with the 25 mg group achieving a -53.2% median percent reduction in monthly seizure frequency versus -10.4% for placebo (p=0.000000000006); the 15 mg group had -34.5% (p=0.00007).

• Placebo-adjusted median percent change for 25 mg was -42.7%, outperforming prior Phase 2b results.

• Rapid onset of efficacy was observed, with significant reduction in weekly seizure frequency at week one for the 25 mg dose.

• RR50 responder rates: 54.8% for 25 mg, 37.6% for 15 mg, and 20.8% for placebo.

• Significant improvements in both patient and clinician global impression of change for both 15 mg and 25 mg groups.

Safety and tolerability

• Azetukalner was generally well-tolerated, with the most common adverse events being dizziness (20.5%), somnolence (8.8%), headache (8.8%), and fatigue (7.6%).

• Serious adverse events were low and similar across groups: 2.4% (placebo), 3.2% (15 mg), 5.6% (25 mg); no severe allergic reactions, retinal, cardiovascular events, or deaths occurred.

• Discontinuation due to adverse events: 3.2% (placebo), 4.8% (15 mg), 14.5% (25 mg); no individual event led to discontinuation in more than 5% of participants.

• Safety profile was consistent with prior studies, and no new safety concerns were identified.