Interim analysis of the long-term efficacy and safety of azetukalner in an ongoing open-label extension study following a phase 2b clinical trial (X-TOLE) in adults with focal epilepsy

Abstract

Objective: To report interim data from an ongoing, open-label extension (OLE) of a Phase 2b study (X-TOLE) of azetukalner in adults with focal onset seizures (FOS) receiving 1-3 antiseizure medications.

Methods: Eligible participants enrolled in the 7-year OLE at 20 mg azetukalner once daily with food. Long-term seizure outcomes included median percentage change (MPC) in monthly (28 days) FOS frequency from the double-blind phase (DBP) baseline and achievement of ≥50%, ≥75%, ≥90%, and 100% seizure reductions.

Results: 285 participants completed the DBP, and 275 (96.5%) enrolled in the OLE. At the 24-month interim analysis (September 5, 2023), 182 participants had been treated for ≥12 months and 165 for ≥24 months; 152 (55.3%) continued in the study. The median (range) treatment duration in the OLE was 26.3 (0.1-46.6) months. MPC reduction was 83.2% at 24 months in the OLE vs. DBP baseline. For all participants who entered the OLE, 56.4% (155/275) and 44.4% (122/275) achieved a ≥50% seizure reduction, 28.4% (78/275) and 19.6% (54/275) achieved a ≥90% seizure reduction, and 22.2% (61/275) and 14.9% (41/275) achieved seizure freedom (100% seizure reduction) for any consecutive ≥6- and ≥12-month period, respectively. For those who reached ≥24 months in the OLE, seizure freedom was achieved by 34.5% (57/165) and 23.6% (39/165) for any consecutive ≥6- and ≥12-month period, respectively. The majority of treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were dizziness (21.8%), headache (15.3%), coronavirus infection (15.3%), somnolence (12.7%), fall (12.7%), and memory impairment (10.9%). Serious AEs were reported in 35 (12.7%) participants.

Significance: The efficacy demonstrated by azetukalner in reducing FOS seizure frequency in the DBP was sustained in this interim analysis. Azetukalner was generally well tolerated, with no new safety signals compared to the DBP. These data suggest sustained long-term efficacy and safety of azetukalner in a difficult-to-treat population.

Plain language summary: This long-term study assessed the safety and efficacy of azetukalner to treat focal seizures. Patients taking azetukalner daily with food for about 2 years had far fewer focal seizures with azetukalner than before taking the medication. For those who had been treated for 24 months, about a third were seizure-free for a consecutive 6-month period, and about a quarter were seizure-free for a consecutive 12-month period. Most side effects were mild or moderate, and these included dizziness, headache, and somnolence (sleepiness).

Keywords: antiseizure medication; azetukalner; epilepsy; focal seizure; open‐label trial; potassium channel opener.

FIGURE 1

Participant disposition. DBP, double‐blind period; OLE, open‐label extension; QD, once‐daily dosing.

FIGURE 2

MPC in monthly FOS frequency during the DBP and OLE. (A) MPC for the overall OLE population. OLE participants separated by prior DBP treatment groups are shown for the first 2 months of the OLE. (B) MPC for the constant cohort (treatment ≥24 months and ongoing participants). ^aAll doses were taken with food with no titration. ^bAt OLE baseline, following DBP, all participants received 20 mg QD at the start of OLE (at month 0). DBP, double‐blind period; FOS, focal onset seizures; MPC, mean percentage change; OLE, open‐label extension; QD, once daily dosing.

FIGURE 3

Proportion of participants maintaining prespecified levels of monthly median percentage seizure reduction and seizure freedom from baseline for consecutive periods during 24 months of the OLE. (A) Overall OLE population (n = 275). (B) Participants treated in the OLE for ≥24 months (n = 165). (C) Proportion of participants maintaining seizure freedom for the overall OLE population (n = 275) and for those treated for ≥24 months (n = 165). OLE, open‐label extension.