Authors :
Presenting Author: Jacqueline French, MD – Department of Neurology and Comprehensive Epilepsy Center, New York University Grossman School of Medicine, NYU Langone Health
Roger Porter, MD – University of Pennsylvania
Emilio Perucca, MD, PhD – Department of Medicine (Austin Health), The University of Melbourne, and Department of Neuroscience
Martin Brodie, MD – University of Glasgow Department of Medicine and Therapeutics, Western Infirmary
Cynthia Harden, MD – Xenon Pharmaceuticals Inc.
Jenny Qian, MS – Xenon Pharmaceuticals Inc.
Constanza Luzon Rosenblut, MD – Xenon Pharmaceuticals Inc.
Christopher Kenney, MD – Xenon Pharmaceuticals Inc.
Gregory Beatch, PhD – Xenon Pharmaceuticals Inc.
Rationale:
Azetukalner, a novel, potent Kv7 potassium channel opener, is in development for treatment of focal onset seizures (FOS), primary generalized tonic-clonic seizures, and major depressive disorder. Efficacy and safety of azetukalner in FOS have been shown in a randomized controlled trial (French JA, et al. JAMA Neurol. 2023;80:1145-1154). The ongoing open-label extension (OLE) in FOS supports the long-term safety and efficacy of azetukalner. Here we provide the latest interim OLE results using a data cut from April 1, 2025.Methods:
Eligible participants who completed the double-blind period (DBP) began treatment with azetukalner 20 mg daily with food in the OLE. Site visits began at OLE week 3 and occurred at 3 or 6 months thereafter. Safety was assessed as frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). The efficacy outcome was median percentage change (MPC) in monthly (28 d) FOS frequency from DBP baseline.
Results:
Out of 285 participants who completed the DBP, 275 (96.5%) enrolled in the OLE. At DBP baseline, those entering the OLE had a median monthly FOS frequency of 13.5 and were taking 1-3 concomitant antiseizure medications, with 52.4% taking 3. As of the current data cut (April 1, 2025), 182 participants had received treatment for ≥12 months, 165 for ≥24 months, and 135 for ≥42 months; 123 (44.7%) are ongoing. As of the cutoff date, the OLE has generated >700 participant-years of safety data. The most common reasons for discontinuation were lack of efficacy (n=50 participants, 18.2%), withdrawal by participant (n=46, 16.7%), and AEs (n=36, 13.1%). TEAEs were reported in 246 (89.5%) participants; 178 (64.7%) reported a treatment-related TEAE. Most TEAEs were mild or moderate; 49 participants (17.8%) reported severe TEAEs. The most common TEAEs (≥10% of participants) were dizziness (n=64, 23.3%), headache (n=50, 18.2%), COVID-19 infection (n=47, 17.1%), somnolence (n=45, 16.4%), fall (n=39, 14.2%), weight increased (n=31, 11.3%), and memory impairment (n=29, 10.5%). The mean (SD) weight change was 0.78 (9.96) kg and the median (Q1, Q3) was 0 (−3, 4) kg at 3.5 years in the OLE. In total, 43 (15.6%) participants reported ≥1 SAE, of which 7 (2.5%) were considered related to the study drug. Across the entire DBP and OLE study duration, 2 deaths have been reported, 1 due to sudden unexpected death in epilepsy and 1 from viral pneumonia, neither considered treatment related. The MPC in seizure frequency was −87% for those remaining in OLE at 42 months. Updated safety and efficacy data will be presented.
Conclusions:
In this updated analysis of the ongoing X-TOLE OLE, azetukalner was generally well tolerated, and no new safety signals were identified. These promising interim data continue to support the long-term safety and efficacy of azetukalner in a difficult-to-treat population of patients with FOS.Funding:
Xenon Pharmaceuticals Inc.