Long-term Safety and Efficacy of Azetukalner, a Novel, Potent KV7 Potassium Channel Opener in Adults with Focal Epilepsy: Update from the Ongoing 7-year Open-label Extension of X-TOLE
Abstract number :
2.361
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
702
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Jacqueline French, MD – New York University Comprehensive Epilepsy Center
Roger Porter, MD – University of Pennsylvania, Philadelphia, PA, USA
Emilio Perucca, MD, PhD – The University of Melbourne
Martin Brodie, MD – University of Glasgow Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, UK
Cynthia Harden, MD – Xenon Pharmaceuticals
Jenny Qian, MS – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada
Constanza Luzon Rosenblut, MD, MHSc – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada
Christopher Kenney, MD – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada
Gregory Beatch, PhD – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada
Rationale: Azetukalner (XEN1101) is in development as a treatment for epilepsy and major depressive disorder. In a randomized, double-blind, placebo-controlled Phase 2b study (X-TOLE) in participants with focal onset seizures (FOS), azetukalner (10, 20, and 25 mg once daily [QD] with food with no titration period) showed a dose-dependent, statistically significant, and rapid-onset reduction in FOS frequency (French JA, et al. JAMA Neurol. 2023;80:1145-1154). We have previously reported early results from the ongoing open-label extension (OLE); here we provide a further update with interim safety and efficacy data using a data cut from April 2024.
Methods: On completion of the double-blind period (DBP), eligible participants enrolled in the 7-year OLE to receive 20 mg QD in the fed state. Assessments were performed at week 3 in the OLE and at 3-month intervals thereafter. Safety assessments included frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), and clinically significant changes in laboratory findings. The primary efficacy outcome was median percentage change (MPC) in monthly (28 d) FOS frequency from DBP baseline.
Results: 285 participants completed the DBP, and 275 (96.5%) enrolled in the OLE. At the DBP baseline, these participants had a median of 13.5 FOS per month and were on stable treatment with 1–3 antiseizure medications (ASMs), with 52.4% taking 3 concomitant ASMs. At this interim analysis of the ongoing OLE (April 2024), 182 participants had been treated for ≥12 months and 152 for ≥30 months. 142 (51.6%) participants are ongoing. More than 600 participant-years of safety data have been generated to date through the OLE study. The most common reasons for discontinuation were lack of efficacy (n=42 participants, 15.3%), withdrawal by participant (n=37, 13.5%), and adverse event (n=34, 12.4%). TEAEs were reported in 241 (87.6%) participants, and 172 (62.5%) reported a treatment-related TEAE. The majority of TEAEs were mild or moderate; 46 participants (16.7%) reported severe TEAEs. The most common TEAEs were dizziness (n=62 participants, 22.5%), coronavirus infection (n=45, 16.4%), headache (n=44, 16.0%), somnolence (n=38, 13.8%), fall (n=36, 13.1%), memory impairment (n=32, 11.6%), and weight increase (n=29, 10.5%). The mean (SD) weight gain was 0.32 (8.0) kg at 2.5 years in the OLE. SAEs were reported in 39 (14.2%) participants; 6 (2.2%) were considered treatment related. There were 2 cases of sudden unexpected death in epilepsy (SUDEP), neither were reported as treatment related. The MPC was –86.9% at 30 months in the OLE. Updated safety and efficacy analyses will be presented.
Conclusions: In the ongoing X-TOLE OLE, azetukalner was generally well tolerated with no new safety signals. These promising interim data continue to suggest long-term safety and efficacy of azetukalner in a difficult-to-treat population.
Funding: This study was funded by Xenon Pharmaceuticals Inc.
Anti-seizure Medications