Azetukalner in Adults With Focal Seizures

Importance Despite more than 30 approved antiseizure medications, many individuals with focal epilepsy continue to experience seizures, indicating a persistent need for novel therapies. Objective To determine efficacy and safety of the novel, potent K V 7 channel opener azetukalner for treatment of focal seizures. Design, Setting, and Participants This phase 3, placebo-controlled randomized clinical trial of azetukalner was conducted over a 12-week double-blind period (November 18, 2022, to February 3, 2026) at 138 sites in North America, South America, Europe, and Asia Pacific. Adults with focal epilepsy experiencing 4 or more focal seizures per month despite stable treatment with 1 to 3 antiseizure medications were enrolled. Data were analyzed using a dataset derived from the database lock dated February 26, 2026. Interventions Participants were randomized 1:1:1 to receive placebo or 15 or 25 mg of azetukalner once daily with the evening meal for 12 weeks with no titration period. Participants completing the double-blind period could enter an open-label extension. Main Outcomes and Measures The primary efficacy end point was median percentage change from baseline in monthly (28-day) focal seizure frequency during the double-blind period for azetukalner vs placebo. Safety and tolerability were assessed by recording treatment-emergent adverse events, changes in clinical laboratory findings, vital signs, and electrocardiogram. Results Of 607 adults screened, 374 participants (190 [50.8%] female; mean [SD] age, 40.0 [12.9] years) were enrolled, randomized and treated with placebo (125 participants), 15-mg azetukalner (125 participants), or 25-mg azetukalner (124 participants). Participants had a baseline median (IQR) of 12.75 (7.56 to 32.97) seizures per month and had previously tried and stopped a median (IQR) of 5 (3 to 8) antiseizure medications. Most (336 participants [89.8%]) were receiving 2 to 3 concomitant antiseizure medications. The median (IQR) change from baseline in monthly seizure frequency was −10.4% (−39.1% to 8.3%) for the placebo group, −34.5% (−61.6% to −12.3%) for the 15-mg azetukalner group ( P < .001 vs placebo), and −53.2% (−77.2% to −28.8%) for the 25-mg azetukalner group ( P < .001 vs placebo). Azetukalner was generally well tolerated, and treatment-emergent adverse events were comparable to those observed in the phase 2b X-TOLE trial. Conclusions and Relevance This randomized clinical trial found that azetukalner demonstrated robust, rapid, and durable reductions in seizure frequency with a favorable benefit-risk profile. Treatment with azetukalner resulted in one of the largest median percentage reductions in seizure frequency vs placebo reported to date in patients with drug-resistant epilepsy, supporting azetukalner as a promising novel antiseizure medication with significant opportunity to improve clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT05614063

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Journal
JAMA Neurology
Published
2026-11-09
DOI
https://doi.org/10.1001/jamaneurol.2026.4141
Primary Topic
Epilepsy research and treatment
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article
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article

Azetukalner in Adults With Focal Seizures

Jonathan M. Gursky, Heidi L. Henninger, Joseph Cahill, Prabal Datta et al.
JAMA Neurology
Epilepsy research and treatment
article

Azetukalner in Adults With Focal Seizures

Jonathan M. Gursky, Heidi L. Henninger, Joseph Cahill, Prabal Datta, Pegah Afra, Shanika R. Samarasekera, Gautam Popli, Rostam Namdari, Robert T. Wechsler, Charles Ákos Szabó, Jenny Qian, Shahram Izadyar, Susanne Knake, Sami Aboumatar, William Curt LaFrance Jr, Monica B. Dhakar, Daniel Winkel, Mark Robert Keezer, Felix Rosenow, Pavel Klein, Rajiv Mohanraj, Evan J. Fertig, Holger Lerche, Joseph W. McIntosh, Jennifer Pritchard, Jacqueline A. French, Nitish Harid, Vicente Villanueva, Tyson Burghardt, Constanza Luzon, Bettina Schmitz, Elizabeth Caruana Galizia, Dan Weber, Toufic A. Fakhoury, 立新 张, Meriem Bensalem‐Owen, Aamr A. Herekar, M Koepp, Arjune Sen, Rachel R. Fabris, Kore Kai Liow, José María Serratosa, Lara Vanessa Marcuse, Elmer López Meza, Gregory N. Beatch, Daniel S. Weisholtz, Dean K. Naritoku, Seyed M. Mirsattari, Eugen Trinka, Claude Steriade, Peter B. Forgacs, Shubhi Agrawal, Vishal Shah, Khalid Hamandi, Padmaja Kandula, Aashit K. Shah, Asfi Rafiuddin, Rainer Surges, Mercedes P. Jacobson, Victor Biton, Melissa Maguire, Christopher Kenney, Jeffrey J. Tsai, Ahmed Sadek, Sergio Jaramillo, Michael Amiri, Daniel Graf, George Li, Rafael Toledano, Jan Wagner, Giovanni Pellegrino, Thomas Mayer, David Labiner, Jan Rémi, Philippe Ryvlin, Tian Wang, Timothy Ryan, Robert Edward Hogan, Toni Winder, Ben Drapcho, X-TOLE2 Study Group, Alison Kostandy, Selim Benbadis, Rajiv Aggarwal, Hina Narendra Dave, Jennifer Haagensen, Roberto Alfonso Suastegui Roman, Aatif Husain, Samden Dorjee Lhatoo, Christian Brandt, Michael Sperling, Alvin Thomas Perkins, Andreas Schulze-Bonhage, Steven Flitman, Marvin Rossi, Samuel Terman, Veronica Sosa, Carlos Escasena, Danny Benmoshe
article en

Abstract

Importance Despite more than 30 approved antiseizure medications, many individuals with focal epilepsy continue to experience seizures, indicating a persistent need for novel therapies. Objective To determine efficacy and safety of the novel, potent K V 7 channel opener azetukalner for treatment of focal seizures. Design, Setting, and Participants This phase 3, placebo-controlled randomized clinical trial of azetukalner was conducted over a 12-week double-blind period (November 18, 2022, to February 3, 2026) at 138 sites in North America, South America, Europe, and Asia Pacific. Adults with focal epilepsy experiencing 4 or more focal seizures per month despite stable treatment with 1 to 3 antiseizure medications were enrolled. Data were analyzed using a dataset derived from the database lock dated February 26, 2026. Interventions Participants were randomized 1:1:1 to receive placebo or 15 or 25 mg of azetukalner once daily with the evening meal for 12 weeks with no titration period. Participants completing the double-blind period could enter an open-label extension. Main Outcomes and Measures The primary efficacy end point was median percentage change from baseline in monthly (28-day) focal seizure frequency during the double-blind period for azetukalner vs placebo. Safety and tolerability were assessed by recording treatment-emergent adverse events, changes in clinical laboratory findings, vital signs, and electrocardiogram. Results Of 607 adults screened, 374 participants (190 [50.8%] female; mean [SD] age, 40.0 [12.9] years) were enrolled, randomized and treated with placebo (125 participants), 15-mg azetukalner (125 participants), or 25-mg azetukalner (124 participants). Participants had a baseline median (IQR) of 12.75 (7.56 to 32.97) seizures per month and had previously tried and stopped a median (IQR) of 5 (3 to 8) antiseizure medications. Most (336 participants [89.8%]) were receiving 2 to 3 concomitant antiseizure medications. The median (IQR) change from baseline in monthly seizure frequency was −10.4% (−39.1% to 8.3%) for the placebo group, −34.5% (−61.6% to −12.3%) for the 15-mg azetukalner group ( P < .001 vs placebo), and −53.2% (−77.2% to −28.8%) for the 25-mg azetukalner group ( P < .001 vs placebo). Azetukalner was generally well tolerated, and treatment-emergent adverse events were comparable to those observed in the phase 2b X-TOLE trial. Conclusions and Relevance This randomized clinical trial found that azetukalner demonstrated robust, rapid, and durable reductions in seizure frequency with a favorable benefit-risk profile. Treatment with azetukalner resulted in one of the largest median percentage reductions in seizure frequency vs placebo reported to date in patients with drug-resistant epilepsy, supporting azetukalner as a promising novel antiseizure medication with significant opportunity to improve clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT05614063

JAMA Neurology
Brown University (US), Paracelsus Medical University (AT), Rhode Island Hospital (US), Centre Hospitalier Universitaire Vaudois (CH), Hospital Universitari i Politècnic La Fe (ES), NYU Langone Health (US), Christian Doppler Klinik (AT), UMIT - Private Universität für Gesundheitswissenschaften, Medizinische Informatik und Technik (AT), Xenon Pharmaceuticals (Canada) (CA), New York University (US), University of Lausanne (CH)
Epilepsy research and treatment
DOISourceOpenAlex
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