Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy
Jacqueline A. French, Roger J. Porter, Emilio Perucca, Martin J. Brodie, Michael A. Rogawski, Simon N. Pimstone, Ernesto Aycardi, Cynthia L. Harden, Jenny Qian, Constanza Luzon Rosenblut, Christopher Kenney, Gregory N. Beatch, X-TOLE Study Group, Robert Armstrong, Ekrem Kutluay, Pavel Klein, Toufic Fakhoury, Kore Liow, Stephen Flitman, Victor Biton, Michael R. Sperling, David Kudrow, Mercedes Jacobson, Kamil Detyniecki, Fawad Khan, Evan Fertig, Ahmad Saeed Ata, Dean K. Naritoku, Bassel Abou‐Khalil, Sasha Alick-Lindstrom, Sami Aboumatar, Stephanie Callow, Shahram Izadyar, Robert Wechsler, Jerzy P. Szaflarski, Nathan B. Fountain, Imran Ali, George Li, Theresa Rodgers-Neame, Elizabeth Waterhouse, Selim R. Benbadis, Steve Chung, Maria Sam, Joanne Rogin, Eric Segal, Claude Steriade, Amir Arain, Richard Pellegrino, Kenneth D. Laxer, Mushtaque Chachar, Conrad C Nievera, Max Benzaquen, David Gloss, Ahmed Sadek, Lixin Zhang, Wei Ma, Aashit Shah, James Valeriano, Heidi Henninger, Jeffrey Tsai, Brian D. Moseley, Ruben Kuzniecky, Jerry J. Shih, Gregory Cascino, Alberto Pinzon-Ardila, Elizabeth E. Gerard, Samiya Rashid, Utku Uysal, Samuel Destefano, William O. Tatum, Suparna Krishnaiengar, Raymond Faught, Eric B. Geller, Rolando Ania, Baljeet Sethi, Barbara Phillips, Micaela Chatman, Eric Segal, A. Lerman, Naoir Zaher, Ricardo Ayala, Michael Gelfand, David Lesch, David G. Vossler, Paul D. Lyons, Ruben Kuzniecky, David Steiner, Martín del Campo, Jean‐François Clément, Seyed M. Mirsattari, Mary Connolly, Craig Heath, M. I. Richardson, Khalid Hamandi, Elizabeth Galizia, Kathleen M. White, Anthony G Marson, Rhys H. Thomas, Bernhard J. Steinhoff, Christian Brandt
Abstract
Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions: Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures: The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results: A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance: The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration: ClinicalTrials.gov Identifier: NCT03796962.