Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy
Authors: French Jacqueline A. , Porter Roger J. , Perucca Emilio , Brodie Martin J. , Rogawski Michael A. , Pimstone Simon , Aycardi Ernesto , Harden Cynthia , Qian Jenny , Rosenblut Constanza Luzon , Kenney Christopher , Beatch Gregory N. ,   X-TOLE Study Group, Armstrong Robert , Kutluay Ekrem , Klein Pavel , Fakhoury Toufic , Liow Kore , Flitman Stephen , Biton Victor , Sperling Michael , Kudrow David , Jacobson Mercedes , Detyniecki Kamil , Khan (Prev: Ramsay) Fawad Ahmed , Fertig Evan , Ata Ahmad Saeed , Naritoku Dean , Abou-Khalil Bassel , Alick Sasha , Aboumatar Sami , Callow (Prev: Moseley) Stephanie , Izadyar (Prev: Beach) Shahram , Wechsler Robert , Szaflarski Jerzy , Fountain Nathan , Ali Imran , Li George , Rodgers-Neame Theresa , Waterhouse Elizabeth , Benbadis Selim , Chung Steve , Sam Maria , Rogin Joanne , Segal Eric , Steriade Claude , Arain Amir , Pellegrino Richard , Laxer Kenneth , Chachar Mushtaque , Nievera Conrad , Benzaquen Max , Gloss David , Sadek Ahmed , Zhang Lixin , Ma Wei , Shah Aashit , Valeriano James , Henninger Heidi , Tsai (Prev: Miller) Jeffrey , Moseley Brian , Kuzniecky Ruben , Shih Jerry , Cascino Gregory , Pinzon-Ardila Alberto , Gerard Elizabeth , Rashid Samiya , Uysal Utku , Destefano Samuel , Tatum William , Krishnaiengar (Prev: Bautista) Suparna , Faught Raymond , Geller Eric , Ania Rolando , Sethi Baljeet , Phillips Barbara , Chatman Micaela , Segal(Satellite) Eric , Lerman Andrew , Zaher Naoir , Ayala Ricardo , Gelfand Michael , Lesch David , Vossler David , Lyons Paul , Kuzniecky (Satellite) Ruben , Steiner David , del Campo Martin , Clement Jean-François , Mirsattari Seyed , Connolly Mary , Heath Craig , Richardson Mark , Hamandi Khalid , Galizia Elizabeth , White Kathleen , Marson Anthony , Thomas Rhys , Steinhoff Bernhard , Brandt Christian , Lerche Holger , Surges Rainer , Kellinghaus Christoph , Moeddel Gabriel , Lehmann Rebekka , Rosenow Felix , Mayer Thomas , Schulze-Bonhage Andreas , Tilz Christian , Toledo Manuel , Villanueva Vicente , Sanchez Juan Carlos , Serrano-Castro Pedro , Rocamora Rodrigo , Saiz-Diaz Rosa Ana , Centeno Maria , Rodriguez-Uranga Juan , Serratosa Jose , Gil-Nagel (Prev: Aledo Antonio , Becerra Juan Luis , López-González Javier , Campos Dulce , Sanchez Violeta , Simon-Talero Manuel , Garcia Morales Irene , Toledano Rafael , Lisnic Vitalie , Kharchuk Sergii , Aguglia Umberto , Galimberti Carlo , Canafoglia Laura , Gambardella Antonio , Bisulli Francesca , Pizzanelli Chiara , Di Bonaventura Carlo , Shakarishvili Roman 
Published: October 2023

ImportanceMany patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.ObjectiveTo 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 ParticipantsThis 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.InterventionsPatients 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 MeasuresThe 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.ResultsA 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 &amp;lt; .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% (P &amp;lt; .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 RelevanceThe efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs.Trial RegistrationClinicalTrials.gov Identifier: NCT03796962