Interim Long-term Safety and Efficacy of XEN1101, a Potent, Selective Potassium Channel Opener: Update from an Ongoing Open-label Extension of a Phase 2b Study (X-TOLE) in Adults with Focal Epilepsy (S19.005)

Author: Rogawski, Michael ; Perucca, Emilio ; French, Jacqueline ; Beatch, Gregory ; Brodie, Martin ; Qian, Jenny ; Porter, Roger ; Harden, Cynthia ; Kenney, Christopher ; Rosenblut, Constanza Luzon

09 Apr 2024·Neurology

The Impact of Disease Severity on Responder Rates in a Phase 2b Study of XEN1101, a Potent, Selective Potassium Channel Opener, in Adults with Focal Epilepsy (X-TOLE) (S19.004)

Author: Kenney, Christopher ; Harden, Cynthia ; Perucca, Emilio ; Brodie, Martin ; French, Jacqueline ; Qian, Jenny ; Rosenblut, Constanza Luzon ; Beatch, Gregory ; Porter, Roger

01 Nov 2023·JAMA Neurology

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy

Article

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

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 &lt; .001 vs placebo; IQR, −80.4% to −16.9%) for 25 mg, 46.4% (P &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

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