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- Title
Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial.
- Authors
French, Jacqueline A.; Porter, Roger J.; Perucca, Emilio; Brodie, Martin J.; Rogawski, Michael A.; Pimstone, Simon; Aycardi, Ernesto; Harden, Cynthia; Qian, Jenny; Luzon Rosenblut, Constanza; Kenney, Christopher; Beatch, Gregory N.
- Abstract
Key Points: Question: Is the novel Kv7.2/Kv7.3 potassium channel opener XEN1101 effective in reducing the monthly seizure frequency in adults experiencing focal-onset seizures (FOSs) despite treatment with 1 to 3 baseline antiseizure medications (ASMs)? Findings: In this phase 2b randomized clinical trial including 325 patients with FOSs, treatment with XEN1101 was associated with a statistically significant and robustly dose-dependent decrease in monthly seizure frequency and was generally well tolerated, with adverse effects similar to those of currently available ASMs. Meaning: The findings of this trial support the continued development of XEN1101 for the treatment of FOSs. 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 This randomized clinical trial evaluates the efficacy and safety of XEN1101, a potassium channel opener, in the treatment of adults with intractable focal-onset seizures.
- Publication
JAMA Neurology, 2023, Vol 80, Issue 11, p1145
- ISSN
2168-6149
- Publication type
Article
- DOI
10.1001/jamaneurol.2023.3542