Therapeutic Efficacy and Seizure Control with KCNQ2/3 Activators in Partial-onset Epilepsy: A Dose-response Network Meta-analysis of Randomized Controlled Trials
Shrideavi Murugan1, Noorul Hidhaya S2, Gurunathan Srinivasan2, Tejaswin Mariappan2, Haran Srinivasan Saravanan3, Praveen Nandha Kumar Pitchan Velammal4, Javed Ahamed Cumbum Syed5
1Tirunelveli Medical College, India, 2Stanley Medical College, India, 3Government Medical College, Omandurar Government Estate, India, 4University of Tennessee Health Science Center, 5University of Michigan, Ann Arbor, USA
Objective:
To compare the efficacy of different doses of KCNQ2/3 activators—retigabine (RTG) and XEN1101—against placebo in reducing partial-onset seizure frequency.
Background:
KCNQ2/3 activators are promising adjunctive treatments for partial onset seizures, targeting neuronal excitability to reduce seizure frequency. They open Kv7.2/7.3 channels to enhance the neuronal M-current, stabilizing membrane potential and suppressing hyperexcitability that drives focal seizures. This NMA evaluates their dose-wise comparative efficacy across RCTs.
Design/Methods:
We performed a systematic review and meta-analysis following PRISMA guidelines. Suitable studies were identified through a comprehensive search performed across major databases up to September 2025. Data were analyzed using R (version 4.5.1) in RStudio, with the packages netmeta, gemtc, BUGSnet, and bnma. Both frequentist and Bayesian methods were employed to indirectly measure the efficacy using random models.
Results:
Four RCTs compared three doses each of retigabine (RTG: 600, 900, 1200 mg) and XEN1101 (10, 20, 25 mg) against placebo for seizure treatment. The highest dose, RTG 1200 mg, ranked highest across several measures: it demonstrated a mean reduction in total partial-seizure frequency of 120.93 (95% CI: [13.84, 228.02]) compared to placebo, and ranked first by SUCRA at 89% (over XEN1101 at 59% and placebo at 23%). RTG 1200 mg also provided the best seizure-free rate (OR 7.09[0.26, 138.5]; SUCRA 97.6% vs placebo 18.3%) and better maintenance phase responder rates (OR 4.26[0.97, 18.6]; SUCRA 54.2% vs placebo 9.7%). Separately, XEN1101 25 mg showed better treatment phase responder rates (OR 6.80[3.15, 14.7]), achieving a SUCRA ranking of 79.7% over RTG 600 mg (52.5%) and placebo (7.5%).
Conclusions:
RTG 1200 mg represents the most effective dose for reducing seizure frequency and achieving seizure freedom, emphasizing the importance of selecting an adequate dose to maximize Kv7.2/7.3 channel activation.
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