Safety Outcomes of KCNQ2/3 Activators in Partial-onset Epilepsy: A Meta-analysis of Randomized Trials
Ashwini R1, Praveen Nandha Kumar Pitchan Velammal2, Gurunathan Srinivasan3, Noorul Hidhaya S3, Haran Srinivasan Saravanan4, Javed Ahamed Cumbum Syed5
1Tirunelveli Medical College, India, 2UTHSC, Memphis,TN,USA, 3Stanley Medical College, India, 4Government Medical College, Omandurar Government Estate, India, 5University of Michigan, Ann Arbor, USA
Objective:
To analyze the safety outcomes of KCNQ2/3 activators
Background:
KCNQ2/3 activators: retigabine(RTG) and azetukalner (XEN1101) are promising treatments for partial onset seizures targeting neuronal excitability to reduce seizure frequency. While they provide promising results, various safety concerns may limit tolerability. This meta-analysis aims to analyse the pooled safety outcomes of KCNQ2/3 activators compared with placebo.
Design/Methods:
A systematic review and meta-analysis was conducted according to PRISMA guidelines. RCTs comparing different doses of KCNQ2/3 activators such as retigabine (RTG- 600, 900, 1200 mg) and azetukalner (XEN1101-10, 20, 25 mg) with placebo were identified through major databases up to September 2025. Pooled odds ratios (ORs) was calculated using fixed or random effects models as appropriate.
Results:
4 RCTs including 1243 participants (773 in KCNQ2/3 and 470 in placebo) were included. KCNQ2/3 activators were associated with significantly higher risks of several adverse events compared with placebo, with all outcomes achieving statistical significance. These include nausea (Odds ratio: OR 1.64), tremor (OR 3.30), blurred vision (OR 3.18), Gait disturbance (OR 5.9), dysarthria (OR 9.68), confusion (OR 7.60), somnolescence (OR 2.29), dizziness (OR 3.49), and fatigue (OR 3.17). Overall, patients receiving KCNQ2/3 activators experienced more treatment-related adverse events and higher discontinuation rates as compared to placebo.
Conclusions:
KCNQ2/3 activators significantly improve seizure control but have very high adverse events, particularly CNS-related effects. Several adverse events, including dysarthria and tremor, showed markedly elevated odds compared with placebo. This can be due to their mechanism of enhancing neuronal hyperpolarization. Hence, careful dose optimization and close patient monitoring are essential to reduce these events. In future, strategies like dose calculation tailored to patients' genetic and clinical profiles should be developed, resulting in achieving the benefits without increasing harmful effects.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.