ezogabine (XEN496) / Xenon - LARVOL DELTA

Therapeutic Efficacy and Seizure Control with KCNQ2/3 Activators in Partial-onset Epilepsy: A Dose-response Network Meta-analysis of Randomized Controlled Trials (AAN 2026) - "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. 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."

Retrospective data • CNS Disorders • Epilepsy

Safety Outcomes of KCNQ2/3 Activators in Partial-onset Epilepsy: A Meta-analysis of Randomized Trials (AAN 2026) - "Objective: To analyze the safety outcomes of KCNQ2/3 activatorsBackground: KCNQ2/3 activators: retigabine(RTG) and azetukalner (XEN1101) are promising treatments for partial onset seizures targeting neuronal excitability to reduce seizure frequency. 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."

Retrospective data • CNS Disorders • Epilepsy • Movement Disorders

Retigabine ameliorates CRS-induced depressive-like behaviors and cognitive impairment by inhibiting endoplasmic reticulum stress-mediated apoptosis. (PubMed, Brain Res Bull) - "Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Psychiatry • Vascular Neurology • HSPA5

Autism-Related Phenotypes in a Heterozygous Scn2aR854Q Mouse Model and Their Partial Rescue via a Potassium Channel Opener. (PubMed, Neuropharmacology) - "Notably, acute administration of retigabine, a potassium channel opener, rescues specific ASD-related phenotypes, possibly by restoring decreased firing through reduction of slow sodium inactivation. Comparative analysis with Scn2a knockout models, which show similar current reduction, highlights the unique severity of R854Q, suggesting a role of Igp in modulating neurobehavioral outcomes and informing potential therapeutic strategies."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Epilepsy • Genetic Disorders • NAV1

C9orf72-derived dipeptide repeat proteins poly-PR disrupt membrane excitability and synaptic function in cortical neurons. (PubMed, Neurobiol Dis) - "The increased membrane excitability can be restored by Nav channel inhibitor riluzole and Kv7 channel activator retigabine. Our results suggest a rescuable ion channel-mediated hyperexcitability induced by poly-PR expression in cortical neurons, providing a foundation for developing targeted therapies for C9orf72 ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Neuro- And Neurite-Protective Benefits of Proprietary Kv7.4-Activating Otoprotective Drug Candidates Through Mitochondrial Modulation (ARO 2026) - "Results : Untreated rat dissociated cortical neuron cultures (control, no glutamate injury) was compared to glutamate-injury (20 μM) alone, or in combination with pre/post-treatment with ACOU082 (10/30/100/300/1000 nM), retigabine (3/10 μM) and BDNF (50 ng/mL)... These results clearly demonstrate a neuroprotective potential of ACOU082 with reduced cytochrome C release from mitochondria after excitotoxic insult, in addition to the previously reported otoprotective benefits in different hearing loss models. In addition to a potential for CNS benefits with systemic treatment, this also suggests potential treatment benefits in hearing loss from Kv7.4 activators on SGNs and neurites in the cochlea."

Otorhinolaryngology • BDNF

Impaired adrenergic regulation of Kv channels underlies LC hyperactivity and early-onset sleep disruption in AD-like amyloidogenic mice. (PubMed, Alzheimers Dement) - "These findings identify LC hyperexcitability as a mechanistic driver of early sleep disruption in AD and implicate α2A receptors and Kv7 channels as promising therapeutic targets for early intervention."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Sleep Disorder

Efficacy of a K+ Channel Agonist, XEN1101, For Preserving Contractility in Mouse Models of Hypokalemic Periodic Paralysis. (PubMed, Muscle Nerve) - "The KV7 potassium channel agonist XEN1101 is effective as both a prophylactic agent and as abortive therapy for management of low-K+ induced weakness in murine models of HypoPP. XEN1101 is more potent than the first-generation Kv7 agonist, retigabine, in our murine models of HypoPP and is also better tolerated in patients. These improvements provide a rationale for future clinical trials of XEN1101 in HypoPP patients."

Journal • Preclinical • CAV1 • NAV1

Efficacy of Retigabine in Treating Weakness in a Mouse Model of Hypokalemic Periodic Paralysis. (PubMed, Muscle Nerve) - "Kv7 channel activation by retigabine preserved contractile force even during sustained depolarization from severe hypokalemia. These findings extend prior work and support development of K+ channel agonists as a therapeutic approach for HypoKPP."

Journal • Preclinical

Anticonvulsant biotargets of digoxin: in silico study and in vivo verification. (PubMed, Ceska Slov Farm) - "To confirm the in silico results in vivo pharmacological studies under conditions of acute bicuculline-induced seizures and pentylenetetrazole kindling in mice have been carried out. It was established that digoxin shows high affinity to GABAergic biotargets and an identical to retigabine affinity to voltage-gated potassium channels KCNQ2 in silico...At the same time, the ability of digoxin to maximally enhance the anticonvulsant potential of sodium valproate has been revealed. Thus, it has been proven that the anticonvulsant properties of digoxin are most likely related to the ability to enhance the inhibitory properties of GABA and GABAergic agents."

Journal • Preclinical • CNS Disorders • Epilepsy

Improving Kv7 targeting anticonvulsants - will repurposing save the day? (PubMed, Br J Pharmacol) - No abstract available

Journal • CNS Disorders • Epilepsy

Evaluation of ASM with new mechanisms of action in the GAERS model of absence seizure (AES 2025) - "Indeed, SWD in GAERS are inhibited by the anti-seizure medications (ASM) used to treat absence seizures, such as ethosuximide, valproate and lamotrigine. But SWD in GAERS are also aggravated by ASM or other drugs known for worsening absence in patients, e.g. carbamazepine or vigabatrin.Some recent compounds with antiseizure properties and specific mechanisms of action have never been evaluated in the GAERS...Retigabine (4-8 mg/kg PO) produced a significant aggravation of SWD... Evaluation of new mechanisms of action in the GAERS may provide fresh hypothesis for the development of new compounds addressing absence seizures. Our study indicates that targeting potassium channels may be at risk of aggravating SWD, whereas targeting the 5-HT system may produce an interesting effect on absence seizures."

Absence Seizure Disorder • Anesthesia • CNS Disorders • Epilepsy

A First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of NS-041, a Novel KCNQ2/3 Activator, in Healthy Subjects (NS041HV101) (AES 2025) - "NS-041, a next-generation KCNQ2/3 activator, demonstrates enhanced potency, selectivity, and pharmacokinetic (PK) properties compared to first-generation agent retigabine. NS-041 demonstrated favorable safety and tolerability up to 45 mg (single-dose) and 35 mg (multiple-dose), with PK properties suitable for once-daily administration without titration. A Phase 2 proof-of-concept study is currently underway in patients with focal-onset seizures as adjunctive therapy."

Clinical • First-in-human • Late-breaking abstract • P1 data • PK/PD data • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Ophthalmology • Psychiatry

Neurodevelopmental features in KCNQ2 developmental and epileptic encephalopathy may have limited associations with KV7.2 dysfunction. (PubMed, Epilepsia Open) - "We examined how changes in the KCNQ2 gene, which affect the function of a brain potassium channel, relate to developmental and seizure features in children with KCNQ2-related epilepsy. Using parent surveys and lab studies of gene variants, we found that variants causing the channel to lose most of its function were linked to slightly worse overall development. Our results suggest that while channel dysfunction plays a role, other biological or environmental factors likely influence how severely children are affected."

Journal • CNS Disorders • Epilepsy

A first-in-human study to assess the safety, tolerability, and pharmacokinetics of NS-041, a novel KCNQ2/3 activator, in healthy subjects (NS041HV101) [WITHDRAWN] (Neuroscience 2025) - "NS-041, a next-generation KCNQ2/3 activator, demonstrates enhanced potency, selectivity, and pharmacokinetic (PK) properties compared to first-generation agent retigabine. NS-041 demonstrated favorable safety and tolerability up to 45 mg (single-dose) and 35 mg (multiple-dose), with PK properties suitable for once-daily administration without titration. A Phase 2 proof-of-concept study is currently underway in patients with focal-onset seizures as adjunctive therapy."

Clinical • First-in-human • P1 data • PK/PD data • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry

An automated patch clamp screen for enhancers of voltage-dependent potassium channels (Neuroscience 2025) - "Enhancement of Kv7 channels by retigabine and flupirtine is effective for treating some forms of epilepsy and pain, and enhancers have been found for a variety of other potassium channels, including BK and SK calcium-activated potassium channels, Kv1 channels, Kv3 channels, and K2P family channels...These results show the feasibility of identifying novel enhancers for Kv1.6 and Kv3.1b channels. On-going experiments to test the selectivity of the strongest enhancers among the channel families and determine activity on native channels in neurons will be discussed."

CNS Disorders • Epilepsy

A high-throughput in vitro functional platform for anti-epileptic drug screening in genetic and chemically induced seizure models (Neuroscience 2025) - "We established a chemically induced seizurogenic model by applying traditional pro-seizurogenic compounds with different mechanisms of action - picrotoxin (PTX), 4-aminopyridine, and pentylenetetrazol - as well as elevated extracellular K⁺ concentrations, to rat hippocampal neurons cultured on mwMEA plates. Then, we evaluated the anti-seizurogenic effects of valproate (VPA) and retigabine (RTG), which act on different molecular targets...Furthermore, VPA exhibited a more pronounced concentration-dependent inhibition in the DS group. Based on our study, the in vitro, cell-based mwMEA assay provides a novel approach for high-throughput screening and evaluation of antiepileptic drug candidates in both chemically induced and genetic defect models, potentially accelerating the discovery of new therapies for neurological disorders."

Preclinical • CNS Disorders • Epilepsy • NAV1

Evaluation of anti-epileptic mechanisms in the entorhinal cortex (EC) ex vivo using different convulsant models and analysis methods (Neuroscience 2025) - "We compared effects of several compounds (with known mechanisms of action) on different measures of epileptiform activity induced by either the GABAA antagonist gabazine, or the potassium channel blocker 4-aminopyridine (4-AP).Epileptiform activity was recorded from adult mouse EC brain slices using extracellular electrodes. Slices were maintained in an interface chamber at 32C and were preincubated for 75 minutes in test compounds including a WNK-kinase inhibitor (WNK463, 1 µM), a KV7 channel enhancer (retigabine, 20 µM), a GABAA receptor positive allosteric modulator (diazepam, 50 µM), a mGlu2/3 receptor agonist (LY354740, 3µM), or vehicle...Retigabine appeared to enhance delta band power (124±7% increase) but reduced other frequency bands' power (73±21% decrease).Taken together, these results show that different analysis methods can reveal distinct facets of epileptiform activity and their modulation by anti-convulsant mechanisms. In..."

Preclinical • CNS Disorders • Epilepsy

Role of Kv7 channels in the disruption of the blood-brain barrier induced by angiotensin II (Neuroscience 2025) - "Cells were exposed to Ang II (100 nM) in presence of Kv7 activators such as retigabine and ML213 (both used at 10 µM), and the effects on permeability of ECs and structure of tight junctions (TJs) were assessed by means of Trans-Endothelial Electrical Resistance (TEER) measurement, immunofluorescence, Western blot and Proximity Ligation Assay (PLA)...In particular, the depolarization prompted by reduced Kv7.5 levels might lead to calcium accumulation and phosphorylation of ZO-1, which, in turn, cause the rearrangement of TJs and the increase of the permeability of the BBB. Overall, these results highlight activation of Kv7 channels as a potential strategy to prevent BBB disruption caused by an overactive RAS."

CNS Disorders • Epilepsy • TJP1

The fast-dissociating D2 antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: potential repurposing for epilepsy treatment (Neuroscience 2025) - "These effects were blocked by the Kv7 inhibitor XE-991 and were not replicated by the D2 receptor antagonist (-)-sulpiride, confirming that the observed effects of JNJ-37822681 were specifically mediated via Kv7 channel activation. In vivo, JNJ-37822681 significantly reduced the severity and frequency of pentylenetetrazole-induced seizures in C57BL mice and sound-induced seizures in genetically epilepsy-prone DBA/2 mice, with a potency comparable to retigabine. Pretreatment with XE-991 attenuated the antiseizure effects of JNJ-37822681 in both models, further supporting a Kv7-dependent mechanism of action. Given its favorable safety profile in humans and lack of the chemical liabilities associated with retigabine, JNJ-37822681 represents a compelling candidate for further development of novel ASMs."

CNS Disorders • Epilepsy • DRD2 • KCNQ1OT1

Kr233: selective kcnq2/3 opener with best-in-class potential for epilepsy (Neuroscience 2025) - "Ezogabine (retigabine), the first KCNQ opener approved in 2011 for the treatment of focal seizures, was voluntarily withdrawn from the market in 2017 due to chemical issues unrelated to its action on Kv7.2/3...In preclinical models, KR233 provided robust protection against seizures in both the pentylenetetrazole (PTZ) and maximal electroshock (MES) -induced seizure models, with a good PK/PD correlation (EC50,plasma <50 ng/ml)...In contrast, XEN-1101 induced significant impairments at equivalent doses with TD50 < 40 mg/kg in the same condition...Overall, these results indicate that KR233 is a promising novel therapeutic candidate for the treatment of epilepsy. IND filling expected in Q3 2025."

CNS Disorders • Epilepsy

Development of an iPSC-derived KCNQ3 encephalopathy drug screening platform for drug discovery (Neuroscience 2025) - "Examination of the spike waveforms of neurons after spike sorting neuronal extracellular electrophysiological readouts identified that this KCNQ3 mutation is likely a gain-of-function variant, mimicking the effects of KCNQ activator retigabine, and opposing the effects of KCNQ blocker XE991, on neuronal spike waveforms that may contribute to identified neuronal network level impairments. These identified KCNQ3 mutation neuronal phenotypes were used to interrogate the efficacy of a therapeutic candidate on restoring normal KCNQ3 function. Taken together, these results describe the use of human iPSC-based models for drug discovery without the need for animal models and in line with the recently announced FDA Modernization Act 3.0."

Late-breaking abstract • CNS Disorders • Cognitive Disorders • Epilepsy • Psychiatry

Kv7 Channels as an Important Contributor to Alcohol-Induced Modulation of Neuronal Excitability in Neonatal Rat Superior Cervical Ganglion. (PubMed, Cells) - "We conducted whole-cell patch clamp recordings on neonatal (P5-P7) rat superior cervical ganglion neurons to assess alcohol impacts on action potential firing and ionic currents, utilizing tetrodotoxin (TTX), XE991, and retigabine (RTG). The combination of TTX with Kv7 modulators replicated the effects observed with each alcohol. These findings suggest Kv7 channel modulation plays an important role in the chain length-dependent effects of alcohol on neuronal excitability."

Journal • Preclinical • Addiction (Opioid and Alcohol)

Drug discovery research with the iPSC models of neurodegenerative diseases. (PubMed, Neurosci Res) - "In addition, clinical trials based on research with iPSCs have been conducted: bosutinib, ropinirole and ezogabine for ALS, WVE-004 and BIIB078 for ALS with frontotemporal dementia (ALS/FTD), and bromocriptine for familial AD. Finally, we also wish to mention screening studies utilizing artificial intelligence (AI)."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration

DECODING DOPAMINERGIC MODULATION OF N-TYPE CA²⁺ CHANNELS IN SUBTHALAMIC NEURONS AND IMPLICATIONS FOR PATHOPHYSIOLOGICAL REGULATION IN PARKINSON'S DISEASE (WCN 2025) - "This study aims to decode the D2R-Cav2.2 interaction and its role in regulating resting membrane potential (RMP) stability and neuronal firing dynamics, identifying novel therapeutic strategies to restore basal ganglia function. A multi-scale computational framework integrated: Biophysical modeling of STN ion channels (Na⁺, K⁺, Cav2.2, Ca²⁺-activated K⁺) using Hodgkin-Huxley equations parameterized with PD-specific electrophysiological data; Kinetic modeling of D2R-GPCR cascades (D2R→Gi/o→AC5→cAMP→PKA) regulating Cav2.2 phosphorylation, informed by FRET-based cAMP biosensors; In silico pharmacology screening FDA-approved agents (e.g., bromocriptine, retigabine) to assess effects on RMP, AP frequency, and β-oscillations. This work identifies a dual-target mechanism wherein D2R-Cav2.2 coupling and K⁺ channel activation synergize to normalize STN excitability. KCNQ openers (e.g., retigabine) offer a non-dopaminergic strategy to mitigate RMP depolarization and..."

CNS Disorders • Movement Disorders • Parkinson's Disease • CACNA1B • CAV2