ezogabine (XEN496) / Xenon - LARVOL DELTA

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

Human iPSC-derived glutamatergic neurons with pathogenic KCNQ2 variants display hyperactive bursting phenotypes. (PubMed, Neurobiol Dis) - "Finally, we detected hyperexcitable neuronal networks in the G256W line with electrical stimulation of the neural networks on a high-density microelectrode array, and this phenotype was rescued with retigabine. These disease-related phenotypes for each of the KCNQ2 pathogenic variants can be used for drug screening to identify treatment options for the patients."

Journal • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Psychiatry

Human iPSCs : a translatable assay for screening novel peripheral analgesics (NeuPSIG 2025) - "Tetrodotoxin (TTx)-insensitive Na+ currents were isolated by manual patch-clamp (MPC) recordings using an Axon 700B amplifier/1332A digitizer interface (Molecular Devices). To functionally validate the expression of key "analgesic targets" we implemented a complementary MEA/Ca2+ imaging approach...Acute dosing with TTx, retigabine, linopirdine and mibefradil revealed that TTx-sensitive Na+, KV7 "M-current" and CaV3.x channels were key ionic mediators of spontaneous EAPs.To examine whether spontaneous EAPs provide a reliable metric for analgesic screening we applied clinically established analgesics. Strikingly, ibuprofen, naproxen, lidocaine, THC and cannabinol induced clear reductions in firing-frequency whilst vehicle controls and the centrally acting analgesic mirogabalin were without effect. In conclusion RealDRGTM hiPSC sensory neurons functionally express many key ion channels commonly targeted in analgesic drug development... In conclusion..."

Addiction (Opioid and Alcohol) • CNS Disorders • Neuralgia • Pain • CAV3 • TRPM3 • TRPM8 • TRPV1

Changing the Channel: Effects of a KCNQ Channel Opener (Ezogabine) on the Functional Connectivity of Reward Circuitry. (PubMed, Biol Psychiatry) - No abstract available

Journal

Activation of Kv7.2/3 channels in the PL-NAcc circuit attenuates methamphetamine-associated contextual memory. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "In METH-administered mice, METH-induced CPP, neuronal excitability and synaptic plasticity in the PL-NAcc circuit could be attenuated by injecting the Kv7.2/3 agonist retigabine in PL. Furthermore, overexpression of Kv7.3 channels' in the PL-NAcc circuit attenuated METH-induced CPP. Our findings identify hat the PL-NAcc circuit could be the main reason in METH-associated contextual memory and provide evidence that Kv7.2/3' activation in the PL may emerge as a novel therapeutic strategy for METH abuse."

Journal • CNS Disorders • Psychiatry • Substance Abuse

Discovery of Functionalized 1H-Benzo[d]imidazoles That Confer Protective Effects in a Phenotypic CLN3 Disease Patient-Derived iPSC Model. (PubMed, J Med Chem) - "Herein, we report the synthesis and characterization of bicyclic analogues of the bioisosteric non-opioid analgesics Flupirtine and Retigabine, previously shown to exhibit neuroprotective effects...Novel 1H-benzo[d]imidazoles that do not incur this metabolic liability are reported that possess enhanced protective effects in a highly phenotypic CLN3 patient-derived induced pluripotent stem cell (iPSC) model. Selected lead compounds 9b and 38b afforded significant protective effect and reduced phenotypic hallmarks of CLN3 pathology while also possessing "drug-like" pharmacokinetics."

IO biomarker • Journal • CNS Disorders • Metabolic Disorders • Pain • Pediatrics • BCL2

IDOR-1104-0086, a novel Kv7 channel activator with antiseizure effects in rodents. (PubMed, Neuropharmacology) - "In the current study, we further investigated IDOR-1104-0086's potency and selectivity profile on Kv7.1-7.5 isoforms and compared it to the known Kv7 channel opener and antiseizure medication retigabine...IDOR-1104-0086 is a potent activator of Kv7.2/3 channels that reduces focal-onset and generalized convulsive seizures in rodent models while being well tolerated. Its efficacious Kv7 channel activation properties make it a promising drug candidate for the treatment of drug-resistant epilepsy with focal-onset or generalized convulsive seizures."

Journal • Preclinical • CNS Disorders • Epilepsy

Translating Basic Science to Clinical Applications: A Narrative Review of Repurposed Pharmacological Agents in Preclinical Models of Diabetic Neuropathy. (PubMed, Biomedicines) - "A wide array of repurposed drugs-including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)-have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN."

Journal • Preclinical • Review • Diabetic Neuropathy • Inflammation • Neuralgia • Pain

The Pharmacokinetic and Pharmacodynamic Relationship of Clinically Used Antiseizure Medications in the Maximal Electroshock Seizure Model in Rodents. (PubMed, Int J Mol Sci) - "We assessed the pharmacokinetic/pharmacodynamic (PK/PD) profiles of six ASMs, namely carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA), lacosamide (LSM), cenobamate (CNB), and retigabine (RTG), using MES models in mice and rats. These results suggest that rats may exhibit greater sensitivity to seizure protection in the MES model, likely reflecting species differences in metabolism and brain penetration. These findings highlight the value of considering concentration-response variations and species-specific differences when assessing the efficacy of both conventional ASMs and novel compounds exhibiting anticonvulsant activity."

Journal • PK/PD data • Preclinical • CNS Disorders • Epilepsy

Machine Learning Resolves Functional Phenotypes and Therapeutic Responses in KCNQ2 Developmental Epileptic Encephalopathy iPSC Models. (PubMed, bioRxiv) - "Importantly, using unbiased machine learning models, we showed that chronic treatment with the K V 7 activator retigabine rescues the disease-associated functional phenotypes with variable efficacy. Our findings highlight SK channel upregulation as a critical pathophysiological mechanism underlying KCNQ2-DEE and provide a robust MEA-based machine learning platform useful for deciphering phenotypic diversity amongst patients, discovering functional disease biomarkers, and evaluating precision medicine interventions in personalized iPSC neuronal models."

Journal • CNS Disorders • Epilepsy

The fast-dissociating D2 antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: Potential repurposing for epilepsy treatment. (PubMed, Br J Pharmacol) - "Our study reveals that JNJ-37822681, which lacks retigabine's potential safety issues due to chemical liability and is already confirmed as safe for human use, represents a potential treatment of Kv7-related neuronal hyperexcitability disorders."

Journal • CNS Disorders • Epilepsy