- |||||||||| ezogabine (XEN496) / Xenon
Preclinical, Journal: Variant-specific in (Pubmed Central) - Nov 26, 2024
Phenytoin and levetiracetam reduced the excitability of GoF cultures, while retigabine showed differential and potentially beneficial effects on cultures with both GoF and LoF variants. We conclude that in
- |||||||||| CB03 / Zhimeng Biopharma
Preclinical Overview of CB03 (KCNQ2/3 Channel Opener) for Epilepsy (South Hall H - Level 1 - LACC) - Nov 26, 2024 - Abstract #AES2024AES_1316;
Preclinical data showed that CB03 was highly selective for KCNQ2/3, inhibited neuronal firing, and was effective in preventing seizures in epileptic animals. CB03 is a potential drug for treating epilepsy.
- |||||||||| ezogabine (XEN496) / Xenon
Pharmacological Assessment of Anti-seizure Medications in the Rat Amygdala-kindling model2.15.0.02.15.0.0 (South Hall H - Level 1 - LACC) - Nov 26, 2024 - Abstract #AES2024AES_1304;
This study highlights the translational relevance of the rat amygdala-kindling model for identifying novel compounds with improved tolerability and efficacy against focal and secondarily generalized seizures. Combining this model with a cross-over design offers a decision-enabling screening platform for epilepsy prevention and treatment, particularly in cases of pharmacoresistant focal seizures.2.15.0.02.15.0.0
- |||||||||| XEN1101 / Xenon, ezogabine (XEN496) / Xenon, BHV-7000 / Biohaven
New kv7 Channel Opener Chemistry for Treatment of Seizures (South Hall H - Level 1 - LACC) - Nov 26, 2024 - Abstract #AES2024AES_1276;
It is anticipated that the lead molecule, based on an in vivo minimum effective brain concentration of >20 nM for MES in mice and rats, a half maximal voltage shift of ~7 mV at 0.7 in rodents, may be effective at a plasma conc. of 30 nM, as a threshold conc., for clinical seizure protection in humans.
- |||||||||| ezogabine (XEN496) / Xenon, Humira (adalimumab) / AbbVie
Journal, Adverse events: Investigating drug-induced urinary retention: a pharmacovigilance analysis of FDA adverse event reports from 2004 to 2024. (Pubmed Central) - Nov 13, 2024
Additionally, less commonly associated drugs, such as adalimumab and others, were implicated, suggesting potential under-recognition of this adverse effect...This study underscores the importance of pharmacovigilance in identifying and understanding DIUR. Further research is needed to confirm these findings and develop strategies to manage and reduce the risk, improving patient outcomes.
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Retigabine increases the conformational stability of the visual photoreceptor rhodopsin. (Pubmed Central) - Oct 12, 2024
Furthermore, retigabine does not significantly affect transducin activation. These results provide novel insights into the potential therapeutic applications of retigabine in the treatment of retinitis pigmentosa caused by rhodopsin mutations that cause a decreased stability of the mutated receptors.
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Donepezil as a new therapeutic potential in KCNQ2- and KCNQ3-related autism. (Pubmed Central) - Aug 23, 2024
Loss-of-function (LoF) variants cause neonatal epilepsy, treatable with the M-current-opener retigabine, which is no longer marketed due to side effects...The CDI increased by 65% (p?<?0.05*), while the ABAS-II remained unchanged. Donepezil should be repurposed as a novel alternative treatment for GoF variants in KCNQ2/KCNQ3 encephalopathy.
- |||||||||| ezogabine (XEN496) / Xenon
The KCNQ (Kv7) potassium channel regulates cognitive and negative symptoms of Schizophrenia (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_9511;
The results suggest that blockade of KCNQ potassium channels may be an effective novel strategy for ameliorating the negative and cognitive symptoms of schizophrenia. Future directions include testing this hypothesis in a sub-chronic PCP model of schizophrenia, to investigate the role of KCNQ channels in regulation of behavior in a drug-free state.
- |||||||||| ezogabine (XEN496) / Xenon
Development and Clinical Modeling of Kv7 Channel Opener Prodrug for Treatment of Neuropathic Pain (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_3711;
In summary, a novel Kv7 prodrug of ezogabine has suitable PK/PD allows for a loading dose and small maintenance doses for targeted efficacy with minimal peak to trough swing that may be suitable for QD dosing for treatment of certain neuropathic pain conditions. As a prodrug of ezogabine, it is patent protected and can be developed under the 505(b)(2) regulatory pathway.
- |||||||||| ezogabine (XEN496) / Xenon
Early Dyshomeostatic Compensation Leads to Synaptic Dysfunction in KCNQ2 Developmental and Epileptic Encephalopathy in Patient-Specific iPSC-Derived Neurons (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_877;
Notably, these reduced evoked responses are phenocopied in control neurons by chronic M-channel inhibition with XE991 and rescued in patient neurons with chronic Kv7 activator (retigabine) treatment. Our findings elucidate the role of synaptic dysfunction in KCNQ2-DEE and offer critical insights into the complex interplay of mechanisms that govern both short- and long-term homeostatic plasticity during neurodevelopment, thereby enhancing our understanding of a genetic disease beyond the immediate effects of the mutation itself.
- |||||||||| Potiga (retigabine) / Bausch Health, GSK, ezogabine (XEN496) / Xenon, Seizalam (midazolam intramuscular) / Pfizer
Development and Clinical Modeling of Kv7 Channel Opener Prodrug for Treatment of Focal Onset Seizures and Status Epilepticus (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_615;
Our findings elucidate the role of synaptic dysfunction in KCNQ2-DEE and offer critical insights into the complex interplay of mechanisms that govern both short- and long-term homeostatic plasticity during neurodevelopment, thereby enhancing our understanding of a genetic disease beyond the immediate effects of the mutation itself. Its efficacy after IM dosing in maximal-electroshock was determined in rat and potential for DDI with IM midazolam was assessed...Allometrically scaled to human, a 200 mg dose is > 2uM at 100 minutes and is sustained for 20 h. The half-life of ezogabine from the administration of the prodrug is simulated to be 31 h by the IM route from the Kv7 prodrug compared to 6-8 h by the oral route from the tablet for Potiga
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity. (Pubmed Central) - Aug 14, 2024
Its efficacy after IM dosing in maximal-electroshock was determined in rat and potential for DDI with IM midazolam was assessed...Allometrically scaled to human, a 200 mg dose is > 2uM at 100 minutes and is sustained for 20 h. The half-life of ezogabine from the administration of the prodrug is simulated to be 31 h by the IM route from the Kv7 prodrug compared to 6-8 h by the oral route from the tablet for Potiga Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Exercise Enhances Anti-contractile Effects of PVAT Through Endogenous H2S in High-Fat Diet-Induced Obesity Hypertension. (Pubmed Central) - Aug 12, 2024
Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy. These results collectively suggest that endogenous H2S is a strong regulator of the anti-contractile effect of PVAT in obesity hypertension by long-term exercise, and KCNQ in the resistance artery might be involved during this process but not the only target channel mediated by H2S.
- |||||||||| ezogabine (XEN496) / Xenon
Preclinical, Journal: Kv7 channel opener retigabine reduces self-administration of cocaine but not sucrose in rats. (Pubmed Central) - Aug 1, 2024
Compared with sucrose-SA, cocaine-SA was associated with reductions in the expression of the Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward-specific reduction in SA behaviour and support the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
- |||||||||| ezogabine (XEN496) / Xenon
Review, Journal: In Silico Methods for the Discovery of Kv7.2/7.3 Channels Modulators: A Comprehensive Review. (Pubmed Central) - Jul 13, 2024
Nevertheless, there is a lack of available therapeutic options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016...In this context, in silico methods have played a major role, since the precise structures of different Kv7 homotetramers have been only recently disclosed. In the present review, the computational methods used for the design of Kv.7.2/7.3 small molecule agonists and the underlying medicinal chemistry are discussed in the context of their biological and structure-function properties.
- |||||||||| ezogabine (XEN496) / Xenon
Review, Journal: The role of KCNQ channel activators in management of major depressive disorder. (Pubmed Central) - Jun 9, 2024
Human studies investigating the effects of KCNQ channel activators, such as ezogabine, have shown promising results in alleviating depressive symptoms and anhedonia. The aforementioned observations underscore the therapeutic potential of KCNQ channel modulation in depression management and highlight the need and justification for phase 2 and phase 3 dose-finding studies as well as studies prespecifying symptomatic targets in depression including anhedonia.
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Glial KCNQ K+ channels control neuronal output by regulating GABA release from glia in C. (Pubmed Central) - Jun 6, 2024
Finally, we show that pathogenic loss-of-function and gain-of-function human KCNQ2 mutations alter glia-to-neuron GABA signaling in distinct ways and that the KCNQ channel opener retigabine exerts rescuing effects. This work identifies glial KCNQ channels as key regulators of neuronal excitability via control of GABA release from glia.
- |||||||||| ezogabine (XEN496) / Xenon
Developing KCNQ (Kv7) Type Channel Openers for Anhedonia and Depression: An Experimental Medicine Approach () - Apr 14, 2024 - Abstract #SOBP2024SOBP_933;
Although p.Arg448Ter is a non-sense decay, the functional study demonstrated an almost-full compensation mechanism after transfection of heteromeric KCNQ2 and KCNQ3. New neuroimaging results contribute to an understanding of the neural circuit-level effects of KCNQ channel modulation in the brain in the context of depression and anhedonia.
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Participation of calcium-permeable AMPA receptors in the regulation of epileptiform activity of hippocampal neurons. (Pubmed Central) - Apr 5, 2024
In turn, the Kv7 activator, retigabine, decreased the duration of the PDS cluster and Ca2+ pulse...The Kv7 channel is believed to be involved in the formation of PDS, as the channel blocker reduced the rate of hyperpolarization in the PDS almost three times. Thus, GABAergic neurons expressing CP-AMPARs, regulate the membrane potential of innervated glutamatergic neurons by modulating the activity of postsynaptic potassium channels of other GABAergic neurons.
- |||||||||| gaboxadol (OV101) / Ovid Therapeutics, Angelini Group, Healx, ezogabine (XEN496) / Xenon, bitopertin (DISC-1459) / Disc Medicine
Preclinical, Journal: Auditory brainstem responses are resistant to pharmacological modulation in Sprague Dawley wild-type and Neurexin1? knockout rats. (Pubmed Central) - Mar 20, 2024
First, we probed how different commonly used anesthetics (isoflurane, ketamine/xylazine, medetomidine) affect ABRs. In the next step, we assessed the effects of different pharmacological compounds (diazepam, gaboxadol, retigabine, nicotine, baclofen, and bitopertin) either under isoflurane or medetomidine anesthesia...Significant modulation was observed with (i) nicotine, affecting the late ABRs components at 90
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Kv7 CHANNELS ACTIVATION REDUCES BRAIN ENDOTHELIAL CELLS PERMEABILITY AND PREVENTS KAINIC ACID INDUCED BLOOD BRAIN BARRIER DAMAGE. (Pubmed Central) - Mar 4, 2024
The Kv7 activator retigabine increased transendothelial electrical resistance (TEER) in both primary ECs and BEND-3 cells; moreover, retigabine reduced paracellular dextran flux in BEND-3 cells...In BEND-3 cells, retigabine prevented the increase of cell permeability and the reduction of TJs integrity induced by KA. Overall, these findings demonstrate that Kv7 channels are expressed in the BBB, where they modulate barrier properties both in physiological and pathological conditions.
- |||||||||| ezogabine (XEN496) / Xenon
The role of the KCNQ (Kv7) potassium channel in regulation of cognitive and negative symptoms of Schizophrenia. (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_12336;
In agreement with our hypothesis, pharmacological activation of the KCNQ channel using a channel opener (Retigabine) exacerbated the PCP mediated deficits in social interaction, spatial working memory, and prepulse inhibition of startle response. The results suggest that the KCNQ potassium channel may provide an effective and novel mechanism for ameliorating the negative and cognitive symptoms of schizophrenia
- |||||||||| ezogabine (XEN496) / Xenon
Differential profile of anti-seizure medications in the rat amygdala-kindling model (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_5775;
This study was intended to highlight translational aspects of the rat amygdala-kindling model to identify new entities with improved tolerability and efficacy on focal and generalized seizures. The combination of this model and a cross-over design will provide a decision-enabling screening platform for the identification of novel compounds for the prevention, treatment, and modification of epilepsy, wherein pharmacoresistant focal seizures constitute the greatest challenge for treatment.
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Vitamin D Receptor Deficiency Upregulates Pulmonary Artery Kv7 Channel Activity. (Pubmed Central) - Aug 16, 2023
However, resistance PA from these mice exhibited increased response to retigabine, a Kv7 activator, compared to controls and heterozygous mice...These results indicate that the absence of Vdr in mice, as occurred with vitamin D deficient rats, is not sufficient to induce PAH. However, the contribution of Kv7 channel currents to the regulation of PA tone is increased in Vdr mice, resembling animals and humans suffering from PAH.
- |||||||||| ezogabine (XEN496) / Xenon, pynegabine (HN37) / Hainan Haiyao, Shanghai Inst. of Materia Medica
Journal: Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine. (Pubmed Central) - Jul 18, 2023
To improve the feasibility of drug production, we developed a concise, three-step process using unconventional methoxycarbonylation and highly efficient Buchwald-Hartwig cross coupling. The new synthetic route generated pynegabine at the decagram scale without column chromatographic purification and avoided the dangerous manipulation of hazardous reagents.
- |||||||||| ezogabine (XEN496) / Xenon
Review, Journal: Identifying the mechanism of action of the Kv7 channel opener, retigabine in the treatment of epilepsy. (Pubmed Central) - Jul 14, 2023
This review discusses the biochemical mechanisms about how retigabine acts on Kv7 channels, significance in neuronal pathophysiology, preclinical efficacy, and clinical stage of development. Additional efforts are being made to emphasize the possible benefits and drawbacks of retigabine compared to currently available medications for treatment-resistant epilepsy.
- |||||||||| ezogabine (XEN496) / Xenon
Enrollment change, Trial completion date, Trial termination, Trial primary completion date: EPIK: XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy (clinicaltrials.gov) - Jun 28, 2023
P3, N=8, Terminated,
We identify novel targets of CBD, contributing to a better understanding of CBD's clinical effects, and provide mechanistic insights into how CBD modulates different K 7 subtypes. N=40 --> 8 | Trial completion date: Dec 2024 --> May 2023 | Recruiting --> Terminated | Trial primary completion date: Nov 2024 --> May 2023; Sponsor decision; Not a safety decision
- |||||||||| ezogabine (XEN496) / Xenon
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: EPIK-OLE: An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE (clinicaltrials.gov) - Jun 28, 2023
P3, N=8, Active, not recruiting,
N=40 --> 8 | Trial completion date: Dec 2024 --> May 2023 | Recruiting --> Terminated | Trial primary completion date: Nov 2024 --> May 2023; Sponsor decision; Not a safety decision Recruiting --> Active, not recruiting | N=40 --> 8 | Trial completion date: Jan 2028 --> Nov 2023 | Trial primary completion date: Dec 2027 --> Sep 2023
- |||||||||| ezogabine (XEN496) / Xenon
Journal: Site and Mechanism of ML252 Inhibition of Kv7 Voltage-Gated Potassium Channels. (Pubmed Central) - Jun 25, 2023
This tryptophan residue in the pore is also required for sensitivity to certain activators, including retigabine and ML213...ML213 and ML252 likely have overlapping sites of interaction in the pore Kv7.2 and Kv7.3 channels, resulting in competitive interactions. In contrast, the VSD-targeted activator ICA-069673 does not prevent channel inhibition by ML252.
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