Potiga (retigabine) / Bausch Health, GSK - LARVOL DELTA

Development and Clinical Modeling of Kv7 Channel Opener Prodrug for Treatment of Focal Onset Seizures and Status Epilepticus (Neuroscience 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®. These data together support that the Kv7 prodrug of ezogabine has suitable PK/PD profile for adjunct therapy to 1st line SE treatments that would allow for transition to oral post exposure treatment with the prodrug. As a prodrug of ezogabine, this prodrug is patent pending and can be developed under the 505(b)(2) regulatory pathway for FOS and SE."

Clinical • CNS Disorders • Epilepsy

Neurocognitive Effects of Antiseizure Medications in Children and Adolescents with Epilepsy. (PubMed, Paediatr Drugs) - "Topiramate and phenytoin are also associated with negative effects on cognition, in particular word-finding difficulties and other language deficits with topiramate, but there are few data available specifically on children. Lamotrigine, levetiracetam and fenfluramine are associated with improvements in some cognitive domains, although it is unclear whether these effects are directly attributable to the medications or are a result of improvements in seizures. Neutral effects on cognition (no substantial evidence of worsening) were suggested for carbamazepine, everolimus, lacosamide, oxcarbazepine, perampanel and valproate. There is limited data for cannabidiol, clobazam, eslicarbazepine acetate, ethosuximide, rufinamide, vigabatrin and zonisamide, although the available evidence suggests these drugs are not associated with severe cognitive impairment. There was too little information to reach conclusions about the effects of brivaracetam, felbamate, gabapentin,..."

Clinical • Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy • Pediatrics

Nicotine Enhances Firing Activity of Layer 5 Pyramidal Neurons in the Medial Prefrontal Cortex through Inhibition of Kv7 Channels. (PubMed, Biol Pharm Bull) - "By contrast, the Kv7 channel opener, retigabine reduced the number of firings, and the addition of nicotine did not increase the spike numbers. These results indicate that nicotine induces long-lasting enhancement of firing activity in mPFC layer 5 pyramidal neurons, which is mediated by the stimulation of the α4β2 and α7 nAChRs and subsequent increase in intracellular Ca levels followed by the suppression of the Kv7 channels. The novel effect of nicotine might underlie the nicotine-induced enhancement of attention, working memory and recognition."

Journal

Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate. (PubMed, J Med Chem) - "We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, HN37 has progressed to clinical trial in China for epilepsy treatment."

Journal • CNS Disorders

KCNQ Current Contributes to Inspiratory Burst Termination in the Pre-Bötzinger Complex of Neonatal Rats in vitro. (PubMed, Front Physiol) - "By contrast, activation of KCNQ with retigabine decreased inspiratory burst duration by ~35%. These data from reduced preparations suggest that the KCNQ current in preBötC neurons contributes to inspiratory burst termination."

Journal • Preclinical

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice. (PubMed, Neurosci Bull) - "In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state."

Journal • Preclinical • Neuralgia • Pain • Peripheral Neuropathic Pain • BDNF

Effects of Antipsychotic Drugs and Potassium Channel Modulators on Spectral Properties of Local Field Potentials in Mouse Hippocampus and Pre-Frontal Cortex. (PubMed, Neuropharmacology) - "Drugs tested were APDs haloperidol and clozapine as well as voltage-gated potassium channel modulators (KVMs) 4-aminopyridine (4-AP), tetraethylammonium, retigabine and E-4031. Phase-amplitude coupling between theta and gamma oscillations in HIP was significantly reduced by the administration of haloperidol and retigabine. These results provide previously undescribed effects of APDs on LFP properties and demonstrate novel modulation of LFP characteristics by KVMs that intriguingly overlap with the APD effects."

Journal • Preclinical • CNS Disorders • Immunology • Psychiatry • Schizophrenia

Pharmacological Activation of Neuronal Voltage-Gated Kv7/KCNQ/M-Channels for Potential Therapy of Epilepsy and Pain. (PubMed, Handb Exp Pharmacol) - "The well-known KCNQ opener retigabine (ezogabine or Potiga) was approved by FDA in 2011 as an anticonvulsant used for an adjunctive treatment of partial epilepsies. Fortunately, these side effects are compound-structures related and can be avoided. Thus, further identification and development of novel potent and selective Kv7 channel openers may lead to an effective therapy with improved safety window for anti-epilepsy and anti-nociception."

Journal • CNS Disorders • Hepatology • Pain

The K7 modulator, retigabine, is an efficacious antiseizure drug for delayed treatment of organophosphate-induced status epilepticus. (PubMed, Neuroscience) - "Retigabine was administered alone or adjunctive to midazolam (MDZ) at delays of 20- or 40-min in the soman model, and 60-min in the DFP model. This study demonstrates the antiseizure and neuroprotective efficacy of retigabine against OP-induced SE. Our data suggest retigabine could be a useful adjunct to standard-of-care and has potential for use in the absence of MDZ."

Journal • CNS Disorders • Epilepsy

Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization. (PubMed, Brain) - "Together these results identify Kcnq2/Kv7.2 as a distinctive SD regulatory gene, and point to SD as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as a potential adjunctive therapeutic target to inhibit SD incidence."

Journal • CNS Disorders • Epilepsy • Immunology • Migraine • Vascular Neurology

Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays. (PubMed, Adv Biol (Weinh)) - "The HD-MEA metrics can also be used to detect the effects of dosing the drug retigabine to human motor neurons. Finally, it is shown that the ability to detect drug effects and the observed culture-to-culture variability critically depend on the number of available recording electrodes."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Movement Disorders • Parkinson's Disease

KCNQ3 is the principal target of retigabine in CA1 and subicular excitatory neurons. (PubMed, J Neurophysiol) - "Additionally, we report that in the absence of KCNQ3 channels, retigabine can enhance CA1 pyramidal neuron activity, leading to a greater number of action potentials and reduced spike frequency adaptation; this finding further supports a key role of KCNQ3 channels in mediating the action of retigabine. Our work provides new insight into the action of retigabine in forebrain neurons, clarifying retigabine's action in the nervous system."

Journal • CNS Disorders • Epilepsy

Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder. (PubMed, Mol Psychiatry) - "In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders."

Clinical • Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial. (PubMed, Am J Psychiatry) - "The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted."

Clinical • Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry

[VIRTUAL] QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for ALS patients (CNSS 2021) - "This motor neuron degeneration was rescued by the Kv7.2/7.3 agonist Retigabine which also reversed hyperexcitability in a clinical trial of ALS patients. Overall, QurAlis is developing QRA-244, a more potent and selective Kv7.2/7.3 activator aimed at normalizing excitability of the ALS motor system, with a significant reduction in off-target driven adverse events. We believe that this compound offers a promising therapeutic approach to counteract disease progression induced by hyperexcitability in ALS patients."

Clinical • Alzheimer's Disease • CNS Disorders • Epilepsy

The ups and downs of alkyl-carbamates in epilepsy therapy: How does cenobamate differ? (PubMed, Epilepsia) - "Since 1955, several alkyl-carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. Given that ceno-bamate's mechanistic profile is unique among the alkyl-carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABA receptor and on persistent Na currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate."

Clinical • Journal • CNS Disorders • Epilepsy • Mood Disorders • Psychiatry

Molecular expression and functional features of Kv7 channels in human prostate smooth muscle. (PubMed, Andrology) - "Our findings suggest that Kv7.4 and 7.5 channels in prosatic smooth muscle play a critical role in the regulation of HPrSM tone and that Kv7 channel subtypes may be novel therapeutic targets for the treatment of LUTS associated with BPH."

Journal • Benign Prostatic Hyperplasia • KCNQ1OT1

The Functional Availability of Arterial Kv7 Channels Is Suppressed Considerably by Large-Conductance Calcium-Activated Potassium Channels in 2- to 3-Month Old but Not in 10- to 15-Day Old Rats. (PubMed, Front Physiol) - "In vessels of adult rats, inhibition of Kv7 channels or BK channels by XE991 or IBTX, respectively enhanced arterial contractility to a similar degree, whereas activation of Kv7 channels or BK channels by retigabine or NS19504, respectively reduced arterial contractility to a similar degree. Importantly, BK channels govern the extent of functional impact of Kv7 channels. This effect depends on the relationship between the functional activities of BK and Kv7 channels."

Journal

Beneficial effect of retigabine on memory in rats receiving ethanol. (PubMed, Pharmacol Rep) - "This beneficial effect of retigabine-ethanol interaction on memory may be a relevant element of the drug's impact on the development of addiction."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Cognitive Disorders • Epilepsy • Psychiatry

[VIRTUAL] Efficacy of 250 antiseizure drug combinations in a zebrafish model of Dravet Syndrome (AES 2020) - "Despite the promise of Epidiolex, most individuals with Dravet continue to be pharmaco-refractory, demonstrating that new treatments are needed...Surprisingly, zonisamide, a third line add on drug was efficacious when combined with a number of first, second, or third line therapy drugs, including VPA, clobazam, stiripentol, topiramate, 3-OH butyrate, ethoxusimide, levetiracetam, lacosamide, retigabine and piracetam. Finally, acetazolamide when combined with either clobazam, 3-OH butyrate, topiramate or ethoxusimide were remarkably efficacious, an effect that was absent when combined with rufinamide, pregabalin or levetiracetam. Alternative combinations of ASD therapies might be efficacious for monogenic intractable epilepsies. Funding: None"

Clinical • CNS Disorders • Epilepsy

Antiepileptic drug reduces early signs of clinical dysfunction in people with ALS (News-Medical) - P2, N=65; “…the ten-week, phase 2 study of 65 participants with ALS at 12 U.S. sites investigated the feasibility of using neuron excitability metrics as predictors of disease progression.…‘That finding could be useful in evaluating other drugs to treat ALS, or even for other diseases where motor neuron metrics could serve as key biomarkers.’"

P2 data • Amyotrophic Lateral Sclerosis • CNS Disorders

The Role of Potassium Channels in Chronic Stress-Induced Brain Injury. (PubMed, Biol Pharm Bull) - "Pharmacological experiments revealed that retigabine, a voltage-gated potassium channel opener, demonstrated a protective effect in CSBI rats. Taken together, our findings suggest that potassium channel function is disrupted in CSBI, and that potassium channel regulators may function as anti-CSBI drugs."

Journal • CNS Disorders • Vascular Neurology

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. (PubMed, JAMA Neurol) - P2 | "Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials. ClinicalTrials.gov Identifier: NCT02450552."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

[VIRTUAL] Administration of Selected Sodium Channel- Blocking Antiseizure Drugs Alters the Development of Pharmacoresistant Kindled Seizures (AES 2020) - "We have previously demonstrated that administration of the ASD, lamotrigine, which preferentially inhibits the fast-inactivation state of sodium channels, during the corneal kindling process can also promote pharmacoresistance to other ASDs that preferentially block the fast-inactivated state of sodium channels (e.g. carbamazepine), as well as valproic acid and retigabine (Koneval, Knox et al...Therefore, we sought to determine whether the chronic administration of lacosamide (LCM), which preferentially inhibits the slow inactivation state of sodium channels, during the corneal kindling process would induce a pharmacoresistant phenotype... This study suggests that early, chronic administration of fast-inactivation state preferring ASDs, such as lamotrigine, versus slow-inactivation state preferring ASDs, like LCM, early in the kindling process may significantly alter the development of pharmacoresistance in the corneal kindled mouse model of chronic neuronal..."

CNS Disorders • Immunology • Inflammation

[VIRTUAL] Preclinical In Vitro and In Vivo Comparison of the Kv7 Activator XEN1101 with Ezogabine. (AES 2020) - "XEN1101 is a novel chemical entity that has a strong rationale and multiple predicted benefits over ezogabine as a potential anti-epileptic drug. XEN1101 provides a mechanism of action not currently available for the treatment of epilepsy and top line data in a large adult focal seizure trial should be available in H1, 2021. Funding: N/A"

Preclinical • CNS Disorders • Epilepsy • Pediatrics