Pronounced antiepileptic activity of the subtype‐selective GABA<sub>A</sub>‐positive allosteric modulator PF‐06372865 in the GAERS absence epilepsy model

Duveau, Venceslas; Buhl, Derek L.; Evrard, Alexis; Ruggiero, Céline; Mandé-Niedergang, Betty; Roucard, Corinne; Gurrell, Rachel

doi:10.1111/cns.13046

Cited by 21 publications

(27 citation statements)

References 31 publications

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“…35 There is preclinical evidence in models of anxiety and epilepsy that PAMs with lower intrinsic activity at the BZD binding site such as CVL-865 need to occupy a greater proportion of the receptors to produce the same magnitude of pharmacological activity as a BZD. 35 In addition, agents like CVL-865 with lower intrinsic activity could be associated with a reduced potential for tolerance induction, as previously demonstrated for other subtype-selective PAMs in animal models. 36 Efficacy in preclinical epilepsy models and in the clinical photosensitive epilepsy model supports the hypothesis that antiseizure activity can be attained with CVL-865, presumably by achieving high receptor occupancy at α2-containing subunits.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…The ability to achieve high receptor occupancy with a subtype‐selective PAM such as CVL‐865 is believed to be an important component of attaining efficacy. Nonselective BZDs are not full agonists at the BZD site of GABA A receptors but are highly effective PAMs with high intrinsic activity, which presumably enables efficacy to be observed in epilepsy with low (<20%) receptor occupancy 35 . There is preclinical evidence in models of anxiety and epilepsy that PAMs with lower intrinsic activity at the BZD binding site such as CVL‐865 need to occupy a greater proportion of the receptors to produce the same magnitude of pharmacological activity as a BZD 35 .…”

Section: Cvl‐865mentioning

confidence: 99%

“…Nonselective BZDs are not full agonists at the BZD site of GABA A receptors but are highly effective PAMs with high intrinsic activity, which presumably enables efficacy to be observed in epilepsy with low (<20%) receptor occupancy 35 . There is preclinical evidence in models of anxiety and epilepsy that PAMs with lower intrinsic activity at the BZD binding site such as CVL‐865 need to occupy a greater proportion of the receptors to produce the same magnitude of pharmacological activity as a BZD 35 . In addition, agents like CVL‐865 with lower intrinsic activity could be associated with a reduced potential for tolerance induction, as previously demonstrated for other subtype‐selective PAMs in animal models 36 .…”

Section: Cvl‐865mentioning

confidence: 99%

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Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older. 2366 | BIALER Et AL 1 | INTRODUCTION The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a virtual conference from July 27 to July 30, 2020 for sessions on drugs and on August 3, 2020 for sessions on devices. The conference attracted a record number of registered delegates, with 534 people from 63 countries attending lectures and interactive discussions, representing stakeholders from a broad range of disciplines from basic science, clinical research, and clinical care. The core of the conference was the presentation of data on compounds that are under development for the treatment of seizures and epilepsy. The identification and selection of these compounds are explained in an accompanying article, which presents summaries of data on eight compounds in preclinical or early (phase 1) clinical development. 1 The current article provides summary updates on compounds in more advanced clinical development, for which at least preliminary efficacy and safety data from relevant epilepsy patient groups are available. The five compounds include anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone. On November 21, 2019, the US Food and Drug Administration (FDA) granted approval to cenobamate for the treatment of partial onset (focal) seizures in adults, and on June 25, 2020, FDA approved fenfluramine oral solution for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Section: Cvl‐865mentioning

confidence: 99%

Section: Cvl‐865mentioning

confidence: 99%

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Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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“…44 In addition, PF-06372865 dose-dependently reduced the number of spike-and-wave discharges in the genetic absence epilepsy rats from Strasbourg (GAERS). 48 The rat half-life of 5.5 h for PF-06372865 translated into a half-life in man of 6.0-8.9 h over a dose range of 0.04 to 100 mg in an oral suspension. 45 Doses of 10 and 65 mg gave whole brain GABAAR occupancy of 69 and 89% in a [ 11 C]flumazenil PET study and there were dose-dependent effects on a number of pharmacodynamic parameters, including saccadic peak velocity, qEEG and a slight increase in body-sway, with the latter possibly being related to sedation and/or myorelaxation that was α1-GABAAR-mediated.…”

Section: α2/α3-gabaar Pamsmentioning

confidence: 99%

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update

et al. 2019

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γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system (CNS) with fast, trans-synaptic and modulatory extrasynaptic effects being mediated by the ionotropic GABA Type A receptors (GABAARs). These receptors are of particular interest since they are the molecular target of a number of pharmacological agents, of which the benzodiazepines (BZDs), such as diazepam, are the best described. The anxiolytic, sedating and myorelaxant effects of BZDs are mediated by separate populations of GABAARs containing either α1, α2, α3 or α5 subunits and the molecular dissection of the pharmacology of BZDs indicates that subtype-selective GABAAR modulators will have novel pharmacological profiles. This is best exemplified by α2/α3-GABAAR positive allosteric modulators (PAMs) and α5-GABAAR negative allosteric modulators (NAMs), which were originally developed as non-sedating anxiolytics and cognition enhancers, respectively. This review aims to summarize the current state of the field of subtype-selective GABAAR modulators acting via the BZD binding site and their potential clinical indications. Recently, high-resolution cryo-electron microscopy (cryo-EM) structures of the human α1β2γ2 and α1β3γ2 GABAARs have been reported. 11,12,19 The analysis of the receptors in complexes with the orthosteric agonist GABA and the GABA binding site antagonist bicuculline as well as the openchannel blocker pycrotoxin and BZD binding site ligands such as diazepam (Figure 1), alprazolam and flumazenil not only provide a detailed insight into the overall assembly and heteromeric interactions of GABAARs, but have also started to reveal the structural basis of receptor activation and allosteric modulation. The focus of the present review will be on compounds that bind to the BZD site with more detailed descriptions regarding the other GABAAR binding sites being available elsewhere. 14,15,20,21

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“…38 Other substances with positive allosteric modulatory action selective for GABA A receptors with α 2 /α 3 subunits that showed anticonvulsant effects in animal models of epilepsy are: AZD7325 (4-amino-8-(2-fluoro-6-methoxy-phenyl) -N-propyl-cinnoline-3-carboxamide), which increased the threshold for hyperthermia-induced seizures in Scn1a +/− mice, 39 and PF-06372865 (7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine), which efficiently suppressed spike-and-wave discharges in rats genetically prone to absence seizures (Genetic Absence Epilepsy Rats from Strasbourg [GAERS] strain). 40 However, only the latter found its way into clinical trials, and is now known under the name CVL-865.…”

Section: Gaba a Receptor Agonists And Allosteric Modulators In Preclimentioning

confidence: 99%

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

Janković

Dješević²

2021

JEP

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GABA A receptors are ubiquitous in the central nervous system and there is a huge diversity of receptor subtypes in almost all regions of the brain. However, the expression of GABA A receptor subtypes is altered in both the gray and white matter of patients with focal epilepsy. Although there is a number of anticonvulsants with marketing authorization for the treatment of focal epilepsy which act through GABA A receptors, potentiating the inhibitory effects of GABA, it is necessary to develop more potent and more specific GABAergic anticonvulsants that are effective in drug-resistant patients with focal epilepsy. There are three orthosteric and at least seven allosteric agonist binding sites at the GABA A receptor. In experimental and clinical studies, full agonists of GABA A receptors showed a tendency to cause desensitization of the receptors, tolerance, and physical dependence; therefore, partial orthosteric agonists and positive allosteric modulators of GABA A receptors were further developed. Preclinical studies demonstrated the anticonvulsant efficacy of positive allosteric modulators with selective action on GABA A receptors with α 2 /α 3 subunits, but only a handful of them were further tested in clinical trials. The best results were obtained for clobazam (already marketed), ganaxolone (in phase III trials), CVL-865 (in phase II trials), and padsevonil (in phase III trials). Several compounds with more selective action on GABA A receptors, perhaps only in certain brain regions, have the potential to become effective drugs against specific subtypes of focal-onset epilepsy. However, their development needs time, and in the near future we can expect only one or two new GABA A agonists to obtain marketing authorization for focal epilepsy, an advance that would be of use for just a fraction of patients with drug-resistant epilepsy.

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Pronounced antiepileptic activity of the subtype‐selective GABA_A‐positive allosteric modulator PF‐06372865 in the GAERS absence epilepsy model

Cited by 21 publications

References 31 publications

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

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Pronounced antiepileptic activity of the subtype‐selective GABAA‐positive allosteric modulator PF‐06372865 in the GAERS absence epilepsy model

Cited by 21 publications

References 31 publications

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

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Product

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Pronounced antiepileptic activity of the subtype‐selective GABA_A‐positive allosteric modulator PF‐06372865 in the GAERS absence epilepsy model

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update