Place of neurosteroids in the treatment of status epilepticus

Rossetti, Andrea O.

doi:10.1111/epi.14481

Cited by 14 publications

(5 citation statements)

References 26 publications

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“…Initial studies showed that BX was well tolerated and moderately successful at weaning from anesthetic third-line agents. Despite its promise as a therapeutic anticonvulsant, further evaluation of BX in SRSE trials did not meet the primary endpoint, primarily due to its lack of efficacy in controlling seizures and achieving satisfactory outcomes in a clinical setting ( Rossetti, 2018 ). Other contributing factors included the poor prognosis of SRS and high mortality and morbidity rates, as well as challenges with study design and inclusion of heterogeneous patient populations.…”

Section: Neurosteroids As Novel Anticonvulsants For Nerve Agents and Rsementioning

confidence: 99%

Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic

Reddy

2023

J Pharmacol Exp Ther

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This article describes recent advances in the use of neurosteroids as novel anticonvulsants for refractory status epilepticus (RSE) and as medical countermeasures (MCs) for organophosphates and chemical nerve agents (OPNAs). We highlight a comprehensive 15-year journey to bring the synthetic neurosteroid ganaxolone (GX) from bench to clinic. RSE, including when caused by nerve agents, is associated with devastating morbidity and permanent long-term neurologic dysfunction. Although recent approval of benzodiazepines such as intranasal midazolam and intranasal midazolam offers improved control of acute seizures, novel anticonvulsants are needed to suppress RSE and improve neurologic function outcomes. Currently, few anticonvulsant MCs exist for victims of OPNA exposure and RSE. Standard-of-care MCs for postexposure treatment include benzodiazepines, which do not effectively prevent or mitigate seizures resulting from nerve agent intoxication, leaving an urgent unmet medical need for new anticonvulsants for RSE. Recently, we pioneered neurosteroids as next-generation anticonvulsants that are superior to benzodiazepines for treatment of OPNA intoxication and RSE. Because GX and related neurosteroids that activate extrasynaptic GABA-A receptors rapidly control seizures and offer robust neuroprotection by reducing neuronal damage and neuroinflammation, they effectively improve neurologic outcomes after acute OPNA exposure and RSE. GX has been selected for advanced, Biomedical Advanced Research and Development Authority–supported phase 3 trials of RSE and nerve agent seizures. In addition, in mechanistic studies of neurosteroids at extrasynaptic receptors, we identified novel synthetic analogs with features that are superior to GX for current medical needs. Development of new MCs for RSE is complex, tedious, and uncertain due to scientific and regulatory challenges. Thus, further research will be critical to fill key gaps in evaluating RSE and anticonvulsants in vulnerable (pediatric and geriatric) populations and military persons. SIGNIFICANCE STATEMENT Following organophosphate and nerve agent intoxication, refractory status epilepticus (RSE) occurs despite benzodiazepine treatment. RSE occurs in 40% of status epilepticus patients, with a 35% mortality rate and significant neurological morbidity in survivors. To treat RSE, neurosteroids are better anticonvulsants than benzodiazepines. Our pioneering use of neurosteroids for RSE and nerve agents led us to develop ganaxolone as a novel anticonvulsant and neuroprotectant with significantly improved neurological outcomes. This article describes the bench-to-bedside journey of bringing neurosteroid therapy to patients, with ganaxolone leading the way.

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Section: Neurosteroids As Novel Anticonvulsants For Nerve Agents and Rsementioning

confidence: 99%

Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic

Reddy

2023

J Pharmacol Exp Ther

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“…By binding to both types of GABA A receptors, ganaxolone can potentiate both phasic and tonic inhibition 32 . Neuroactive steroids, such as ganaxolone, have the potential to increase GABAergic signaling when synaptic GABA A receptors are internalized and benzodiazepines are less effective, such as in RSE 35 …”

Section: Introductionmentioning

confidence: 99%

“…32 Neuroactive steroids, such as ganaxolone, have the potential to increase GABAergic signaling when synaptic GABA A receptors are internalized and benzodiazepines are less effective, such as in RSE. 35 In multiple preclinical seizure models, including treatment-resistant SE, ganaxolone exhibited was considered related to ganaxolone; all occurred 9-22 days after completing ganaxolone.…”

Section: Introductionmentioning

confidence: 99%

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Intravenous ganaxolone for the treatment of refractory status epilepticus: Results from an open‐label, dose‐finding, phase 2 trial

Vaitkevicius

Ramsay²,

Swisher

et al. 2022

Epilepsia

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Objective: Patients with refractory status epilepticus (RSE) have failed treatment with benzodiazepines and ≥1 second-line intravenous (IV) antiseizure medication (ASM). Guidelines recommend IV anesthesia when second-line ASMs have failed, but potential harms can outweigh the benefits. Novel treatments are needed to stop and durably control RSE without escalation to IV anesthetics. Ganaxolone is an investigational neuroactive steroid in development for RSE treatment. This study's objective was to determine the appropriate dosing for IV ganaxolone in RSE and obtain a preliminary assessment of efficacy and safety. Methods: This was an open-label, phase 2 trial conducted from February 19, 2018 to September 18, 2019, at three sites in the United States. Patients were aged ≥12 years, had convulsive or nonconvulsive SE, and failed to respond to ≥1 second-line IV ASM. Twenty-one patients were screened; 17 were enrolled.Patients received IV ganaxolone added to standard-of-care ASMs. Ganaxolone infusion was initiated as an IV bolus (over 3 min) with continuous infusion of decreasing infusion rates for 48-96 h followed by an 18-h taper. There were three ganaxolone dosing cohorts: low, 500 mg/day; medium, 650 mg/day; and high, 713 mg/day. The primary end point was the number of patients not requiring escalation to IV anesthetic treatment within 24 h of ganaxolone initiation.Results: Most of the 17 enrolled patients (65%) had nonconvulsive SE, and had failed a median of three prior ASMs, including first-line benzodiazepine and second-line IV ASM therapy. Median time to SE cessation following ganaxolone initiation was 5 min. No patient required escalation to third-line IV anesthetics during the 24-h period following ganaxolone initiation. Two treatment-related serious adverse events (sedation) were reported. Of the three deaths, none

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“…Some of this may be related to inherent difficulties when comparatively studying antiseizure medications, but it bears repeating that potential economic gains for the pharmaceutical industry to develop new medications specifically aimed at status epilepticus are low . Unfortunately, recent studies exploring the efficacy of allopregnanolone for super refractory status epilepticus and hypothermia for neuroprotection in GCSE did not demonstrate improved outcomes, but it is these types of novel pathophysiological studies that are sorely needed in status epilepticus research.…”

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confidence: 99%