Intravenous Ganaxolone Attenuates Sarin Nerve Agent Induced Seizures
Abstract number :
3.065
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2023
Submission ID :
894
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
First Author: Poojya Anantharam, PhD – MRI Global
Presenting Author: Michael Saporito, PhD – Marinus Pharmaceuticals
Kelsey Burenheide, BS, RVT – MRI Global; Amy Hunziger, BS – MRI Global; John Moore, BS – MRI Global; Phillip Beske, PhD – MRI Global; Monica Metea, PhD – Preclinical Electrophysiology Consulting, LLC; Michael Saporito, PhD – Marinus Pharmaceuticals, Inc.
Rationale: Ganaxolone (GNX) is a neuroactive steroid and positive allosteric modulator that targets synaptic and extrasynaptic GABAA receptors. It is FDA-approved for the treatment of seizures associated with CDKL5 Deficiency Disorder. An IV formulation is currently in Phase 3 clinical trials for the treatment of refractory status epilepticus (RSE). The Biomedical Advanced Research and Development Authority (BARDA), within the Administration for Strategic Preparedness and Response in the US Department of Health and Human Services (HHS), is partnering with Marinus to develop GNX as a treatment for RSE following organophosphate nerve agent exposure in subjects that are not responsive to agents FDA-approved for nerve agent induced seizures (Seizalam® midazolam hydrochloride) or other benzodiazepines.
Methods: These studies were designed to determine the effects of IV GNX on RSE associated with Sarin nerve agent exposure in rodents, to establish a PK/PD relationship, and to provide information on neuroprotective activity of GNX. Rats of both sexes were exposed to Sarin and then immediately treated with atropine methyl nitrate and pralidoxime chloride (2-PAM). Forty minutes after seizure onset, rats were treated with an IV bolus ( 0.5, 1, 2 or 4 mg/kg; 20 sec) followed by a continuous IV infusion of GNX (0.5, 1, 2 or 4 mg/kg/hr, respectively) for 24 hrs. Video-EEG was collected over 24 hours via implanted telemetry and analyzed post-collection. The severity of seizures or status epilepticus (SE) were scored based on EEG and behaviors in ten minute intervals over the duration of each collection using a Likert scale. GNX plasma and brain levels were measured in a parallel group of animals. Histopathological analyses of post-mortem brains were assessed to determine effects of GNX on neurodegeneration.
Results: GNX administration (bolus followed by infusion) produced a dose-dependent and proportional increase in steady-state GNX plasma and brain levels ranging from 212 ng/ml (0.5 mg/kg/hr) to 1,693 ng/ml (4 mg/kg/hr). Exposure to Sarin did not alter GNX plasma PK characteristics. However, Sarin exposure increased GNX brain penetrance two fold, suggesting a Sarin-mediated disruption of the blood-brain barrier. Sarin challenge elicited SE onset between ten and fifteen minutes after exposure. GNX administration produced a dose-dependent reduction in seizure severity score and a dose-dependent reduction in transition time out of SE, with the highest doses producing transition within 30 minutes after GNX treatment. Sarin exposure elicited neuronal death in areas of the cerebral cortex, hippocampus, thalamus, and hypothalamus. Administration of GNX reduced the neuropathology caused by Sarin challenge in these regions.
Conclusions: GNX administration attenuated RSE in Sarin exposed rats in a dose-dependent manner and established a PK/PD relationship between GNX plasma levels and the anti-seizure response. GNX was also shown to prevent Sarin-mediated neuronal loss in various brain regions. These studies support the ongoing development of GNX as a medical countermeasure for the treatment of individuals exposed to organophosphate nerve agents.
Funding: Marinus Pharmaceuticals, Inc.
Basic Mechanisms