First Patient Enrolled in Ganaxolone Phase 3 Refractory Status Epilepticus Trial

Lawrence Hirsh, MD

Marinus Pharmaceuticals announced that they have enrolled their first patient in the phase 3 RAISE clinical trial of intravenous (IV) ganaxolone, which will evaluate the drug in patients with refractory status epilepticus (RSE).¹

RAISE, a randomized, double-blind, placebo-controlled trial, is expected to enroll approximately 125 patients with status epilepticus (SE) who have failed benzodiazepines and 2 or more second-line IV antiepileptic drugs (AEDs). Researchers will evaluate the efficacy and safety of IV ganaxolone by examining the proportion of patients with RSE who experience SE cessation within 30 minutes of IV ganaxolone as well as the rate of progression to IV anesthesia 36 hours following treatment initiation.

Ganaxolone is a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It exhibits antiseizure, anti-depressant, and anti-anxiety effects, and is noted to be generally safe and well-tolerated in studies.

"With this number of participants, the study is designed to provide over 90% power to detect a 30% efficacy difference between ganaxolone and placebo,” the company noted in their statement.

Cessation will be measured and determined by clinical and electroencephalogram (EEG) findings using Ceribell’s Rapid Response EEG system across 80 study sites. The EEG devices are designed to be compact and easy to use and will facilitate the rapid diagnosis of nonconvulsive SE, which is confirmed by EEG demonstration of ongoing ictal activity.

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Clinicians using the Rapid Response EEG system will have the ability to quickly triage and continuously monitor patients at risk for seizures. The EEG system includes a Rapid Response EEG headband that collects EEG data via a web-based portal, allowing the hospital neurology team to access the data remotely.

In 2019, Marinus presented positive results from its phase 2 trial of ganaxolone in patients with SE, which showed that no patients progressed to IV anesthetics within 24 hours of treatment initiation.²

The phase 2, open-label, dose-finding study evaluated 3 different doses, a low dose of 500 mg/day, a medium dose of 650 mg/day, and a target dose of 713 mg/day of ganaxolone as adjunctive therapy to existing second-line IV AEDs. Prevention of progression to third line IV anesthetics within 24 hours of treatment was the primary end point, while safety, tolerability, and other efficacy analyses served as secondary end points.

Treatment with ganaxolone not only prevented progression to third-line IV anesthetics, but also reduced median time to status cessation to 5 minutes. Notably, 16 of 17 patients were status-free 24 hours from infusion initiation. During the follow-up period, 3 patients in the 500-mg group escalated to additional IV AEDs or IV anesthetics due to status relapse during that time.

Throughout the trial, 10 serious adverse events (SAEs) were recorded, 8 of which were considered not related to treatment. Somnolence, mild hypotension, and sedation were among the most common treatment-related adverse events (TEAEs).

At the time, Lawrence Hirsh, MD, professor of neurology, and chief, division of epilepsy and EEG, and co-director, Yale Comprehensive Epilepsy Center and Critical Care EEG Monitoring Program, Yale School of Medicine, said in a statement, “Maintaining control of status epilepticus without progressing to addition IV anesthetics or antiepileptic drugs (AEDs) is a remarkable clinical response to IV ganaxolone treatment.”

Ganaxolone has also shown the ability to positively impact children and young adults with CDKL5 deficiency disorder (CDD), a rare, genetic epilepsy accompanied by refractory seizures. In September 2020, Marinus announced their top-line results from the phase 3 MARIGOLD clinical trial.³

All told, those treated with the positive allosteric GABAA receptor modulator showed a significant median reduction of 32.2% in 28-day major motor seizure frequency in comparison to a 4.0% reduction for those in the placebo group, which achieved the primary end point (P = .002).

The company also noted that they plan to submit a new drug application (NDA) for ganaxolone for the treatment of CDD to the FDA by mid-2021. Previously, Marinus received a rare pediatric disease designation from the FDA for ganaxolone for the treatment of CDD.

REFERENCES

1. Marinus enrolls first patient in pivotal phase 3 clinical trial of IV ganaxolone in refractory status epilepticus. News release. January 26, 2021. Accessed February 4, 2021. https://ir.marinuspharma.com/news/news-details/2021/Marinus-Enrolls-First-Patient-in-Pivotal-Phase-3-Clinical-Trial-of-IV-Ganaxolone-in-Refractory-Status-Epilepticus/default.aspx

2. Vaitkevicius H, Husain AM, Swisher CB, et al. Phase 2 open-label study of intravenous ganaxolone for the treatment of refractory status epilepticus. Presented at: Neurocritical Care Society 17th Annual Meeting. October 15-18, 2019; Vancouver, British Columbia. Oral Abstract 2.

3. Ganaxolone Achieves Primary Endpoint in Phase 3 Trial for CDKL5 Deficiency Disorder (CDD), a Rare Form of Genetic Epilepsy. News release. Marinus Pharmaceuticals. September 14, 2020. Accessed February 4, 2021. biospace.com/article/releases/ganaxolone-achieves-primary-endpoint-in-phase-3-trial-for-cdkl5-deficiency-disorder-cdd-a-rare-form-of-genetic-epilepsy