Trial finds new drug safe, effective to treat deadliest form of epilepsy
At the Neurocritical Care Society's (NCS) 22nd Annual Meeting this week, a University of Cincinnati researcher presented Phase 3 clinical trial results finding a new drug is a safe and effective treatment for the most severe and deadly form of epilepsy.
Brandon Foreman, MD. Photo/Andrew Higley/UC Marketing + Brand.
UC’s Brandon Foreman, MD, explained the trial focused on status epilepticus (SE), a disorder he described as “seizures that don’t stop.” Seizures are the second most common neurologic emergency in the United States, and more than 150,000 Americans develop SE each year.
Based on factors including age and the cause and duration of SE, between 20% to 30% of patients with SE do not survive. Those that do survive go on to experience cognitive dysfunction, functional disability and nearly three times the risk for epilepsy.
Current standards of care include administering an intravenous antiseizure medicine, a benzodiazepine such as midazolam, as soon as possible to stop seizures. When those do not work, a second intravenous antiseizure medication is started, but about one quarter of patients continue to experience seizures, termed refractory status epilepticus (RSE).
“Right now, the only way to manage patients with RSE is to put them on anesthetic medications, continuous infusions that are used to induce coma,” said Foreman, associate professor and an associate director of neurocritical care research in the Department of Neurology and Rehabilitation Medicine in UC’s College of Medicine and a UC Health neurocritical care physician. “That’s been associated with some bad outcomes, and previously there’s been nothing to fill the gap.”
Study details and results
The Phase 3 RAndomized Therapy In Status Epilepticus (RAISE) trial tested a neurosteroid called ganaxolone for patients hospitalized with seizures that progressed to RSE despite receiving two or more antiseizure medications.
These patients would typically next be intubated and given anesthetic sedation. However, in this study, patients were randomized to either receive the trial drug or a placebo prior to initiating coma-induced anesthesia.
“The study looked at how many patients stopped seizing within the first 30 minutes of study drug and the proportion of patients who needed to escalate to anesthetics to control their refractory status epilepticus,” Foreman said.
Researchers found a statistically significant proportion of patients who received ganaxolone stopped seizing within 30 minutes: 80% of those patients receiving ganaxolone saw their RSE stop a median of just 4 minutes after the drug was administered.
Ganaxolone as a rapidly effective medication would fill a specific gap in care.
Brandon Foreman, MD
In comparison, only 13% of those in the placebo group had control of their RSE after 30 minutes, and their seizures lasted a median of five hours.
The study did not meet its second co-primary endpoint of no escalation of intravenous anesthesia within the first 36 hours of administering the study drug. Although 63% of patients receiving ganaxolone avoided anesthesia compared with 51% of those who received placebo, this endpoint was not statistically significant.
Despite the mixed results, Foreman noted that during the first 24 hours after the study drug was started, 81% of patients who received placebo required further escalation of antiseizure medications, including new medications or intravenous anesthetics. This was significantly more than the 55% of patients who received ganaxolone and needed additional therapies to control their RSE.
“Even 72 hours after the start of ganaxolone, there were significantly fewer patients requiring further escalation of medical treatment in the patients receiving ganaxolone,” he said.
Electroencephalogram (EEG) data from patients in the trial showed a significant 93% reduction in seizure burden for patients in the ganaxolone group, compared to a 36% seizure burden reduction in the placebo group.
“Importantly, the incidence of serious adverse events was not unexpected. Taking into account the frequent use of anesthetics and the critical nature of RSE, serious adverse events were not too different between the treatment and placebo arms. Hypotension was the most consistently seen adverse effect in the IV ganaxolone arm,” Foreman added.
There are no FDA-approved medications to treat RSE, Foreman said, and there is little evidence to guide best practices. Ganaxolone represents the first and only medication found to be safe and effective in a randomized controlled trial for patients with RSE.
“Ganaxolone as a rapidly effective medication would fill a specific gap in care for which there are no current treatment options beyond intubation and anesthetic medications if standard antiseizure medications fail,” he said. “It is recognized that the use of anesthetics increases the morbidity and mortality of RSE, so ganaxolone has the potential to save lives and avoid prolonged intensive care.”
Moving forward, Foreman said Marinus Pharmaceuticals — the company that developed intravenous ganaxolone — will next review the data package with the Food and Drug Administration as it works toward receiving approval.
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Foreman presented “Efficacy and Safety of Intravenous Ganaxolone for Treatment of Refractory Status Epilepticus: Results from the Phase 3, Double-Blind, Randomized, Placebo-Controlled RAISE Trial” Oct. 17 at the NCS Annual Meeting in San Diego, California.
The RAISE trial (NCT04391569) has been supported in part by the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA) under contract number 75A50120C00159. Foreman received honoraria and consulting fees from Marinus and served as the site principal investigator for the RAISE study at the University of Cincinnati.
Featured photo at top of Foreman looking at a brain monitor. Photo/Andrew Higley/UC Marketing + Brand.
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