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Marinus Pharmaceuticals reported that it will continue to analyze the full dataset and engage with the FDA to discuss the future of ganaxolone for treating refractory status epilepticus.
Scott Braunstein, MD
(Credit: Marinus)
Topline results from the phase 3 double-blind, randomized, placebo-controlled RAISE trial (NCT04391569) assessing intravenous (IV) ganaxolone (Ztalmy; Marinus Pharmaceuticals) for the treatment of patients with refractory status epilepticus (RSE) showed that the treatment met the first coprimary end point but failed to meet the second end point in the study.1 The company plans to continue analyzing the full dataset from RAISE and will engage with the FDA for a discussion on the potential path forward for IV ganaxolone in RSE.
Findings showed that a statistically significant proportion of patients had status epilepticus cessation within 30 minutes of initiating IV ganaxolone compared with placebo (80% vs. 13%, respectively; P <.0001). Notably, the trial failed to achieve statistical significance in the proportion of patients not progressing to IV anesthesia for 36 hours after initiation of IV ganaxolone compared with placebo (63% vs. 51%, respectively; P = .162).
“Although the RAISE trial did not achieve statistical significance on one of its co-primary endpoints, these findings provide valuable insights that will guide our ongoing research and development in our mission to bring innovative and effective treatment options to those in need,” Scott Braunstein, MD, chairman and chief executive officer at Marinus, said in a statement.1 “We would like to thank the patients, families, investigators and their clinical trial sites for their contributions to this important research.”
The trial featured patients with RSE that failed at least 2 antiseizure medications who were randomized to receive either IV ganaxolone or placebo in addition to standard of care treatment. The intent-to-treat population consisted of 96 patients, which included 49 in the IV ganaxolone arm and 47 in the placebo arm. In terms of safety, the incidence of serious adverse events was similar between both arms (IV ganaxolone, n = 19; placebo, n = 18), with hypotension reported as the most common in the IV ganaxolone group.
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“We are proud to have conducted the first randomized phase 3 trial in patients with RSE, a highly variable and complex seizure disorder. We noted that patients were enrolled late in their course of status, with study drug initiated, on average, 38 hours following onset. This appears to be inconsistent with the urgency to initiate therapy emphasized in treatment guidelines,” Joseph Hulihan, MD, chief medical officer at Marinus, commented in a statement.1
The company noted that it continues to believe in the potential of the treatment for RSE, which was supported not only by the rapid onset of its antiseizure effect but also the objective evidence of status epilepticus control observed from additional analyses of continuous electroencephalogram (EEG) monitoring. The preliminary EEG analyses indicated that patients who received IV ganaxolone had durable reductions in seizure burden through 36 hours with an 88% median reduction compared with 38% for those on placebo. These findings suggest that the need for IV anesthesia was caused by factors other than status severity and may not represent an accurate measure of seizure control.
“Also disappointing to us was the imbalance in baseline characteristics between the two treatment arms, with a higher proportion of patients in the IV ganaxolone arm presenting with stupor or coma, entering the trial on mechanical ventilation, having a higher baseline status epilepticus severity score, and higher incidences of underlying disorders associated with significant morbidity and mortality, such as glioblastoma and encephalitis,” Hulihan added in a statement.1 “We believe this imbalance confounds the assessment of potential differences in patient outcomes for IV ganaxolone compared to placebo.”
Marinus noted that it intends to continue to offer IV ganaxolone for patients with super refractory status epilepticus under emergency investigational new drug applications. 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 adults.
“Stopping status epilepticus as quickly as possible is critical, as each passing minute heightens the risk of permanent neurologic impairment,” Aatif M. Husain, MD, epileptologist, neurologist, professor of neurology, and chief of the Division of Epilepsy, Sleep, and Clinical Neurophysiology at Duke University Medical Center, said in a statement.1 “The findings in the RAISE trial indicate that objective measures such as EEG should be considered in future trials to assess control of status epilepticus rather than endpoints dependent on a proxy measure such as use of IV anesthesia.”
In April 2023, the independent data monitoring committee recommended the continuation of investigating IV ganaxolone for the treatment of RSE following an interim analysis although the trial did not meet pre-defined stopping criteria.2 In the announcement, Marinus noted that it decided to complete enrollment for RAISE at approximately 100 patients with RSE. The RAISE trial protocol provided for an independent data monitoring committee to perform an unblinded interim analysis when two-thirds of participants or approximately 82 patients completed the study.
