Marinus Reports Mixed Topline Results from Phase 3 Trial of IV Ganaxolone in Refractory Status Epilepticus

Rare Daily Staff

Marinus Pharmaceuticals said that intravenous ganaxolone met just one of two co-primary endpoints in a late-stage trial evaluating its safety and efficacy for the treatment of refractory status epilepticus, in which prolonged continuous or rapidly recurring seizures do not respond to first- and second-line therapy, is associated with significant morbidity and mortality.

In the RAISE trial, a double-blind, randomized, placebo-controlled phase 3 study, patients with refractory status epilepticus (RSE) who failed at least two antiseizure medications were randomized to IV ganaxolone or placebo in addition to standard of care treatment. The intent-to-treat population consisted of 96 patients, including 49 in the IV ganaxolone arm and 47 in the placebo arm.

The trial met the first co-primary endpoint: a statistically significant proportion of patients had status epilepticus cessation within 30 minutes of initiating IV ganaxolone (80 percent) compared to placebo (13 percent).

The trial did not meet the second co-primary endpoint: RAISE failed to achieve statistical significance in the proportion of patients not progressing to IV anesthesia for 36 hours following initiation of IV ganaxolone (63 percent) compared to placebo (51percent).

The incidence of serious adverse events was similar between the treatment and placebo arms with hypotension being more commonly seen in the IV ganaxolone arm.

“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,” said Scott Braunstein, chairman and CEO of Marinus.

Status epilepticus (SE) is a life-threatening condition resulting from either the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures. SE is the one of the most common neurological emergencies in the United States affecting up to 150,000 patients each year, and is associated with substantial morbidity, mortality, and healthcare costs. Patients who do not respond to first- and second-line treatments (benzodiazepines and intravenous antiseizure medications) are considered to have refractory SE (RSE).

Ganaxolone is a neuroactive steroid that works by modulating both synaptic and extrasynaptic GABAA receptors via a unique binding site to potentiate two types of inhibitory signaling. IV ganaxolone has pharmacokinetic and pharmacodynamic properties well-suited for the treatment of status epilepticus. IV ganaxolone received orphan drug designation from the FDA for the potential treatment of status epilepticus.

“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,” said Joseph Hulihan, chief medical officer of Marinus. “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. We believe this imbalance confounds the assessment of potential differences in patient outcomes for IV ganaxolone compared to placebo.”

Marinus said it continues to believe in the potential of IV ganaxolone as a treatment for RSE, supported not only by the rapid onset of its antiseizure effect but also the objective evidence of status epilepticus control observed with an additional analyses of continuous electroencephalogram (EEG) monitoring. Preliminary EEG analyses indicate patients receiving IV ganaxolone demonstrated durable reductions in seizure burden through 36 hours with an 88 percent median reduction compared to 38 percent for placebo. This suggests that the need for IV anesthesia was driven by factors other than status severity and may not represent an accurate measure of seizure control.

The company will continue to analyze the full RAISE dataset and plans to engage with the U.S. Food and Drug Administration to discuss a potential path forward for IV ganaxolone in RSE. Marinus expects to present the RAISE data at an upcoming medical meeting.

Marinus intends to continue to offer IV ganaxolone for patients with super refractory status epilepticus under emergency investigational new drug applications.