IV-administered Ganaxolone and Diazepam synergistically block seizures in animal model of SE
Marinus Pharmaceuticals presented preclinical data showing that the combination of its CNS-selective GABAA modulator ganaxolone and diazepam administered intravenously (IV) produced a synergistic effect in blocking pilocarpine-induced seizures in a benzodiazepine refractory model of status epilepticus (SE).
Marinus is developing ganaxolone IV for the treatment of status epilepticus, a life-threatening medical emergency associated with high mortality and limited treatment options.
The data was presented during a poster presentation at Neuroscience 2016, the annual meeting of the Society for Neuroscience, which occurred November 12 – 16, 2016 in San Diego, CA.
The poster entitled, “Ganaxolone and diazepam administered IV produce a synergistic anti-epileptic effect in treatment refractory model of status epilepticus,” was presented by Michael S. Saporito, Ph.D., a preclinical consultant to Marinus Pharmaceuticals.
The data in the poster demonstrated that sub-therapeutic doses of diazepam and ganaxolone when administered in combination 15 minutes after onset of status epilepticus produced a partial or complete block of treatment-resistant status epilepticus in a rat model of SE, a clinically translatable model of this condition.
Ganaxolone and diazepam plasma levels were measured alone and in combination and were identical, indicating that neither drug affected the pharmacokinetic disposition of the other. In addition, the study suggests that the synergistic enhancement of anti-epileptic activity occurred at the level of the GABAA receptor.
Marinus chief medical officer Albena Patroneva said: “The synergistic effect seen with the combination of ganaxolone and diazepam has the potential to deliver a meaningful combination for the treatment of status epilepticus, where more than 30% of patients become resistant to benzodiazepines.
“These results, along with previous preclinical studies, show that ganaxolone IV not only has potential as a standalone therapy in producing a complete block of status epilepticus, but could also be used in combination with benzodiazepines to produce a rapid break of continuous seizures. We look forward to advancing our ganaxolone IV into clinical studies for patients with status epilepticus.”
Following positive Phase 1 results of ganaxolone IV in healthy volunteers, Marinus is preparing to commence its Phase 2 clinical study in patients with SE in 2017. Earlier this year, the U.S. Food and Drug Administration granted Orphan Drug Designation to ganaxolone IV for the treatment of SE.
About Ganaxolone
Ganaxolone is a CNS-selective GABAA modulator being developed in three different dose forms (IV, capsule, and liquid) intended to maximize therapeutic reach to adult and pediatric patient populations in both acute and chronic care settings. Ganaxolone acts on a well-characterized synaptic and extrasynaptic GABAA target known for its anti-seizure and anti-anxiety activity.
Ganaxolone has been studied in more than 1,400 subjects, both pediatric and adult, at therapeutically relevant dose levels and treatment regimens for up to two years. In these studies, ganaxolone was generally safe and well tolerated, with the most commonly reported adverse events of somnolence, dizziness and fatigue.