Approximately 1.8 million people in the U.S. have epilepsy in the form of complex partial seizures. Refractory complex partial seizures occur in about 35% of persons with epilepsy, where seizures remain uncontrolled despite multiple treatment attempts with drug therapy, surgery and/or vagal nerve stimulation.Ganaxolone provides a novel mechanism for the adjunctive treatment of seizures, providing allosteric modulation of extra-synaptic, as well as synaptic, central GABA A receptors.

Marinus Pharmaceuticals has completed a placebo-controlled, randomized, 10 week Phase 2 study in adults of ganaxolone for adjunctive treatment of refractory complex partial seizures (Study 600; N=147). At study endpoint, ganaxolone subjects had a reduction in mean seizure frequency that was 20% greater than the placebo group (p=.014), and more subjects who received ganaxolone were classified as responders (p=.057). Ganaxolone 1500mg/day was shown to be well-tolerated and safe as adjunctive therapy for adults with complex partial seizures. (Manuscript in preparation.)

Ninety-two percent of eligible subjects from the Phase 2 study entered an open-label extension, where all subjects were treated with active ganaxolone as adjunctive therapy. Preliminary results presented at the American Epilepsy Society Meeting in December 2010 reported that efficacy was maintained during long-term treatment with ganaxolone, and that the treatment was safe and well-tolerated without emergence of new adverse events or development of tolerance.

Infantile spasms (also known as West Syndrome) is a disorder of the developing nervous system typically arising in children less than one year old. The disorder manifests as flexion jerks of the neck, trunk and limbs often occurring in clusters. Infantile spasms is associated with mental and developmental impairment, high mortality, and significant caregiver burden.

Safety of ganaxolone in pediatric populations and proof-of-concept for efficacy in Infantile Spasms was established through three open-label studies in highly refractory subjects aged 7 months to 15 years which showed evidence of anti-convulsant effect, including reduction of epileptic spasms (Kerrigan et al. 2000, Pieribone et al, 2007). Marinus has completed a double-blind, randomized, placebo-controlled Phase 2 study of ganaxolone in 56 subjects with infantile spasms. Ganaxolone treatment reduced spasm cluster frequency compared to baseline but not compared to placebo after 8 days of treatment at doses up to 56mg/kg. One-third (33%) of ganaxolone-treated subjects met responder criteria at endpoint, as did 22% of subjects treated with placebo.

Ganaxolone is a positive allosteric modulator of GABAA receptors with potency and efficacy comparable to its endogenous neurosteroid analog allopregnanolone. Neurosteroids including ganaxolone have two separate effects on GABAA receptors: at low concentrations they potentiate the action of GABA via extrasynaptic receptors that generate a tonic, steady signal, while at higher concentrations they directly activate the synaptic receptors generating phasic currents in response to GABA release. These actions occur at two distinct sites on the receptor complex that do not correspond with the modulatory sites of benzodiazepines and barbiturates.

Ganaxolone has protective activity in diverse rodent seizure models, including clonic seizures induced by chemoconvulsants PTZ, bicuculline, and others; limbic seizures in the 6 Hz model; amygdala and cocaine-kindled seizures; and corneal kindled seizures. Rodents treated chronically with ganaxolone do not develop tolerance. Additionally, evidence suggests that neurosteroids can retard or attenuate development of spontaneous recurrent seizures in kindling and pilocarpine-induction models of epileptogenesis. The mechanism of the anticonvulsant effects of neurosteroids such as ganaxolone may provide a novel avenue for addressing human seizure disorders through tonic modulation of extrasynaptic GABAA receptors in addition to phasic modulation from synaptic binding site activity.

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