Ganaxolone acts on a well-characterized synaptic and extrasynaptic GABAA target known for antiepileptic (anti-seizure) and anxiolytic (anti-anxiety) activity. Ganaxolone is being evaluated in clinical trials for the treatment of pediatric genetic orphan epilepsies, behaviors in Fragile X Syndrome, and status epilepticus.
How Ganaxolone Works
Ganaxolone is a synthetic analog of endogenous allopregnanolone, which has been shown to be an effective anticonvulsant by restoring electrical balance to the seizing brain. While allopregnanolone’s anticonvulsant and anti-anxiety activities are well documented, allopregnanolone has the potential to convert back to its metabolic precursor progesterone, which could lead to hormonal side effects. Ganaxolone has been designed with an added methyl group that prevents back conversion to an active steroid which unlocks ganaxolone’s potential for chronic use. In preclinical studies, ganaxolone exhibited potency and efficacy comparable to allopregnanolone.
GABA (gamma-aminobutyric acid) is the chief inhibitory neurotransmitter in the brain. One of the subclasses of receptors that respond to GABA is the GABAA receptor. When activated, these receptors selectively conduct chloride ions through a pore that results in the inhibitory effect of hyperpolarization of the neuron. Synaptic GABAA receptors respond quickly to inhibit neurotransmission, while extrasynaptic GABAA receptors provide ambient tonic inhibition.
Both ganaxolone and allopregnanolone bind to GABAA at the synaptic and extrasynaptic binding sites. Activity with extrasynaptic GABAA receptors are of particular importance for treating patients who developed tolerance to benzodiazepines and barbiturates. Ganaxolone binds to the GABAA receptors, which opens the pore to allow chloride ions to move into the postsynaptic neuron, leading to the inhibition of neurotransmission.
Ganaxolone has been studied in more than 1,300 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.
Years of in-house research at Marinus resulted in the invention of a patented nanoparticulate composition for solid and liquid oral dose forms of ganaxolone that are highly stable and provide good exposure in both the fed and fasted state. This discovery resulted in the issuance of U.S. and foreign patents covering use of these complexed ganaxolone nanoparticles in solid and liquid dose forms. The nanoparticulate composition patents for oral liquid and solid dose forms of ganaxolone is expected to provide intellectual property protection through at least 2026.
Marinus has been granted U.S. and foreign patents for the manufacture of ganaxolone drug substance. This application identified a novel process using organometallic methylating agent, which is significantly more cost effective in the manufacture of ganaxolone than previous processes. This synthesis patent is expected to provide intellectual property protection through at least 2030.