Authors: Muzzammil Ahmadzada1 and Waqas Haque2, MPH, MPHil
Affiliations: 1Johns Hopkins University; 2University of Texas Southwestern Medical School
Disclosures: The authors have no financial conflicts of interest.
Ganaxolone is an experimental drug under development from Marinus Pharmaceuticals, a clinical stage pharmaceutical company founded in 2003 that focuses on treating drug-resistant seizures and neuropsychiatric disorders.1 Their leading drug, Ganaxolone (GNX), is designed to be an antiepileptic, antidepressant, anxiolytic, and sedative, due to its GABAA receptor modulating properties.2 The drug is in Phase 2 development for two seizure disorders (Tuberous Sclerosis Complex (TSC) and PCDH19-Related Epilepsy (PCDH19)), in Phase 3 for an additional two seizure disorders (Status Epilepticus (SE) and CDKL5 Deficiency Disorder (CDD)), and in Phase 1 for a depressive disorder (Treatment Resistant Depression).3
The disorder that is currently furthest along in the GNX study trials is CDKL5 Deficiency Disorder (CDD).3 CDD arises from the mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene located on the X chromosome.4 This has become increasingly prevalent, presenting in roughly 1 out of every 40,000-75,000 live births, making it one of the most common forms of genetic epilepsy.5 Overall, there are an estimated 12,500 children in the United States and European Union that are afflicted, with majority of them being females.3
CDD typically presents as early-onset treatment refractory seizures and severe neuro-developmental delay.3 In particular, most afflicted individuals are unable to talk, walk, or care for themselves. They also suffer from scoliosis, visual impairment, gastrointestinal difficulties, and sleeping disorders. Although there is genetic testing available to detect the gene, there remains no approved disease-specific treatment.4,5
Similar to CDD is a rare disease called Rett Syndrome. Like CDD, Rett Syndrome is an X-linked disease that presents with developmental delays, gastrointestinal dysfunction, scoliosis, limited or absent speech, and sleep disturbances. Also, similar to CDD, there is no approved single treatment.6 There are also a few key differences between the two diseases. While CDD is due to a mutation in the CDKL5 gene, Rett Syndrome (RTT) is due to a mutation in the MECP2 gene, which codes for the MECP2 protein, a protein that is essential in the normal function of nerve cells.6
While developmental delays can be noticed from birth in CDD patients, individuals with Rett Syndrome present symptoms in infancy (typically after 6 months of apparently normal phenotype).5,6 Additionally, seizures and sleep disturbances are more common in CDD patients than RTT patients, while regression and spine curvature are more common in RTT patients.6 Marinus’ proposed treatment, GNX, for diseases such as CDD and RTT, is a synthetic analog of the currently existing therapeutic Allopregnanolone that is used to treat both of the aforementioned conditions. The difference is an additional methyl group that prevents GNX from being converted into Allopregnanolone’s metabolic precursor, progesterone. Thus, while long-term use of Allopregnanolone can result in hormonal side effects, GNX does not because of this prevention of conversion.2
GNX binds to and activates a subclass of the gamma-aminobutyric acid (GABA) inhibitory receptors in the brain, GABAA, selectively conducting chloride ions through a pore that results in inhibiting neuronal signaling. Ganaxolone binds to GABAA at the synaptic and extrasynaptic binding site to calm over-excited neurons. The synaptic GABAA receptors quickly inhibit neurotransmission, while the extrasynaptic GABAA receptors provide ambient tonic inhibition. This last feature is especially important for treating patients who develop tolerance to benzodiazepines and barbiturates.2
As mentioned above, GNX is focused on rare genetic epilepsies that have few or no treatment options. Marinus hopes that the drug will be delivered via IV and oral, in order to meet the needs of adult and pediatric patients in acute and chronic care settings.3 The Phase 2 study design for CDD consisted of 2 sites in the U.S. and 1 site in Italy, a total of 7 participants (6 females and 1 male, ages ranging from 2-16) that had confirmed CDKL5 mutation with stable background treatment, and a minimum of 4 seizures per 28-day period. The baseline clinical characteristics were a mean of 206 seizures (range 34 to 669) and a median number of 4 seizure free days (ranging from 0-9).3 The baseline was recorded for 12 weeks, followed by 26 weeks of treatment (of 600mg of GNX 3 times a day minimum), and ending with 52 weeks of the Open-Label Phase (600mg GNX 3 times a day minimum).3
There was a 44.4% reduction in seizure frequency observed, and clinician reports indicating that patients experienced a median ‘minimally improved’ rating on a clinical functional rating scale correlated with the percent change in seizure frequency. GNX was generally safe and well tolerated (no severe adverse effects (SAE), somnolence, or dizziness reported).3 Additionally, 4 out of the 7 CDD patients entered an extension period, where GNX demonstrated preliminary evidence of sustained, long-term (up to 18 months) efficacy.3
In Phase 2 of the CDD trials, there were no SAEs reported, nor any somnolence or dizziness. In phase 2 of the Status Epilepticus trials (which consisted of 17 patients, mean age of 57), there were 10 SAEs in 6 patients, but only 2 were related, in 2 patients (severe sedation). There were 8 other non-related SAEs in other 4 patients.3In the near future, GNX can be expected to undergo the Global Phase 3 Pivotal Trial Design which will evaluate the use of oral GNX in children and young adults. The global, double-blind, placebo-controlled, clinical trial has 101 patients enrolled between the ages of 2 and 21 that have a confirmed disease-related CDKL5 gene variant.3
The primary endpoint of this trial is the percent change in 28-day seizure frequency, while the non-seizure secondary outcome measures will be behavioral/neuropsychiatric changes correlated with attention and sleep. The data is expected in Q3 2020.3
In the distant future, Marinus Pharmaceuticals aims to establish GNX as a first-in-class neuropsychiatric therapy to treat drug-resistant seizures and neuropsychiatric disorders. We look forward to seeing the Global Phase 3 trial data later this year.
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