Pediatric Orphan Indications

Marinus is leveraging the pediatric safety profile of ganaxolone to expand its development into pediatric orphan indications.

Ganaxolone has been administered in more than 200 children, as young as four months old and dosed for more than two years. Ganaxolone is generally safe and well tolerated, with the most commonly reported side-effects being agitation, sedation, and dizziness. In clinical studies, ganaxolone has shown both anti-seizure as well as anti-anxiety activity. This dual benefit has the potential to address both the seizures and behavioral co-morbidities associated with a variety of orphan, genetic disorders.

Ganaxolone was evaluated in a Phase 2 open-label exploratory study as a treatment for orphan, genetic epilepsies (CDKL5 Defiency Disorder, PCDH19 Epilepsy, & Lennox Gastaut Syndrome). Currently, there are no FDA approved therapies for these conditions. More information about the trial can be found on, using Identifier NCT02358538.

CDKL5 Deficiency Disorder (CDD)

CDKL5 Deficiency Disorder (CDD) is a serious and rare genetic disorder that is caused by a mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene, located on the X chromosome. The CDKL5 gene encodes proteins essential for normal brain function. CDKL5 mutations have been found in children previously diagnosed with cerebral palsy and autism, among other conditions, and the resulting disorder had also been previously classified as an early onset seizure variant of Rett Syndrome but it is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and therefore a separate disorder with its own distinct characteristics. Mutations in the gene are usually spontaneous ‘de novo’ occurrences, rather than inherited.

CDD predominantly affects girls and is characterized by early-onset, difficult-to-control seizures and severe neuro‑developmental impairment. Most children affected by CDD cannot walk, talk, or feed themselves, and many are confined to wheelchairs, dependent on others for everything. Many also suffer from scoliosis, visual impairment, sensory problems, gastrointestinal difficulties, and sleeping disorders. Currently, there are no approved therapies for CDD.

Most children affected by CDD cannot walk, talk, or feed themselves, and many are confined to wheelchairs, dependent on others for everything. Many also suffer from scoliosis, visual impairment, sensory problems, gastrointestinal difficulties, and sleeping disorder.

Clinical Development of Ganaxolone in CDKL5 Deficiency Disorder

We recently reported top-line data from the Phase 2 open-label study in patients with CDKL5 deficiency disorder (CDD). Oral ganaxolone, in addition to baseline treatment, showed a sizable and durable seizure-frequency reduction in the majority of patients, with some achieving an increase in the number of seizure-free days and reporting behavioral benefits.  Ganaxolone was generally safe and well-tolerated with no serious adverse events. Based upon these robust CDD clinical results and etiologic fit with ganaxolone’s mechanism of action, we have prioritized CDD as our lead pediatric orphan program for advancement into later stage clinical development. We plan to meet with regulatory agencies to discuss the clinical development plan with the goal of commencing a clinical study to further evaluate ganaxolone in patients with CDD.

PCDH19 Pediatric Epilepsy

PCDH19 pediatric epilepsy is a serious and rare epileptic syndrome characterized by highly variable early-onset cluster seizures with comorbid cognitive and behavioral disturbances with or without intellectual disability. PCDH19 pediatric epilepsy is caused by a mutation in the PCDH19 gene. There is indirect evidence linking progesterone and allopregnanolone to the onset and offset of seizures in girls with PCDH19 pediatric epilepsy.

Clinical Development of Ganaxolone in PCDH19 Pediatric Epilepsy

We have completed the PCDH19 cohort in the study which enrolled 11 females.  In this severe patient population, ganaxolone reduced seizure frequency from baseline in the majority of patients and was generally safe and well tolerated.

Fragile X Syndrome

Photo Credit: Peter Saxon (CC BY-SA)

Fragile X Syndrome (FXS) is a genetic condition, caused by a mutation in the fmr1 gene, and is characterized by the development of a range of developmental problems, including cognitive impairment, learning disabilities and behavioral challenges. Ganaxolone and other agents that have been shown to improve GABA function have also been shown to improve FXS symptoms in a mouse model. Ganaxolone may increase signaling at existing receptors to normalize GABA function, thereby reducing anxiety, hyperactivity and other disabilities associated with this inherited disorder.

FXS is estimated to affect 100,000 children and adults in the U.S. Currently, there are no known cures or approved therapies for FXS.

Clinical Development of Ganaxolone in FXS

Ganaxolone was evaluated for the treatment of anxiety and attention in children with FXS in a Phase 2 exploratory clinical trial.  Consistent with our expectations and ganaxolone’s mechanism of action, treatment with ganaxolone improved anxiety and hyperactivity across multiple measures in FXS patients with high baseline anxiety.  In addition ganaxolone was generally safe and well tolerated. The results from this study support the anxiolytic effect of ganaxolone and provide a strong rationale to advance the clinical development of ganaxolone in anxious FXS patients.


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