Ganaxolone Being Investigated as Treatment for Tuberous Sclerosis and CDKL5 Deficiency Disorder

Marinus Pharmaceuticals is a pharmaceutical company that works to create treatments for epilepsy and other neuropsychiatric disorders. They are in the process of conducting clinical trials to evaluate the safety and efficacy of ganaxalone, and there are specific programs within the study to examine the effects of this drug on those with tuberous sclerosis and those with CDKL5 deficiency disorder (CDD).

About Tuberous Sclerosis

Tuberous sclerosis is a disorder that is characterized by the growth of noncancerous tumors throughout the body. This disorder contains a wide variety of symptoms, and it has a wide range of severity. Some people may have mild symptoms, which would lead to a diagnosis later in life, while others have very severe symptoms and are diagnosed during infancy.

Tuberous sclerosis is the result of inheritance or an error in cell division. A parent who also has this disorder can pass it down to a child, or a random mutation can occur that results in tuberous sclerosis. Both of these causes have to do with the TSC1 or TSC2 genes, which are the genes that result in tuberous sclerosis.

Symptoms of this disorder are a result of the tumors, which most commonly grow in the kidneys, brain, eyes, heart, lungs, and skin. The size and location of the tumors can affect the severity of the symptoms. These symptoms include skin abnormalities, seizures, cognitive disabilities, behavioral problems, kidney problems, heart issues, lung problems, and abnormalities in the eyes. Depending on the size and location of the tumors, life-threatening complications can occur. Tumors can block the flow of cerebral spine fluid, which then creates an excess of fluid in and around the brain. Tumors in the heart can cause heart issues like dysrhythmia. Lung failure is a possibility if tumors grow in the lungs, and vision damage can happen if they grow in the eyes. There is also a higher possibility of developing malignant tumors in the brain or kidneys.

In order to reach a diagnosis, a physical examination and a discussion of symptoms and family history must occur. Doctors will look for the benign tumors that are associated with tuberous sclerosis. Tests will be ordered in order to locate and assess the severity of the tumors. Genetic tests may be ordered as well. Specialists will often be ordered for the effected organs.

There is no cure for this disorder, but there are treatments available to manage the symptoms. Medications can be prescribed to help many of the symptoms, including seizures. Surgeries can remove growths if they become harmful. Speech, occupational, and physical therapy may also help if the tumors cause issues in these areas. As tumors in the brain can cause developmental delays, educational services and psychiatric or behavior management may also be helpful.

About CDKL5 Deficiency Disorder (CDD)

CDD is a disorder that is characterized by seizures during infancy, which are followed by developmental delays. The majority of those with CDD are females, and males with this disorder tend to experience more severe symptoms. It is inherited in an X-linked dominant pattern. This disorder used to be identified as Rett syndrome, but more research has been conducted, which distinguishes CDD from Rett syndrome.

CDKL5 is caused by a mutation in the CDKL5 gene, which produces instructions that are needed for brain development. It is likely involved with the growth, movement, and formation of neurons. The mutation causes a deficiency of the protein, which disrupts normal brain development.

Symptoms of this disorder begin in infancy, as babies experience seizures. Seizures will begin within the first three months of life, with the most severe cases having seizures every day. The main issue with these seizures is that they are resistant to treatment. As children grow, they will have developmental delays. Most children with CDD have severe intellectual disabilities and little to no speech. Gross motor skills like sitting and walking are delayed as well. Fine motor skills are also impaired. Other symptoms of CDD are repetitive hand movements, tooth grinding, issues with feeding, disrupted sleep, gastrointestinal problems, and irregular breathing. Distinct facial features are another symptom of this disorder. People may have high and broad foreheads, deep-set eyes, full lips, widely spaced teeth, a defined space between the nose and upper lip, and a high roof of the mouth. Some are also affected by a small head, scoliosis, and tapered fingers.

Molecular genetic testing is necessary to confirm a diagnosis after a physical exam and study of symptoms and history. After a diagnosis is confirmed, treatment is supportive and symptomatic. Occupational, physical, speech, and augmentative communication therapy are all heavily recommended. The seizures associated with this disorder have not been effectively treated by any one medication, but more research is being done. Investigational therapies are also being researched to help those with CDD.

About Ganaxolone

Ganaxolone is a positive allosteric modulator of GABAA receptors. It is being developed in oral and intravenous forms. It has been shown to treat the seizures that characterize both tuberous sclerosis and CDD. It has been studied in over 1,600 participants in treatment regiments that have lasted over four years for some. The studies found that ganaxolone was safe and well-tolerated. The most common side effects were dizziness, fatigue, and somnolence.

About the Tuberous Sclerosis Program

Marinus Pharmaceuticals plans to conduct Phase 2 of their clinical study focused on tuberous sclerosis in the first half of 2020. This phase will evaluate the safety and tolerability of ganaxolone. This phase plans to enroll 20 to 40 participants in 4 to 6 sites across the United States. These participants will be aged anywhere from 2 to 65. The study will last for 16 weeks in total.

About the CDD Program

Ganaxolone has been granted the orphan drug designation by the European Medicines Agency for the treatment of CDD. This drug will be evaluated in the third phase of the Marigold study, and the company is currently enrolling patients for this phase. They will evaluate the oral use of this drug in children and young adults. It is a double-blind, placebo-controlled study and will enroll up to 100 participants between the ages of two and 21. They hope to release data from this phase in the third quarter of 2020.

Marinus Pharmaceuticals is excited for the results of all of the programs involved with ganaxolone. They hope that the outcomes will continue to be positive and that this drug will better the lives of those with CDD and tuberous sclerosis.

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