番茄社区

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder is a rare, genetically determined developmental and epileptic encephalopathy characterized by early-onset refractory seizures and severe neurodevelopmental impairment. Recently, the FDA approved ganaxolone (Ztalmy) as the first treatment for seizures associated with the disease, a landmark decision that was based on the phase III , which was presented at the American Academy of Neurology annual meeting.

In this exclusive 番茄社区 video, primary investigator , a pediatric epileptologist at the Cleveland Clinic Epilepsy Center, discusses the Marigold data.

Following is a transcript of her remarks:

The Cleveland Clinic is one of the centers of excellence for CDKL5 deficiency disorder research. And as such, we had the opportunity to offer patients the participation in the Marigold clinical trial, which is an international randomized clinical trial for children and young adults with CDKL5 deficiency disorder.

CDKL5 deficiency disorder affects around one in 40,000 children -- or people. And it is one of the top 10 monogenic epilepsies, as we know them today. One of the characteristics of this disease is they have an early onset of seizures. So, seizure is one of the first identifiable symptoms, but it's not the only symptom that the patients will experience in the central nervous system and peripheral nervous system. The patients could also have a cortical visual impairment, global developmental delay, in particular they have deficiency developing language and the use of the fine finger movements of their hands. They can have autonomic symptoms, constipation, hypotonia, scoliosis, movement disorder, etc.

The seizures in this genetic disease are very refractory to traditional anti-seizure medications. Therefore, there has been an interest in developing drugs to target, to control seizures, but also that will provide improvement in the disease.

So, what we did, the Marigold trial had a placebo and a medication branch -- with the medication being ganaxolone and produced by Marinus Pharmaceuticals. After an initial screen and after we had seizures recorded in an electronic diary, the patients were randomized to placebo or medication. And we measured the percentage of major motor seizure change in 28 days.

Why did we pick major motor seizures? Because the seizures in CDKL5 don't follow the traditional definition of seizures that the International League Against Epilepsy has out there. And they can be very valuable in one subject. They can have chronic seizures, atonic or sequential seizures, in which the seizures start looking one way, but they can end up looking a different way. So, that was our target. That's what we measured. We also measured the Clinician and the Caregiver Global Impression of Change or improvement.

And what we found is that patients who receive ganaxolone, they had a percentage change in 28-day major motor seizure of 30.7% compared to 6.9% in the placebo group. In general, the medication was well tolerated, and the major adverse events were somnolence, pyrexia, and some patients of course developed seizures. But [the rate of] seizure treatment-emergent adverse events was 12% in the ganaxolone group and 9.8% in the placebo group. In the ganaxolone group, the discontinuation rate was 4%, and in the placebo group it was 8%.

So, with this, I think that we have a medication that offers a new mechanism of action compared to the conventional anti-seizure medications. Ganaxolone is a neurosteroid that enhances the GABAergic neurotransmission, and it has been recently also approved by the FDA. So, we are hoping to have it in the market by July 2022.

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