NeuroVoices: Elia Pestana-Knight, MD, on the Importance of Ganaxolone’s Approval in CDD


The pediatric epileptologist at Cleveland Clinic’s Epilepsy Center discussed data presented at AAN 2022 on the use of ganaxolone in CDD, as well as how its recent approval sets the stage for the future.

Elia Pestana-Knight, MD

Elia Pestana-Knight, MD

CDKL5 deficiency disorder (CDD) is a rare, genetically determined developmental and epileptic encephalopathy characterized by early-onset refractory seizures and severe neurodevelopmental impairment. CDD-associated seizures are often refractory to treatment with existing antiseizure medications and improvements have been shown to be short-lived. Most recently, the FDA approved ganaxolone (Ztalmy; Marinus Pharmaceuticals) as the first treatment for seizures associated with the disease, a landmark decision for the CDD community.1

The decision was based on the phase 3 Marigold study (NCT03572933), which was a double-blind, placebo-controlled trial that randomized 101 patients to adjunctive ganaxolone or placebo for 17 weeks. The primary end point, change in major motor seizure frequency, was observed in 30.7% of ganaxolone-treated patients compared with 6.9% for those on placebo.2 Ganaxolone, a neuroactive steroid that acts as a positive allosteric modulator of the GABAA receptor, is expected to be available via a specialty pharmacy in July 2022.1

One of the investigators of Marigold, Elia Pestana-Knight, MD, believes this was a historic win for the CDD community. Pestana-Knight, a pediatric epileptologist at Cleveland Clinic’s Comprehensive Epilepsy Center, presented the data at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington. She sat down as part of a new iteration of NeuroVoices to discuss the meaning behind the results, the importance of the approval, and how the field can build on it for the future.

NeurologyLive®:Can you first just explain the results that you're presenting at AAN, as well as some of the major take home points?

Elia Pestana-Knight, MD: The study we’re presenting at the American Academy of Neurology meeting is a result from the Marigold study, in which we tested the efficacy and safety of ganaxolone for the treatment of seizures in patients with CDKL5 deficiency disorder aged 2 to 21 years. It was an international, global, multicenter study that was randomized and double-blind. There was a branch of patients that were assigned to placebo and a branch that was assigned to ganaxolone as the main drug of interest.

The study had different segments. We started out with an 8-week seizure diary that parents brought to the clinic at the time of enrollment. After that, they collected seizure data in a literary diary for 6 more weeks. The patients were then assigned to one or another branch once eligibility for the study was fulfilled. After a 4-week titration, the patients began a total of 17 weeks of treatment with this medication and were then given the option to go to the open-label study, which is ongoing.

The primary end point was a percentage of change in 28-day major motor seizure frequency. In this trial, we demonstrated that ganaxolone was able to reduce the seizures by 30.7% in the ganaxolone group compared to 6.9% in the placebo. Ganaxolone was generally very well-tolerated. The main adverse events that we encountered were somnolence, pyrexia, and fever. Some patients had more seizures. In reality, there was only 12% for treatment-emergent adverse events in the ganaxolone group compared to 9.8% in the placebo group. In the ganaxolone group, the discontinuation rate was 4% vs 8% in the placebo group. I think this speaks to what the medication brings to the table for the treatment of seizures in children with CDKL5 deficiency disorder.

This is a young disease when we compare it to other epilepsies that have been known in the field for centuries. It was discovered in 2004. This is a disease characterized by early-onset refractory seizures, developmental delay, and intellectual disability, particularly patients having poor language development, difficulty using their hands, and trouble developing fine motor skills. Some are able to walk or sit by themselves, but many of them don’t have the joy to achieve those milestones. They also have a diffused low muscle tone, which affects with the ambulation. Many of them have cortical visual impairment, which is an inability to properly interpret what they’re seeing due to a deficiency in the brain. They also can have hand stereotypies and other movement disorders such as dyskinesia and choreoathetosis.

What does the approval of ganaxolone mean for the CDD community?

We are excited as a community in general. We physicians and caregivers of patients with CDKL5 deficiency disorder consider ourselves a big family. This was a reason for big celebration. Ganaxolone is a neurosteroid that enhances the GABAA-ergic neurotransmission. Therefore, it brings a new mechanism of action to the medications that we already have now known as the conventional antiseizure medications. One of the characteristics of this disease is that the patients exhibit a variable and low response to traditional antiseizure medications. Sometimes when you get a response over the following three months, you lose that response. There’s a lack of efficacy and loss of efficacy to traditional antiseizure medications in this population. Last year we published data from different centers of excellence for the treatment of CDKL5 deficiency disorder and found that the response rate of medications at 2 weeks was between 14% and 48%. That dropped after 3 months from 5% to 36%. This speaks to how refractory the seizures are for this population.

Can this approval jumpstart more drug development? Now that there’s been a proven mechanism of action

We hope. We hope there will be development of drugs with similar mechanisms of action. I don’t know if that’s the case just yet. There’s a conversation of initiating a study with fenfluramine, which is a small pilot study. But of course, the efficacy of that medication needs to be tested in a randomized study, which is similar to the one that we’re presenting at AAN.

What other types of research is needed for these patients?

The next big milestone for our community is getting ready for clinical trials in which we move beyond just counting seizures, which is what we’ve been doing now in epilepsy. We have been counting seizures, measuring quality of life, and caregiver global impression, but we need to move to more objective measurements to determine that the medication is also impacting the disease itself. Are we getting better development for medications? For that, we have to understand and have tools that are disease specific and not taken from the general use of epilepsy. If we do that, we’re going to be dealing with the limitations of having significant symptoms that are different from other epilepsies. That’s why we’re working with the community, talking to the parents and caregivers of CDKL5 deficiency disorder.

Transcript edited for clarity. Click here for more iterations of NeuroVoices.

1. Marinus Pharmaceuticals Announces FDA Approval of ZTALMY® (ganaxolone) for CDKL5 Deficiency Disorder. News release. Marinus. March 18, 2022. Accessed March 21, 2022.
2. Olson H, Moosa AN, Rybak E, et al. Extended Duration Safety and Efficacy of Adjunctive Ganaxolone Treatment in Patients with CDKL5 Deficiency Disorder: 8-Month Minimum Open-Label Extension Follow-up. Presented at: AAN Annual Meeting; April 2-7, 2022; Seattle, WA, and virtual. Abstract 003540.
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