Pediatric Epileptologist, Cleveland Clinic

Elia Pestana-Knight, MD

"We need to move toward more objective measurements to determine if that medication is also impacting the disease itself. Are we getting better with the development of medications? For that, we have to have tools that are disease specific and that are not taken from general use on epilepsy because then we are going to be dealing with the limitations of these significant symptoms that are different from other epilepsies."

In March 2022, the FDA made a landmark decision, 

 (Ztalmy; Marinus Pharmaceuticals) as the first medication to treat seizures associated with CDKL5 deficiency disorder (CDD). The oral neuroactive steroid that acts as a positive allosteric modulator of the GABAA receptor, was approved based on data from the phase 3 Marigold trial (NCT03572933), which showed that patients on the drug experienced a median reduction of 30.7% in 28-day major motor seizure frequency compared with a 6.9% reduction for those on placebo.

As the patient population with CDD has historically struggled with using the standard antiseizure medications meant for epilepsies, the decision represented a major breakthrough. Now, the attention should be focused on improving quality of life and including more patient-focused measures in future clinical trials, says Elia Pestana-Knight, MD. Pestana-Knight, a pediatric epileptologist at Cleveland Clinic, was the lead investigator for the Marigold study and presented the latest data at the 

2022 American Academy of Neurology (AAN) Annual Meeting

While the disease has only been formally recognized for less than 20 years, several prominent neurology-based organizations have begun to recognize the importance of addressing it, Pestana-Knight said. In an interview with 

, she broke down the types of research needed to advance the state of care for CDD, along with some of the major efforts currently underway.

Click here for more coverage of AAN 2022.

REFERENCE
1. 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.

Videos

The pediatric epileptologist from Cleveland Clinic provided commentary on the changes needed to improve research and drug development in CDKL5 deficiency disorder, as well as the organizations committed to advancing the state of care. [WATCH TIME: 3 minutes]

Next Steps in Tackling CDKL5 Deficiency Disorder Following First Approval: Elia Pestana-Knight, MD

"One of the characteristics of the disease is that the patients exhibit a variable and low response to traditional antiseizure medications. Even sometimes when you get a response over the following 3 months, you lose that response. There is a high lack of efficacy and loss of efficacy to the traditional antiseizure medications."

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition caused by pathogenic variants in the 

gene, which is responsible for creating a protein necessary for normal brain development and function. The disorder can cause a wide range of symptoms with varying severity, making it one of the more complex encephalopathies out there. Seizure control remains a challenge for patients with the disorder and has historically been addressed through a combination of several antiseizure medications (ASMs).

After years of finding little drug development success, the field had a major breakthrough. In March 2022, 

 (Ztalmy; Marinus Pharmaceuticals) as the first treatment for patients with CDD. Ganaxolone, a neuroactive steroid that acts as a positive allosteric modulatory of the GABAA receptor, was approved based on data from the phase 3 Marigold trial (NCT03572933), a double-blind placebo-controlled trial that randomized 101 patients with the disorder.

 Primary investigator Elia Pestana-Knight, MD, who presented some of the data from Marigold at the 

2022 American Academy of Neurology (AAN) annual meeting

, believes there is good reason to celebrate the approval.

Pestana-Knight, a pediatric epileptologist at 

, noted that drug development is of high importance for this patient group, considering the severity of their refractory seizures. As part of 

®’s coverage of AAN 2022, she sat down to discuss the implications of the approval, ganaxolone’s unique mechanism of action, and how it can hopefully springboard future drug development.

The pediatric epileptologist at Cleveland Clinic discussed the impact of ganaxolone’s approval for CDKL5 deficiency disorder and how it may create an opportunity for future pipeline agents. [WATCH TIME: 3 minutes]

Elia Pestana-Knight, MD

Articles

Next Steps in Tackling CDKL5 Deficiency Disorder Following First Approval: Elia Pestana-Knight, MD

Ganaxolone’s Approval Springboards Future CDD Drug Development: Elia Pestana-Knight, MD

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