Ganaxolone: A Treatment for Major Motor Seizures in CDKL5 Deficiency Disorder

01AFTC2Z – Illustration of a brain showing epileptic seizure activity, front view. Electroencephalogram (EEG) tracings show abnormal waveforms emanating from the temporal lobe (blue-green) ofthe brain.
In a global, phase 3 trial, researchers evaluated the efficacy of ganaxolone as an adjunctive treatment compared to placebo for major motor seizures in patients with CDKL5 deficiency disorder.

The following article is part of conference coverage from the 2022 American Academy of Neurology (AAN) Annual Meeting. Neurology Advisor’s staff will be reporting breaking news associated with research conducted by leading experts in neurology. Check back for the latest news from the 2022 AAN Annual Meeting.


Ganaxolone as an adjunctive treatment for major motor seizures (MMS) was well tolerated and associated with a reduction in the frequency of seizures compared with placebo in patients with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) and uncontrolled MMS. These findings were presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, held from April 2 to April 7 in Seattle, Washington, and virtually from April 24-26, 2022.

“CDD is a rare, genetically determined developmental and epileptic encephalopathy,” the researchers explained. Early-onset refractory seizures and severe neurodevelopmental impairment are characteristic of patients who have CDD. Seizure onset from CDD is often resistant to treatment and antiseizure medications only offer short-term improvements for patients.

As of March 18, Ztalmy (ganaxolone) has received U.S. Food and Drug Administration (FDA) approval to treat seizures in patients with CDD who are 2 years or age and older.

The objective of the current study was to determine the efficacy of ganaxolone, a gamma aminobutyric acid type A (GABAA) receptor modulator, as an adjunctive treatment for MMS in patients with CDD compared to placebo.

The global, phase 3 trial included 101 patients (79% female) between the ages of 2 and 21 years (median age, 6 years) who had a pathogenic CDKL5 variant as well as ≥16/month MMS. Patients were randomly assigned to receive either adjunctive ganaxolone (n=50) at a maximum of 63 mg/kg/day or 1800 mg/day or placebo (n=51) for a total of 17 weeks.

In the study, the researchers defined MMS as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral clonic, or focal to bilateral tonic-clonic. For the primary endpoint, they examined the percentage change in MMS frequency (MMSF) from baseline and during the double-blind phase. Additionally, secondary endpoints of the study included a 50% or more responder rate as well as clinical global impression of improvement (CGI-I).

Prior to study entry, patients had received a median of 7 antiseizure medications. At baseline, the median 28-day MMSF rates were 54.0 and 49.2 in the ganaxolone group and the placebo group, respectively.

Treatment with ganaxolone was associated with a median 30.7% reduction in MMSF relative baseline vs only a 6.9% reduction in the placebo group (P =.0036). Although not statistically significant, the researchers reported that ganaxolone demonstrated numerical trends in the secondary endpoints.

Subgroup analyses showed that treatment with ganaxolone was associated with MMSF reductions across the broad studied population with CDD. The most common adverse events that occurred in more than 10% of patients as well as more frequently in the ganaxolone group included pyrexia, somnolence, and upper respiratory tract infections.

The researchers concluded that the “data provide strong evidence that ganaxolone is effective and generally well tolerated in the treatment of refractory epilepsy in patients with CDD.”


Pestana-Knight E, Amin S, Benke T, et al. Ganaxolone significantly reduces major motor seizures associated with CDKL5 deficiency disorder: A randomized, double-blind, placebo-controlled phase 3 study. Presented at: the 2022 AAN Annual Meeting; April 2-7, 2022; Seattle, Washington; April 24-26, 2022; Virtual Meeting. Abstract S13.009.