Long-Term Efficacy and Safety of Ganaxolone for Treatment of Cyclin-Dependent Kinase-Like 5 Deficiency Disorder—A Developmental Encephalopathic Epilepsy 

Ganaxolone (Ztalmy; Marinus Pharmaceuticals, Radnor, PA) was recently approved for adjunctive treatment of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in people, age 2 years or more.  

CDD, which can be diagnosed with a genetic test, is among the developmental encephalitic epilepsies, now understood as a distinct entity, separate from other epilepsy syndromes. CDD is characterized by early onset, difficult to control seizures, cortical visual impairment, hyperkinesis, neurodevelopmental delays, autonomic symptoms, and inability to communicate verbally.  

Participants, age 2 to 21 years, in the clinical trial who were treated with ganaxolone vs placebo for 17 weeks had a median 30.7% vs 6.9% decrease (P=.004) from baseline in major motor seizure frequency (MMSF). Baseline MMSF in those treated with ganaxolone vs placebo were 54.0 vs 49.2. Major motor seizures were defined as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral clonic, or focal to bilateral tonic-clonic seizures.  

Elia Pestana Knight, MD, investigator on these trials and pediatric epileptologist, Cleveland Clinic Epilepsy Center, 1 of the initial 3 Centers of Excellence for CDKL5 Deficiency Disorder, said, “We are pleased to have an effective treatment that is also well tolerated for children with CDD. Having tools for treatment makes earlier diagnosis essential, and we want to encourage all clinicians treating children, age 8 year and under, to take advantage of the no-cost genetic testing available from sponsored programs such as Behind the Seizures for earlier diagnosis of CDD and other genetic epilepsies.” Dr. Pestana Knight joined the scientific advisory board of Marinus Pharmaceuticals after completion of the Marigold randomized trial.  

In an open-label extension study, participated in by 87.1% of those who were in the double-blind trial, all participants received ganaxolone for a median 262 days. Median MMSF reduction from baseline at 8 months in those who received ganaxolone in the double-blind trial was 30.1% and and 33.3% in those who had first received placebo. After 12 months, median MMSF reduction from baseline was 46.5% (n=22) and 53.8% (n=26), respectively. At the time this data was reported, 35.2% of participants withdrew for lack of efficacy (38.7%) or adverse events (29%).  

Ganaxolone is a novel neurosteroid treatment that enhances GABAergic transmission. Adverse events that occurred in more than 10% of participants most frequently were somnolence, fever, and upper respiratory tract infections. Serious adverse events occurred in 4% of those treated with ganaxolone and 9.8% of those who received placebo.