Ganaxolone reduces seizure frequency in patients with CDKL5 deficiency disorder

Ganaxolone was generally well tolerated and significantly reduced the frequency of seizures associated with CDKL5 deficiency disorder, according to a study published in The Lancet Neurology.

“[CDKL5 deficiency disorder (CDD)] is a developmental and epileptic encephalopathy characterized by early-onset, refractory seizures and severe global developmental impairment,” Elia M. Pestana Knight, MD, of The Charles Shor Epilepsy Center at the Cleveland Neurological Institute, and colleagues wrote. “CDD-associated seizures are usually refractory to antiseizure medications, and when responsive to therapy, improvements are often short-lived (median duration of response 6 months).

“Thus, there is a considerable need for treatment that can durably decrease seizure burden (frequency, duration or severity of seizures, or a combination thereof) in patients with CDD.”

Knight and colleagues sought to further assess the safety and efficacy of ganaxolone, an investigational neuroactive steroid that previously reduced seizure frequency in patients with CDD-associated refractory epilepsy in an open-label, phase 2 trial.

They conducted a double-blind, randomized, placebo-controlled trial at 39 outpatient clinics in Australia, France, Israel, Italy, Poland, Russia, the U.K. and the U.S. and included patients aged 2 to 21 years, who were diagnosed with a pathogenic or likely pathogenic CDKL5 variant and who had at least 16 major motor seizures per 28 days in each 4-week period over 8 weeks.

Of 114 patients screened for eligibility, 101 (median age, 6 years) were randomized to receive either adjunctive ganaxolone or matching placebo (maximum dose, 63 mg/kg per day for patients weighing 28 kg or 1,800 mg per day for patients weighing > 28 kg) for 17 weeks.

Results showed a median percentage change in 28-day major motor seizure frequency of

–30.7% (IQR, –49.5 to –1.9) in the ganaxolone group and –6.9% (IQR, –24.1 to 39.7) in the placebo group. The Hodges-Lehmann estimate of median difference in responses to ganaxolone vs. placebo was –27.1% (95% CI, –47.9 to – 9.6).

Adverse events were reported in 43 of 50 patients in the ganaxolone group and 45 of 51 in the placebo group and included somnolence, pyrexia and upper respiratory tract infections, which were recorded in at least 10% of ganaxolone patients, more frequently than in the placebo group. Serious adverse events were reported in six ganaxolone patients and five placebo patients. There were no deaths in the double-blind phase.

“Results from the randomized part of this phase 3 trial provide clinical evidence that ganaxolone is generally well tolerated and efficacious in reducing the frequency of major motor seizures, supporting the potential for ganaxolone as a treatment option for patients with CDD-associated refractory epilepsy,” Knight and colleagues wrote.