Ganaxolone Significantly Reduces Major Motor Seizures Associated with CDKL5 Deficiency Disorder: A Randomized, Double-blind, Placebo-Controlled Phase 3 Study
Elia Pestana-Knight1, Sam Amin2, Timothy Benke3, J. Helen Cross4, Heather Olson5, Thomas Fleming6, Scott Demarest7, Nicola Specchio8
1Epilepsy Center, Cleveland Clinic Neurological Institute, 2Pediatric Neurology, University Hospitals Bristol, 3Dept. of Pediatrics, University of Colorado, 4UCL-Institute of Child Health, 5Boston Children's Hospital Peabody, 6Dept. of Biostatistics, University of Washington, 7University of Colorado Health Science Center, Child Neurology, 8Bambino Gesù Children’s Hospital, IRCCS
To evaluate theefficacy of ganaxolone compared to placebo as adjunctive treatment of major motor seizures (MMS) in CDKL5 deficiency disorder (CDD).
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
(ASMs) and improvements may be short-lived.
In this global, double-blind, placebo-controlled, phase 3 trial, patients aged 2-21 years with a
pathogenic CDKL5 variant and uncontrolled major motor seizures (MMS ≥16/month) were
randomized to adjunctive ganaxolone (maximum 63 mg/kg/day or 1,800 mg/day, TID) or placebo
for 17 weeks. MMS were defined as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral
clonic or focal to bilateral tonic-clonic. The primary endpoint was percentage change from baseline
in major motor seizure frequency (MMSF) during the double-blind phase. Key secondary
endpoints included ≥50% responder rate and clinical global impression of improvement (CGI-I).
A total of 101 patients (79% female) were randomized, 50 to ganaxolone and 51 to placebo.
Patients were a median age of 6 years and had tried a median of 7 prior ASMs. Baseline median
28-day MMSF was 54.0 in the ganaxolone group and 49.2 in the placebo group. Patients taking
ganaxolone experienced a median 30.7% reduction in MMSF relative to baseline compared to a
6.9% reduction in the placebo group during the treatment period (p=0.0036, Wilcoxon Rank-Sum
Test). Ganaxolone showed numerical trends (not statistically significant) in key secondary endpoints. In
subgroup analyses, ganaxolone showed MMSF reductions across the broad CDD population
studied. Adverse events occurring in > 10% of patients and more frequently in the ganaxolone
group were somnolence, pyrexia and upper respiratory tract infections.
These data provide strong evidence that ganaxolone is effective and generally welltolerated in the treatment of refractory epilepsy in patients with CDD.