Effect of Concomitant Antiseizure Medications on the Safety and Efficacy of Ganaxolone for the Treatment of Seizures Associated with CDKL5 Deficiency Disorder (CDD): Findings from the Phase 3 MARIGOLD Study
John Flatt1, Sam Amin2, Rajsekar Rajaraman3, Alex Aimetti1, Joseph Hulihan1, Scott Perry4
1Marinus Pharmaceuticals, Inc., 2University Hospitals Bristol and Weston, 3UCLA Medical Center, 4Cook Children's Medical Center
Objective:
Here we report the safety and efficacy of ganaxolone in patient subgroups who were taking the most frequently-used concomitant antiseizure medications (ASMs) in the Marigold Study (NCT03572933).
Background:
CDD is a developmental and epileptic encephalopathy characterized by global developmental impairment and early-onset, refractory seizures. In Marigold, ganaxolone significantly reduced seizures associated with CDD. Major motor seizure frequency (MMSF) was reduced with ganaxolone treatment by a difference of 27.1% over placebo.
Design/Methods:
N=101 patients with CDD aged 2-19 were enrolled in the study. Patients were permitted to take ≤4 concomitant ASMs during the study. The four most frequently-used ASMs were valproate (n=34), levetiracetam (n=26), clobazam (n=25), and vigabatrin (n=24). Efficacy was assessed by the placebo-adjusted percent reduction in MMSF during the 17-week treatment period versus baseline. Safety outcomes included treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
Results:
The greatest placebo-adjusted percent reductions in MMSF were observed in patients who were taking clobazam or valproate; a 53.4% (28.1, 83.1) and 46.1% (13.4, 78.2) Hodges-Lehmann difference (95% CI) was observed in these groups, respectively. The difference was 15.9% (-19.4, 76.8) and 14.2% (-13.2, 37.3) in patients who were taking vigabatrin and levetiracetam, respectively. TEAEs and SAEs were similar in ganaxolone-treated patients across all concomitant ASM subgroups. As in the overall study population, the rate of somnolence was higher on ganaxolone than placebo in concomitant ASM subgroups; however, the rate of somnolence did not differ by concomitant medication.
Conclusions:
Placebo-adjusted reduction in MMSF was larger for patients who were taking concomitant clobazam or valproate. However, these results may be confounded by baseline differences in patient characteristics in concomitant ASM subgroups and varying placebo responses. Safety findings were comparable with different concomitant ASMs. Further research could provide insight on the impact of concomitant medications on the efficacy and safety of ganaxolone therapy in patients with CDD.