Authors :
Presenting Author: Rajsekar Rajaraman, MD – UCLA Mattel Children's Hospital
John Flatt, MD – Marinus Pharmaceuticals, Inc.; Alex Aimetti, PhD – Marinus Pharmaceuticals, Inc.; Joseph Hulihan, MD – Marinus Pharmaceuticals, Inc.; M. Scott Perry, MD – Cook Children's Jane and John Justin Neurosciences Center
Rationale:
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy characterized by global developmental impairment and early-onset, refractory seizures. Ganaxolone, a neuroactive steroid and positive allosteric modulator that acts on both synaptic and extrasynaptic GABA
A receptors, was shown to significantly reduce seizures associated with CDD. In the multinational, placebo-controlled, double-blind Marigold Study (NCT03572933), major motor seizure frequency (MMSF) was reduced with ganaxolone treatment over 17 weeks by a Hodges-Lehmann difference of 27.1% over placebo. Here we report on the safety and efficacy of ganaxolone in subgroups of patients who were taking the most frequently used concomitant antiseizure medications (ASMs).
Methods:
A total of 101 patients with CDD aged two to nineteen were enrolled in the study. Eligible patients were permitted to take up to four concomitant ASMs during the study. Safety and efficacy were evaluated in subgroups of patients taking each of the four most frequently used ASMs (valproate, levetiracetam, clobazam, and vigabatrin). Efficacy was assessed by the placebo-adjusted percent reduction in MMSF during the 17-week treatment period relative to the four week baseline. Safety outcomes included treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
Results:
The most commonly used concomitant ASMs were valproate (n=34), levetiracetam (n=26), clobazam (n=25), and vigabatrin (n=24). 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) difference (Hodges-Lehmann difference, 95% CI) was observed in these groups, respectively. The placebo-adjusted 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.
Funding:
Marinus Pharmaceuticals, Inc.