Abstracts

Rationale:
CDKL5 deficiency disorder (CDD) is a rare, genetically determined epileptic encephalopathy with an estimated incidence in the range of 1:40,000-60,000. The clinical characteristics commonly associated with a pathogenic CDKL5 variant include early-onset refractory epilepsy, hypotonia, intellectual and gross motor impairment, and sleep disturbances.  Seizures associated with CDD are often refractory to treatment with existing antiepileptic drugs (AEDs) and improvements may be short-lived.  The Marigold Study (NCT03572933) is the first Phase 3, randomized, placebo-controlled trial to evaluate adjunctive investigational ganaxolone in patients with refractory epilepsy associated with CDD.
Method:
This was a randomized, double-blind, placebo-controlled trial conducted at 36 sites in 8 countries. Eligible patients were 2-21 years of age with a pathogenic CDKL5 variant and uncontrolled seizures ( >16 major motor seizures per month). Major motor seizures were defined as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral clonic or focal to bilateral tonic-clonic. Enrolled patients prospectively tracked seizure frequency during a 6-week baseline period and were then randomized (1:1) to receive ganaxolone or placebo for 17 weeks (treatment period: 4 week titration and 13 week maintenance).  Ganaxolone was taken TID at a maintenance dose of up to 63 mg/kg/day or 1,800 mg/day maximum. The primary endpoint was the percentage change from baseline in major motor seizure frequency during the treatment period. Key secondary endpoints included ≥50% responder rate and clinical global impression of improvement (CGI-I) at the end of the treatment period. Results101 patients were randomized (50 ganaxolone, 51 placebo) of median 6 years of age (79% female and 21% male). Prior to the study, patients had tried a median of 7 prior antiepileptic drugs (AEDs).  In the baseline period, patients experienced a median 28-day major motor seizure frequency of 50.0 and 57.3 in the placebo and ganaxolone groups, respectively.  Patients on ganaxolone experienced a median 32.2% reduction in major motor seizure frequency compared to a 4.0% reduction in the placebo group during the treatment period relative to baseline (p=0.002, Wilcoxon Rank-Sum Test). Ganaxolone demonstrated improving trends but did not achieve statistical significance in the key secondary endpoints.  Adverse events occurred in 86% of ganaxolone patients and 88% of placebo patients.  Ganaxolone was generally well tolerated with a less than 5% discontinuation rate in the treatment arm with somnolence being the most frequent adverse event (36% of patients).
Conclusion:
These data provide strong evidence that ganaxolone is effective and generally well-tolerated in the treatment of refractory epilepsy in patients with CDD.
Funding:
:This work was sponsored by Marinus Pharmaceuticals.