Authors :
Elia Pestana-Knight, MD – Epilepsy Center, Cleveland Clinic; Scott Demarest, MD – Department of Pediatrics and Neurology – University of Colorado School of Medicine; Orrin Devinsky, MD – New York University Langone Comprehensive Epilepsy Center; Sam Amin, MD – Pediatric Neurology – University Hospitals Bristol and Weston; Eric Marsh, MD – University of Pennsylvania; Alex Aimetti, PhD – Marinus Pharmaceuticals, Inc.; Eva Rybak, PharmD – Marinus Pharmaceuticals, Inc.; Ian Miller, MD – Marinus Pharmaceuticals, Inc.; Joseph Hulihan, MD – Marinus Pharmaceuticals, Inc.; Heather Olson, MD – Boston Children’s Hospital and Harvard Medical School
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. In a recent placebo-controlled study, ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with CDD. Here we report on safety and clinical outcomes data at a minimum of 1-year in the open-label extension (OLE).
Methods: Patients with CDD (aged 2-19 years) who completed the double-blind phase were eligible to receive ganaxolone in the OLE. Assessments included changes in MMSF from pre-randomization baseline to 3-month intervals in the OLE, notable responder rates (≥50% and ≥75% MMSF reductions), Clinical Global Impression of Improvement (CGI-I), safety, and tolerability. At the time of this analysis (data cut June 22, 2021), all patients had entered the OLE at least 1-year prior.
Results: Eighty-eight patients (87.1%; median age of 5; 79.5% were female) continued into the OLE (101 patients were randomized to the double-blind portion of the study). Median baseline 28-day MMSF was 50.6.
The one-year retention rate was 70.5% with 26 patient discontinuations during that time. At the time of this analysis, 34 subjects had discontinued due to lack of efficacy (n=12), adverse event (n=10), or withdrawal by caregiver (n=10) as the most common reasons. During Months 1-3, 4-6, 7-9, and 10-12 in the OLE, patients experienced a median reduction in MMSF of 24.7% (n=87), 32.1% (n=79), 30.0% (n=73), and 42.2% (n=67), respectively (see Figure 1). During months 13-24, MMSF reductions ranged from 44.2% to 56.1%. At 1-year (10-12 month interval), 46.3% and 23.9% of patients experienced a ≥50% and ≥75% reduction in MMSF, respectively. In the OLE, clinicians and caregivers rated 60.6% and 72.5% of the patients, respectively, as improved better at 1-year. The most commonly reported adverse events in the OLE were seizure (22.7%), somnolence (20.5%), vomiting (18.2%), and pyrexia (17.0%). There was one death reported due to sepsis, but it was deemed unrelated to study treatment.
Conclusions: Reductions in MMSF at 1-year and beyond provide supportive evidence for the maintenance of effect of ganaxolone in seizures associated with CDD. Ganaxolone was generally well-tolerated in the OLE with safety findings consistent with the double-blind phase.
Funding: This work was funded by Marinus Pharmaceuticals, Inc.