Abstract
Objective
In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold.
Methods
Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from pre-randomization baseline, responder rates, and Clinical Global Impression of Improvement scale (CGI-I) scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation.
Results
Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age 5 years; 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (Months 22-24), MMSF was reduced by a median of 48.2% (n=50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During Months 22-24, 23/50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12/50 (24.0%) patients experienced MMSF reductions of ≥75%. During Months 22-24, 40/49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to: lack of efficacy (n=13), withdrawal by caregiver (n=12), adverse event (n=10), physician decision (n=1), or death (n=1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n=28, 31.8%); those reported in ≥3% of patients were: seizure (n=6), pneumonia (n=5), acute respiratory failure (n=3), aspiration pneumonia (n=3), and dehydration (n=3).
Significance
Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.
NOV