Scott Demarest

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 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 prerandomization baseline, responder rates, and Clinical Global Impression–Improvement 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 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22–24, 40 of 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.