Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

Autor: Olson HE; Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA., Amin S; University Hospitals Bristol and Weston, Bristol, UK., Bahi-Buisson N; Pediatric Neurology, Necker Enfants Malades University Hospital, Paris, France., Devinsky O; New York University Langone Comprehensive Epilepsy Center, New York, New York, USA., Marsh ED; Departments of Neurology and Pediatrics, University of Pennsylvania Perelman School of Medicine and Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Pestana-Knight E; Epilepsy Center, Cleveland Clinic, Cleveland, Ohio, USA., Rajaraman RR; UCLA Mattel Children's Hospital, Los Angeles, California, USA., Aimetti AA; Marinus Pharmaceuticals, Inc., Radnor, Pennsylvania, USA., Rybak E; Marinus Pharmaceuticals, Inc., Radnor, Pennsylvania, USA., Kong F; Marinus Pharmaceuticals, Inc., Radnor, Pennsylvania, USA., Miller I; Marinus Pharmaceuticals, Inc., Radnor, Pennsylvania, USA., Hulihan J; Marinus Pharmaceuticals, Inc., Radnor, Pennsylvania, USA., Demarest S; Department of Pediatrics and Neurology, University of Colorado School of Medicine, Precision Medicine Institute, Children's Hospital Colorado, Aurora, Colorado, USA.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2024 Jan; Vol. 65 (1), pp. 37-45. Date of Electronic Publication: 2023 Nov 29.
DOI: 10.1111/epi.17826
Abstrakt: 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.
(© 2023 Marinus Pharmaceuticals, Inc. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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