Authors :
Eric Marsh, MD PhD – Children's Hospital of Philadelphia
Presenting Author: John Flatt, MD – Marinus Pharmaceuticals, Inc.
Alex Aimetti, PhD – Marinus Pharmaceuticals, Inc.
Joseph Hulihan, MD – Marinus Pharmaceuticals, Inc.
Dennis Dlugos, MD – The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Rationale: Lennox-Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy caused by structural or genetic disorders, including CDKL5 deficiency disorder (CDD). LGS diagnosis is based on three clinical features: multiple drug resistant seizures (including tonic), slow spike-and-wave (SSW) or generalized paroxysmal fast activity (GPFA) on EEG, and neurodevelopmental disability. Ganaxolone, a neuroactive steroid modulating synaptic and extrasynaptic GABA
A receptors, was shown to significantly reduce frequency of major motor seizure (MMS) in CDD. Here we report the safety and efficacy of ganaxolone in a post hoc analysis of patients with CDD meeting defined criteria for an LGS-like subgroup.
Methods: The Marigold study enrolled 101 patients 2-19 years of age with CDD and ≥16 MMS per month. LGS-like subgroup identification was based on aligning LGS diagnostic criteria with available clinical trial data. Seizure criteria, including tonic seizures, were assessed using seizure history, seizures during the clinical trial, and history of ≥2 failed medications. Cognitive delay was assessed via medical history or baseline neurodevelopmental evaluation of speech.
Presence of “generalized epileptiform discharges” or GPFA on a pre-enrollment EEG was used as a proxy for the SSW/GPFA EEG pattern. Patients must have met all three criteria for inclusion in the analysis. Baseline characteristics, drop seizures (atonic, clonic, tonic, tonic–clonic, or focal-to-bilateral tonic-clonic), clinical global improvement (CGI) scales, and treatment-emergent adverse events (TEAEs) are reported.
Results: The LGS-like subgroup included 17 ganaxolone and 20 placebo-treated patients. The groups had similar demographics and median baseline drop seizure frequencies (ganaxolone, 45.5; placebo, 49.6). The median percent reduction in drop seizure frequency was 28.2% for ganaxolone and 2.8% for placebo, a median difference of 29.2% (Hodges-Lehmann estimate). This compared to a median difference of 23.8% for patients not meeting the LGS criteria (ganaxolone, N=33; placebo, N=31). CGI-improvement scores from caregivers and clinicians were reported as minimally improved or better in 69.3% and 71.4%, respectively, for patients on ganaxolone compared to 47.4% and 36.8% for placebo. CGI scores for change in seizure intensity or duration reported as minimally improved or better were 64.3% for ganaxolone vs. 36.8% for placebo. TEAEs and serious adverse events were similar in the two groups.
Conclusions: Patients with CDD meeting the defined LGS criteria demonstrated greater decreases in seizure frequency with ganaxolone compared to placebo and similar to those not meeting LGS criteria. Safety and tolerability were comparable between groups. Although there are limitations in diagnostic confirmation, the results suggest that ganaxolone could be safe and effective in treating patients with LGS.
Funding: Marinus Pharmaceuticals, Inc.