Abstract Details

Title Ganaxolone Significantly Reduces Major Motor Seizures Associated with CDKL5 Deficiency Disorder: A Randomized, Double-blind, Placebo-Controlled Phase 3 Study

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S13 - Epilepsy/Clinical Neurophysiology (EEG): Antiseizure Medications (2:36 PM-2:48 PM)

Poster/Presentation
Number 009

Objective To evaluate theefficacy of ganaxolone compared to placebo as adjunctive treatment of major motor seizures (MMS) in CDKL5 deficiency disorder (CDD).

Background CDD is a rare, genetically determined developmental and epileptic encephalopathy
characterized by early-onset refractory seizures and severe neurodevelopmental impairment.
CDD-associated seizures are often refractory to treatment with existing antiseizure medications
(ASMs) and improvements may be short-lived.

Design/Methods In this global, double-blind, placebo-controlled, phase 3 trial, patients aged 2-21 years with a
pathogenic CDKL5 variant and uncontrolled major motor seizures (MMS ≥16/month) were
randomized to adjunctive ganaxolone (maximum 63 mg/kg/day or 1,800 mg/day, TID) or placebo
for 17 weeks. MMS were defined as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral
clonic or focal to bilateral tonic-clonic. The primary endpoint was percentage change from baseline
in major motor seizure frequency (MMSF) during the double-blind phase. Key secondary
endpoints included ≥50% responder rate and clinical global impression of improvement (CGI-I).

Results A total of 101 patients (79% female) were randomized, 50 to ganaxolone and 51 to placebo.
Patients were a median age of 6 years and had tried a median of 7 prior ASMs. Baseline median
28-day MMSF was 54.0 in the ganaxolone group and 49.2 in the placebo group. Patients taking
ganaxolone experienced a median 30.7% reduction in MMSF relative to baseline compared to a
6.9% reduction in the placebo group during the treatment period (p=0.0036, Wilcoxon Rank-Sum
Test). Ganaxolone showed numerical trends (not statistically significant) in key secondary endpoints. In
subgroup analyses, ganaxolone showed MMSF reductions across the broad CDD population
studied. Adverse events occurring in > 10% of patients and more frequently in the ganaxolone
group were somnolence, pyrexia and upper respiratory tract infections.

Conclusions These data provide strong evidence that ganaxolone is effective and generally welltolerated in the treatment of refractory epilepsy in patients with CDD.

Authors/Disclosures
Ian Miller, MD PRESENTER	Dr. Miller has received personal compensation for serving as an employee of Marinus Pharmaceuticals. Dr. Miller has stock in Marinus Pharmaceuticals.
Elia Pestana-Knight	No disclosure on file
Sam Amin	No disclosure on file
Timothy A. Benke, MD, PhD	The institution of Dr. Benke has received research support from NIH, RSRT, IRSF and Children's Hospital Colorado. The institution of Dr. Benke has received research support from Acadia, GW, RSRT, Ovid/Takeda, Marinus. The institution of Dr. Benke has received research support from Acadia, CUREGRI, GRINtherapeutics, GW, IRSF, Marinus, Neurogene, Taysha, Ultragenyx and Zogenix/UCB; .
J. Helen Cross (UCL-Institute of Child Health)	Dr. Cross has nothing to disclose.
Heather E. Olson, MD (Boston Children's Hospital Peabody)	Dr. Olson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda pharmaceuticals. The institution of Dr. Olson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ovid Therapeutics. The institution of Dr. Olson has received research support from NINDS. The institution of Dr. Olson has received research support from International Foundation for CDKL5 Research. The institution of Dr. Olson has received research support from Marinus Pharmaceuticals. The institution of Dr. Olson has received research support from Ovid Therapeutics.
	No disclosure on file
Scott T. Demarest, MD (University of Colorado Health Science Center, Child Neurology)	The institution of Dr. Demarest has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ovid. The institution of Dr. Demarest has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biomarin. The institution of Dr. Demarest has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tysha. The institution of Dr. Demarest has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Marinus. The institution of Dr. Demarest has received research support from NIH. The institution of Dr. Demarest has received research support from International Foundation for CDKL5 Research. Dr. Demarest has a non-compensated relationship as a SMAB with SLC6A1 Connect that is relevant to AAN interests or activities. Dr. Demarest has a non-compensated relationship as a SMAB with Ring 14 USA that is relevant to AAN interests or activities. Dr. Demarest has a non-compensated relationship as a SMAB with FamilieSCN2A that is relevant to AAN interests or activities.
Nicola Specchio	Nicola Specchio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Nicola Specchio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for stoke.

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