Contributions to mineralogy; No. 46, On the occurrence of corundum, in Patrick Co., Va

Abstract

<h3>Objective:</h3> To evaluate theefficacy of ganaxolone compared to placebo as adjunctive treatment of major motor seizures (MMS) in CDKL5 deficiency disorder (CDD). <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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). <h3>Results:</h3> 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 &gt; 10% of patients and more frequently in the ganaxolone group were somnolence, pyrexia and upper respiratory tract infections. <h3>Conclusions:</h3> These data provide strong evidence that ganaxolone is effective and generally welltolerated in the treatment of refractory epilepsy in patients with CDD. <b>Disclosure:</b> Dr. Amin has nothing to disclose. The institution of Dr. Benke has received research support from NIH, RSRT, IRSF and Children9s Hospital Colorado. The institution of Dr. Benke has received research support from GW and Neuren. Dr. Cross has nothing to disclose. 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. 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.