Abstracts

Rationale: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with highly drug-resistant epilepsy. Various antiseizure medications (ASMs) used to treat CDD-associated seizures have shown limited and short-lived efficacy. In a recent placebo-controlled phase 3 clinical study, ganaxolone (GNX), a neuroactive steroid, significantly reduced major motor seizure frequency (MMSF) over the 17-week treatment period (ganaxolone 30.7% vs placebo 6.9% p=0.0036) in patients with CDD. Here we report an 8-month minimum follow-up analysis of the open-label extension (OLE) study designed to assess the long-term safety and efficacy of ganaxolone in the treatment of CDD.

Methods: Patients with CDD (aged 2-21 years) who completed the 17-week double-blind phase were eligible to enroll in the OLE. The blinding of the original treatment assignment was maintained during the transition to the open-label phase. The maximum allowed daily dose of ganaxolone during the OLE was 63 mg/kg/day up to 1,800 mg/day taken in three divided doses. Reductions in MMSF from the pre-randomization baseline to 2-month intervals in the OLE were assessed. Other outcomes included safety and tolerability, MMSF (bilateral motor, >3 seconds) reduction evaluated at 2-month intervals, and Clinical Global Impression—Improvement (CGI-I) Assessments by clinicians and caregivers. Efficacy outcomes are presented using available data for subjects with a minimum of 8 months of follow-up in the OLE (cut-off date 24Feb2021). There was no imputation of missing data for patients who discontinued before 8 months.

Results: Of 101 patients entering the double-blind phase, 88 (87.1%) continued into the OLE (43 were initially randomized to ganaxolone (GNX-GNX) and 45 to placebo (PBO-GNX)). At the time of entry into the double-blind study, median age of patients was 5 years; 79.5% were female. Baseline monthly MMSF was 50.6 (median). The most common concomitant ASMs were valproic acid (36.4%), clobazam (29.5%), levetiracetam (26.1%), and vigabatrin (22.7%). Median treatment time (range) in the OLE was 262 days (16, 706). At the time of this analysis, 31 (35.2%) patients dropped out of the OLE, with lack of efficacy (13.6%) and adverse events (10.2%) being the most common reasons for discontinuation. Ganaxolone was generally well-tolerated and no new safety findings emerged.

The median MMSF reduction from baseline in the OLE was 30.1% in the GNX-GNX arm (n=38) and 33.3% in the PBO-GNX arm (n=34) at 8 months and 46.5 (n=22) and 53.8 (n=26), respectively, at 12 months (figure 1). Improvements on CGI-I assessments (minimally improved or better) were similar between GNX-GNX and PBO-GNX groups ranging 66.6% to 82.1% for the caregiver and 68.9% to 76.9% for the clinician observations at approximately 8 months.

Conclusions: Safety findings from this OLE analysis are consistent with the safety in the double-blind phase as well as the known safety profile of gananxolone. Data from the OLE provides supportive evidence for maintenance of effect in reducing major motor seizures associated with CDD at approximately 8 months and longer inpatients who continue treatment.

Funding: Please list any funding that was received in support of this abstract.: Supported by Marinus Pharmaceuticals.