Ganaxolone delivers sustained reductions in CDD-related seizures

Treatment with ganaxolone in paediatric patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD) leads to reductions in major motor seizure frequency (MMSF) over 2 years, according to data from the open-label extension phase of the Marigold trial.

The analysis included 88 patients with CDD (median age 5 years, 79.5 percent girls) who had completed the double-blind phase of the trial and entered the extension phase. These patients underwent a 4-week blinded cross-titration to open-label ganaxolone at up to 63 mg/kg/day (body weight ≤28 kg) or 1,800 mg/day maximum (body weight >28 kg) following the same protocol as the double-blind phase. Those who were unable to tolerate the said doses were maintained on a lower dose (minimum 33 mg/kg/day or 900 mg/day). 

The median 28-day MMSF of 50.6 at baseline decreased by 48.2 percent at 2 years in the open-label extension phase. In an analysis where missing data were imputed, the median reduction in MMSF was 43.8 percent using a mixed effects model and 27.4 percent using a last observation carried forward model.

Over months 22–24, 23 of 50 (46.0 percent) patients had ≥50-percent reductions in MMSF, with 12 (24.0 percent) having 75-percent reductions. Furthermore, 40 of 49 (81.6 percent) patients showed improvements in seizure-related outcomes based on Caregiver Global Impression of Change in Seizure Intensity/Duration (CGI-CSID) scores.

A total of 37 patients ceased ganaxolone therapy due to lack of efficacy (n=13), withdrawal by caregiver (n=12), adverse event (n=10), physician decision (n=1), or death unrelated to study drug (n=1).

Somnolence (17.0 percent) was the most common treatment-related treatment-emergent adverse event (TEAE), followed by seizure (11.4 percent) and decreased appetite (5.7 percent). Twenty-eight patients (31.8 percent) had serious TEAEs, such as seizure, pneumonia, acute respiratory failure, aspiration pneumonia, and dehydration, among others.