Abstracts

Rationale: CDKL5 Deficiency Disorder (CDD) is a developmental and epileptic encephalopathy with a complex phenotype including drug-resistant epilepsy. CDD is a genetic diagnosis resulting from variants in the CDKL5 gene. Lennox-Gastaut Syndrome (LGS) is a clinical diagnosis characterized by multiple seizure types, a slow spike-and-wave pattern on EEG, and neurodevelopmental disability. As a result, patients with CDD as an etiological diagnosis may also have a phenotypic diagnosis of LGS. Ganaxolone (GNX), an investigational neuroactive steroid, demonstrated a significant reduction in major motor seizures in a phase 3, placebo-controlled trial in CDD. A sub-group analysis in patients who also met diagnostic criteria for LGS was performed to gain preliminary insights on the effects of GNX in LGS.

Methods: The Marigold Study (NCT03572933) was a phase 3, double-blind (DB), placebo-controlled trial of GNX in patients aged 2-19 years with a pathogenic CDKL5 mutation and >16 major motor seizures per month. Major motor seizures (MMS) were defined as bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral clonic or focal to bilateral tonic-clonic. The study consisted of a 6-week baseline (BL) followed by a 17-week double-blind treatment period. Patients who completed the double-blind period were eligible to enter the open-label extension (OLE). Patients with LGS were identified from their medical history. To compare efficacy and safety over comparable durations of treatment that encompassed both titration and maintenance of GNX, the percent reduction in MMS frequency (MMSF) was assessed as change from baseline to the 17-week double-blind period in patients randomized to GNX, and to the first 17 weeks of GNX treatment in the OLE in patients who had received placebo during DB. Adverse effects were assessed for the same 17-week treatment periods.

Results: Of 101 patients randomized, 7 (6 female) had a co-diagnosis of LGS. Of the 7 patients, 2 were randomized to GNX (GNX DB) and 5 to placebo (GNX OLE). Patients ranged in age from 3-19 years (median 11), experienced a median of 88.7 MMS per 28 days at baseline, and were being treated with 3 (median) concomitant antiseizure medications. One placebo patient did not enter the OLE therefore 6 patients were evaluable for this analysis. Compared to BL, the 2 GNX DB patients experienced a percent change in MMSF of -25.4% and -43.5% during 17 weeks of GNX treatment. Two of the 4 GNX OLE patients demonstrated improvements in seizure frequency during 17 weeks of GNX treatment (-21.0% and -36.3% change in MMSF). Two GNX OLE patients did not show improvement while on GNX (4.6% and 27.1% change in MMSF). Ganaxolone was generally well-tolerated and no new safety findings emerged in the LGS subgroup.

Conclusions: In this post-hoc analysis, ganaxolone treatment was associated with decreases in MMSF in 4 of 6 patients with CDD and LGS. Larger studies may further elucidate the potential of ganaxolone as a treatment for seizures associated with LGS.

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