Four out of 6 patients with CDKL5 deficiency disorder and comorbid Lennox-Gastaut syndrome had a decrease in frequency of major motor seizures when treated with ganaxolone.
Ian Miller, MD
Data from a post-hoc analysis of a recent study suggest treatment with the positive allosteric GABAA receptor modulator, ganaxolone (Marinus Pharmaceuticals), was associated with decreases in major motor seizure frequency (MMSF) in patients with CDKL5 deficiency disorder (CDD) and comorbid Lennox-Gastaut syndrome (LGS). Findings were presented at the 2021 American Epilepsy Society (AES) Annual Meeting, December 3-7, in Chicago, Illinois, and virtually.
A total of 7 patients in the phase 3 MARIGOLD study (NCT03572933) had a codiagnosis of LGS, and during the double-blind period, 2 were randomized to receive treatment with ganaxolone, and 5 were randomized to placebo. Patients in this subgroup ranged in age from 3 to 19 years, experiencing a median of 88.7 major motor seizures (MMS) over 28-day increments. Patients were also being treated with a median of 3 concomitant antiseizure medications (ASMs).
After 1 patient did not enter the 17-week open-label extension (OLE) period, a total of 6 patients from the subgroup were included in analyses from the OLE, with 4 patients continuing to receive ganaxolone, and 2 patients receiving ganaxolone after previously receiving placebo. During the OLE, Investigators, led by Ian Miller, MD, VP of clinical development, Marinus Pharmaceuticals, observed percent changes in MMSF of –25.4% and –43.5% in the 2 patients who had previously been treated with ganaxolone over the 17-week double-blind period.
Of those who received ganaxolone in the OLE after receiving placebo in the double-blind period, 2 patients demonstrated a percent change of –21.0% and –36.3% change in MMSF, while 2 patients showed no improvement in MMSF (4.6% and 27.1% change). Investigators noted that the treatment was well-tolerated in the LGS subgroup, with no new safety findings identified.
“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. LGS is a clinical diagnosis characterized by multiple seizure types, a slow spike-and-wave pattern on EEG, and neurodevelopmental disability,” Miller et al wrote. “As a result, patients with CDD as an etiological diagnosis may also have a phenotypic diagnosis of LGS. Ganaxolone, 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 ganaxolone in LGS.”
A total of 101 patients were randomized in the MARIGOLD study, a phase 3, double-blind, placebo-controlled trial of ganaxolone in patients with a pathogenic CDKL5 mutation and 16 or more major seizures each month. Major motor seizure types included bilateral tonic, generalized tonic-clonic, atonic/drop, bilateral clonic, and focal to bilateral tonic-clonic.
Patients with comorbid LGS were located via medical history and were between the age of 2 and 19 years. Participants in the MARIGOLD study underwent a 6-week baseline period and a 17-week double-blind treatment period. The 17-week OLE was also open to those who completed the double-blind period.
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