The investigational compound ganaxolone (Marinus Pharmaceuticals), a central nervous system–selective gamma-aminobutyric acid A (GABAA) modulator, has failed to demonstrate a statistically significant difference from placebo (the primary endpoint) in a pivotal phase 3 study of adults with drug-resistant focal-onset seizures. Marinus plans to discontinue its program in adult focal-onset seizures and focus its efforts on evaluating ganaxolone in status epilepticus and in pediatric orphan indications.
The pivotal double-blind, randomized, placebo-controlled study was conducted at 61 sites in the United States and Europe. A total of 359 patients were randomly assigned to receive treatment with ganaxolone 1,800 mg per day (n = 179) or placebo (n = 180). The patients’ mean age was 41 years, and 63% were female. Most of the patients (76%) were receiving two or more concomitant antiepileptic drugs, and 12% had been treated with a vagus nerve stimulator.
The study missed its primary endpoint of a percent change in the 28-day seizure frequency from baseline (P = 0.1537). The median percent reduction of focal-onset seizures in the ganaxolone group was 21.3% compared with 10.3% in the placebo group during the titration and 12-week treatment periods.
Serious adverse events were reported in 5.0% and 5.1% of the active-treatment and placebo groups, respectively. The most common adverse events reported in ganaxolone-treated patients compared with those given placebo included somnolence (23.5% vs. 4.5%, respectively), dizziness (19.6% vs. 4.5%), and fatigue (11.7% vs. 6.8%). Most of these adverse events were mild in severity. Forty-four patients (25%) in the ganaxolone group discontinued treatment compared with 26 patients (14%) in the placebo group. The most common reason for discontinuation was an adverse event.
Ganaxolone was being developed for adult and pediatric patients in both the acute and chronic-care settings. The compound acts on a synaptic and extrasynaptic GABAA target known for its antiseizure and antianxiety activity. Ganaxolone has been studied in more than 1,300 pediatric and adult subjects at therapeutically relevant dose levels for up to two years.
Source: Marinus Pharmaceuticals; June 13, 2016.