Phase 2 Open-label Clinical Study Evaluating Oral Ganaxolone for the Treatment of Seizures Associated with Tuberous Sclerosis Complex
Abstract number :
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Submission ID :
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Mary Kay Koenig, MD - University of Texas McGovern Medical School, Houston, TX, USA; Rajeshwari Mahalingam, MD - Saint Barnabas Medical Center, Livingston, NJ, USA; Jurriaan Peters, MD, PhD - Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Brenda Porter, MD, PhD - Stanford University of School of Medicine, Stanford, CA, USA; Rajsekar Rajaraman, MD - UCLA Mattel Children's Hospital, Los Angeles, CA, USA; Muhammad Zafar, MD - Duke University School of Medicine, Durham, North Carolina, USA; Alex Aimetti, PhD - Marinus Pharmaceuticals; Ian Miller, MD - Marinus Pharmaceuticals; Joseph Hulihan, MD - Marinus Pharmaceuticals; Darcy Krueger, MD, PhD - University of Cincinnati College of Medicine, Cincinnati, OH, USA
Rationale: Tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1 or TSC2 genes, are associated with malformations and benign tumors in the brain and other organs. Seizures are present in more than 80% of TSC patients and are often refractory to existing antiseizure medication (ASMs). Therapeutic options with novel/unique mechanisms of action are needed. Ganaxolone (GNX) is an investigational neuroactive steroid that acts as a positive allosteric modulator of both synaptic and extrasynaptic GABAA-receptors, which increases both phasic and tonic inhibitory signaling. We evaluated GNX in a Phase 2 study as add-on therapy for refractory epilepsy in patients with TSC.
Methods: This was an open-label trial conducted at 7 clinical sites in the United States. Patients with TSC aged 2-65 years and refractory epilepsy were eligible if they had ≥8 seizures during a 4-week baseline. Seizures included focal motor seizures without impairment of consciousness or awareness, focal seizures with impairment of consciousness or awareness, focal seizures evolving to bilateral tonic-clonic seizures, and generalized, countable motor seizures (tonic, atonic, clonic and tonic-clonic). Study participants (or caregivers) tracked seizure frequency during a 4-week baseline and then received GNX for a 12-week treatment period inclusive of a 4-week titration. GNX was taken TID at a maintenance dose of up to 63 mg/kg/day or 1,800 mg/day maximum. The primary endpoint was the median percentage change in the frequency of TSC-associated seizures during the treatment period relative to baseline; secondary endpoints included a responder rate (≥50% reduction in seizure frequency).
Results: Twenty-three patients were enrolled. Median age was 11 years and median 28-day baseline seizure rate was 36.6 with a median of 3 concomitant ASMs. Participants experienced a median 16.6% (95% CI: 59.1%, -18.8%) reduction in TSC-associated seizures. The proportion of patients achieving ≥50% seizure frequency reduction was 30.4% (7/21). Four patients (17.4%) discontinued due to adverse events (AE). The most reported treatment-emergent AE was somnolence (43.5%). Serious AEs occurred in 4 patients with 1 event (seizure worsening) assessed by the PI as treatment-related.
Conclusions: Ganaxolone was studied in a highly refractory TSC patient population in which 83% of the patients were on concomitant newer generation ASMs including cannabidiol, everolimus, or both. Participants treated with GNX experienced a modest median percent reduction in seizure frequency with approximately 1/3rd of patients experiencing a greater than 50% seizure reduction. Ganaxolone was generally well-tolerated with somnolence reported as the most common adverse event, consistent with previous trials. Based on the results of this proof-of-concept trial, a Phase 3 study of GNX in refractory TSC-associated seizures is planned.
Funding: Please list any funding that was received in support of this abstract.: This study was funded by Marinus Pharmaceuticals.