A Study of Ganaxolone in Seizures Associated With Tuberous Sclerosis Complex: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study (TrustTSC)
Abstract number :
1.504
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1672
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Joseph Hulihan, MD – Marinus Pharmaceuticals, Inc.
Author: Mary Kay Koenig, MD – McGovern Medical School at the University of Texas Health Science Center
Philippe Major, MD, FRCPC – Centre Hospitalier Universitaire Sainte-Justine, University of Montréal
Rajsekar Rajaraman, MD, MS – UCLA Mattel Children's Hospital
Edouard Hirsch, MD – University of Strasbourg
Rani Singh, MD – Atrium Health/Levine Children's Hospital, Wake Forest University School of Medicine
Sam Amin, MD – University Hospitals Bristol and Weston
David Ritter, MD, PhD – Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine
John Flatt, MD – Marinus Pharmaceuticals, Inc.
Maciej Gasior, MD, PhD – Marinus Pharmaceuticals, Inc.
Alex Aimetti, PhD – Marinus Pharmaceuticals, Inc.
Federico Ramos, MD – Hospital Sant Joan de Déu, Esplugues de Llobregat
Rationale: Tuberous sclerosis complex (TSC) is a rare, multisystem genetic disorder characterized by non-cancerous tumors, skin abnormalities, and severe neurological manifestations including refractory seizures and neurodevelopmental delay. The disorder is caused by pathogenic variants in the TSC1 or TSC2 genes. Epilepsy affects up to 90% of patients with TSC with two-thirds refractory to conventional treatment. Ganaxolone is a neuroactive steroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA-receptors, resulting in increases in both phasic and tonic inhibitory signaling. The phase 3 TrustTSC study (NCT05323734) assesses the safety and efficacy of adjunctive ganaxolone versus placebo for refractory seizures in children and adults with TSC-related epilepsy.
Methods: Patients aged 1-65 years with confirmed diagnosis of TSC and inadequately controlled seizures (≥ 8 countable seizures/month after exposure to ≥ 2 anti-seizure medications) were eligible to enroll. Concomitant use of mTOR inhibitors and pharmaceutical cannabidiol were allowed. Following a 4-week baseline phase, patients underwent a 1:1 randomization to the ganaxolone or placebo arm of the double-blind phase, which was comprised of a 4-week titration and a 12-week maintenance period. Ganaxolone was dosed using a newly modified titration schedule to a target daily dose of 63 mg/kg (patients weighing ≤ 28 kg) or 1800 mg (patients weighing > 28 kg). The primary endpoint is the percent change from baseline in the 28-day frequency of countable motor seizures (focal motor seizures with/without impairment of consciousness or awareness, focal to bilateral, tonic-clonic seizures, and generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures) during the double-blind phase. Key secondary endpoints include the percent change from baseline in the 28-day frequency of primary endpoint seizures during the maintenance period, the proportion of patients with ≥ 50% seizure frequency reduction, and Clinical Global Impression of Improvement outcomes. Safety assessments include incidence and severity of adverse events (AEs), serious AEs, and early discontinuations or dose-reductions due to AEs.
Results: A total of 129 patients ages 1-50 years (median 12 years) were enrolled, comprised of 65 females and 64 males from 60 clinical sites across 10 countries. The safety and efficacy of ganaxolone for the treatment of countable motor seizures associated with TSC will be presented.
Conclusions: This global, placebo-controlled trial is designed to generate rigorous clinical evidence on the safety and efficacy of ganaxolone for the treatment of seizures associated with TSC.
Funding: Marinus Pharmaceuticals, Inc.
Anti-seizure Medications