Abstract Details

Title Phase 2 Open-label Clinical Study Evaluating Oral Ganaxolone for the Treatment of Seizures Associated with Tuberous Sclerosis Complex

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P12 - Poster Session 12 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-002

Background Tuberous sclerosis complex (TSC) is caused by pathogenic variants in TSC1 or TSC2 genes.
and is associated with malformations and benign tumors in the brain and other organs. More than 80% of TSC patients experience seizures, which are often refractory to existing antiseizure medications (ASMs). GNX is an investigational neuroactive steroid and positive allosteric modulator of GABAA-receptors. We evaluated GNX in a Phase 2 study as add-on therapy for refractory epilepsy in patients with TSC.

Objective To evaluate ganaxolone (GNX) as add-on therapy for TSC-associated refractory epilepsy.

Design/Methods This was an open-label trial. TSC patients aged 2-65 years with refractory epilepsy (>8 seizures
during 4-week baseline) were eligible. Seizures included focal motor with or without impairment of
consciousness or awareness, focal evolving to bilateral tonic-clonic, and generalized, countable motor
seizures (tonic, atonic, clonic and tonic-clonic). GNX was taken TID at a maintenance dose of up to 63
mg/kg/day or 1,800 mg/day maximum for a 12-week treatment period inclusive of a 4-week titration. The primary endpoint was median percentage change in frequency of TSC-associated seizures during the treatment period relative to baseline; secondary endpoints included responder rate (≥50% reduction in seizure frequency).

Results Twenty-three patients (median age 11 years) were enrolled. Patients had a 36.6 median 28-day
baseline seizure rate and median 3 concomitant ASMs. Participants experienced a median 16.6% reduction in TSC-associated seizures. Four patients (17.4%) discontinued due to adverse events (AE), with somnolence the most frequently reported (43.5%). Serious AEs occurred in 4 patients with 1 event
(seizure worsening) considered treatment-related.

Conclusions In this study ganaxolone was evaluated in highly refractory TSC patients. Participants
experienced a modest median percent reduction in seizure frequency. Ganaxolone was generally well tolerated with somnolence reported as the most common adverse event. Results of this proof-of-concept ttrial support further investigation in a Phase 3 study of TSC-associated seizures.

Authors/Disclosures
Mary Kay Koenig, MD (University of Texas Health Science Center-Houston) PRESENTER	Dr. Koenig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Marinus Pharmaceuticals. Dr. Koenig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceuticals. Dr. Koenig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stealth BioTherapeutics. Dr. Koenig has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Reneo Pharmaceuticals. Dr. Koenig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia Pharmaceuticals. Dr. Koenig has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Koenig has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz Pharmaceuticals. The institution of Dr. Koenig has received research support from Abliva AB. The institution of Dr. Koenig has received research support from EryDel SPA. The institution of Dr. Koenig has received research support from PTC Therapeutics. The institution of Dr. Koenig has received research support from Noema Pharmaceuticals. The institution of Dr. Koenig has received research support from Marinus Pharmaceuticals. The institution of Dr. Koenig has received research support from Jazz Pharmaceuticals. The institution of Dr. Koenig has received research support from Nflexion Therapeutics. The institution of Dr. Koenig has received research support from Stealth BioTherapeutics. The institution of Dr. Koenig has received research support from Astellas Pharmaceuticals. The institution of Dr. Koenig has received research support from Reneo Pharmaceuticals.
Rajeshwari Mahalingam, MD	Dr. Mahalingam has nothing to disclose.
Jurriaan Peters, MD (Boston Childrens Hospital)	Dr. Peters has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurelis. Dr. Peters has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurelis.
Brenda E. Porter, MD, PhD (Stanford University)	An immediate family member of Dr. Porter has received personal compensation for serving as an employee of Sangamo. Dr. Porter has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Taysha. An immediate family member of Dr. Porter has received stock or an ownership interest from Johnson and Johnson.
Rajsekar R. Rajaraman, MD (UCLA Medical Center)	Dr. Rajaraman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Marinus Pharmacueticals.
Muhammad S. Zafar, MBBS (Duke University Hospital)	Dr. Zafar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Xenon Pharmaceuticals. Dr. Zafar has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for LivaNova . The institution of Dr. Zafar has received research support from UCB. The institution of Dr. Zafar has received research support from SK life. The institution of Dr. Zafar has received research support from Marinus. The institution of Dr. Zafar has received research support from LivaNova. The institution of Dr. Zafar has received research support from Biopharma. The institution of Dr. Zafar has received research support from Neurocrine. The institution of Dr. Zafar has received research support from Hartwell Foundation.
Alex Aimetti (Marinus Pharmaceuticals)	No disclosure on file
Ian Miller, MD	Dr. Miller has received personal compensation for serving as an employee of Marinus Pharmaceuticals. Dr. Miller has stock in Marinus Pharmaceuticals.
Joseph Hulihan, Jr., MD (Marinus Pharmaceuticals)	Dr. Hulihan has received personal compensation for serving as an employee of MARINUS PHARMACEUTICALS. Dr. Hulihan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ZYNERBA PHARMACEUTICALS.
Darcy Krueger, MD (Cincinnati Children'S Hospital Medical Center)	Dr. Krueger has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NobelPharma USA. Dr. Krueger has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for RegenxBio. Dr. Krueger has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis Pharmaceuticals. Dr. Krueger has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Greenwich Biosciences. The institution of Dr. Krueger has received research support from Greenwich Bioscience. The institution of Dr. Krueger has received research support from Marinus Pharmaceuticals. The institution of Dr. Krueger has received research support from National Institutes of Health. The institution of Dr. Krueger has received research support from Food and Drug Administration. The institution of Dr. Krueger has received research support from TSC Alliance.