Phase 2, Placebo-Controlled Clinical Study of Oral Ganaxolone in PCDH19-Clustering Epilepsy
Abstract number :
3.281
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2021
Submission ID :
1825760
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:50 AM
Authors :
Joseph Sullivan, MD - University of California San Francisco Weill Institute for Neurosciences, Benioff Children's Hospital; Boudewijn Gunning, MD - Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands; Muhammad Zafar, MD - Duke University School of Medicine, Durham, North Carolina, USA; Renzo Guerrini, MD - Meyer Children Hospital, Florence, Italy.; Marta Zolnowska, MD - Medical Center Pleiades, Krakow, Poland; Jozef Gecz, PhD - University of Adelaide, Adelaide, South Australia, Australia; Debopam Samanta, MD - University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Rationale: PCDH19-clustering epilepsy (PCDH19-CE) is a distinct developmental and epileptic encephalopathy characterized by early-onset refractory seizures often occurring in clusters, intellectual disability, autism spectrum, and behavioral disorders. Previous research has linked pathogenic PCDH19 variants to reduced neurosteroidogenesis including allopregnanolone. Ganaxolone (GNX) is a synthetic analog of allopregnanolone that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. Ganaxolone is an investigational drug that was evaluated in a Phase 2, double-blind, placebo-controlled study (Violet Study) to assess its efficacy and safety in PCDH19-CE.
Methods: This was a randomized, double-blind, placebo-controlled trial conducted at 20 sites in 7 countries. Eligible patients were females, aged 1-17 with a pathogenic PCDH19 variant and uncontrolled seizures (≥12 seizures during a 12-week period prior to screening). Included seizure types were countable focal or generalized seizures with a clear motor component. Enrolled patients prospectively tracked seizure frequency during a 12-week baseline and were then randomized (1:1) to receive GNX or placebo added to standard of care for the 17-week treatment period. 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 percentage change in seizure frequency from baseline during the treatment period. Additional secondary endpoints included ≥50% responder rate and clinical global impression of improvement (CGI-I).
Results: Twenty-one patients were randomized with a median age of 7.0 years old. Patients in the GNX (n=10) and placebo (n=11) groups experienced a median 28-day baseline seizure frequency of 14.5 and 17.7, respectively. Following the 17-week treatment period, patients on GNX had a median 61.5% reduction in PCDH19-associated seizures compared to a 24.0% reduction in the placebo group (p=0.17). The proportion of patients that achieved a ≥50% seizure frequency reduction in the GNX and placebo groups were 50% and 36%, respectively. Clinicians rated 78% (n=9) of patients on GNX as minimally improved or better compared to 36% of patients on placebo. Treatment emergent adverse events (TEAE’s) occurred in 70% of GNX and 100% of placebo patients with somnolence being the most common (40% on GNX compared to 27% on placebo). One patient on GNX discontinued the study due to a serious TEAE (psychogenic nonepileptic seizure) which the investigator assessed as related to treatment.
Conclusions: Despite the limited sample size, patients treated with GNX experienced directional improvements in seizure frequency compared to those on placebo. Ganaxolone was generally well-tolerated with no new safety findings. Due to seizure cluster fluctuation in PCDH19-CE, novel epilepsy clinical trial designs may be needed for future studies.
Funding: Please list any funding that was received in support of this abstract.: This work was supported by Marinus Pharmaceuticals.
Anti-seizure Medications