Abstracts

Rationale: Dravet syndrome (DS) is a severe and progressive epileptic encephalopathy that begins in the first year of life and is characterized by high seizure frequency and severity, intellectual disability, and a risk of sudden unexpected death in epilepsy. Approximately 85% of DS cases are caused by de novo loss-of-function (LOF) mutations in a voltage-gated sodium channel gene, SCN1A. Preclinical drug discovery using a LOF SNC1A zebrafish model for DS identified clemizole (EPX-100), an antihistamine with serotonergic properties, as a potential antiseizure medication (ASM) for these patients (Baraban et al. Nat. Comm. 2013). Here we describe results of a completed EPX-100 Phase 1 double-blind, placebo-controlled trial and the Phase 2 protocol for an ongoing randomized, double-blind, placebo-controlled clinical trial in DS patients.

Methods: Phase 1 enrolled adult healthy patients 24-50 years old with escalating single and multiple oral doses (20-80mg/kg/day). ARGUS Phase 2 is enrolling patients at least 2 years of age with a diagnosis of DS and in whom seizures are not completely controlled by their current ASM regimen. Patients with four or more convulsive seizures during a 4-week baseline observation period were randomized in a 1:1 ratio to EPX-100 (oral solution) or placebo. Daily doses are 2 mg/kg/day up to a maximum tolerated dose (or a maximum 160 mg/day). After a 4-week titration period, patients are maintained on their randomized dose for an additional 12 weeks. Countable convulsive seizure frequency (CCSF) is recorded daily in a diary by caregivers. The primary efficacy endpoint is mean percentage change in CCSF between EPX-100 and placebo during the 12-week treatment period compared to the 4-week baseline observation period. Patients are eligible for an Open Label Extension period at the completion of the 20-week trial.  Adverse events are monitored throughout the study. Plasma samples will be collected at multiple timepoints. Change in Quality of Life in Childhood Epilepsy (QOLCE-55) will also be monitored.

Results: A total of 24 adult patients completed the Phase 1 safety and pharmacokinetic study. No clinically significant adverse effects were reported. Drowsiness/grogginess was only observed at the highest (80 mg/kg) dose, consistent with evidence supporting EPX-100 crossing the blood brain barrier. A total of 60 DS patients will be enrolled in the Phase 2 study. These studies will provide insight into the safety, tolerability, and pharmacokinetic profile of EPX-100 in DS patients. In addition, the impact of EPX-100 on CCSF and QOL measures will provide insight on clinical efficacy._x000D_
Conclusions: EPX-100 was well-tolerated with all adverse events being mild or moderate, with drowsiness being the most common finding in Phase 1 trials. EPX-100 has the potential to be a safe and effective treatment option for patients with DS.

Funding: Epigenyx, Inc