Objective:

To evaluate the efficacy, tolerability and safety of different doses of ES-481 as an add-on anti-seizure medication in adults with drug resistant epilepsy (DRE).

Background:

ES-481 is a novel potent and selective antagonist of the transmembrane alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor regulatory protein (“TARP”)-γ8-dependent AMPA receptor.

Design/Methods:

A Phase 2A randomized, double-blind, dose-titration, crossover, placebo-controlled trial (NCT04714996) followed by an Open Label Extension (OLE). Subjects received 4 incrementing doses of ES-481 (i.e. 25 mg qd, 25 bid, 50 bid and 75 mg bid or placebo) for a week, and then crossed over to the other treatment arm. The primary efficacy endpoint was the weekly clinical seizure frequency as assessed by paper diaries for each treatment week compared to baseline analyzed by change from baseline in log-transformed weekly seizure frequency.  Safety was assessed by monitoring AEs, hematology, clinical chemistry and 24-hour EEGs acquired at baseline and weekly during the treatment period.

Results:

22 patients were randomized, 17 (77.3%) completed the DBT phase with 16 entering the OLE study. Subjects had 68%-80% improvements on ES-481 treatment, compared to 38%-49% under placebo treatment. For the top dose of ES-481 treatment subjects had 80% improvement (90% confidence interval [CI] 43%-97%), while subjects under placebo for the corresponding week had 49% improvement (90% CI 1%-74%) (p=0.047). No patients died during the study. The rate of Serious Adverse Events (SAEs) was higher while taking placebo (14.3%) than ES-481 (4.8%), while adverse events of special interest (AESI) were more common while taking ES-481 (52.4% vs. 19.0%). There were no safety concerns on the blood tests or EEG recordings.

Conclusions:

ES-481 demonstrated evidence of anti-seizure efficacy compared to the placebo in patients with DRE. ES-481 dosing up to 75 mg bid was safe and well tolerated.