A first in disease trial of the safety, tolerability, and anti-seizure effects of ES-481 in drug-resistant epilepsy.

OBJECTIVES

ES-481 is a novel potent and selective antagonist of TARP-y8-dependent AMPA receptors. We aimed to assess the potential efficacy, safety and tolerability, and pharmacokinetics of different doses of ES-481 as an add-on anti-seizure medication (ASM) in adults with drug-resistant epilepsy (DRE).

METHODS

This was a Phase 2A double-blind, randomized, dose-titration, cross-over, placebo-controlled trial followed by an open-label extension (OLE) conducted across four Australian Comprehensive Epilepsy Centers. The primary outcomes were: (i) efficacy, measured via change in seizure frequency for each treatment week, (ii) safety and tolerability, and (iii) pharmacokinetics. Secondary endpoints were change in anxiety and depressive symptom scores.

RESULTS

22 participants were randomized, 17 (77.3%) completed the double-blind treatment phase, and 16 entered the OLE study. Overall, based on seizure diaries, participants had 68%-80% improvement in seizure frequency on ES-481 treatment, compared with 38%-49% on placebo treatment (p = 0.097). For the highest dose of ES-481 treatment (75 mg bid), subjects had 80% improvement (90% confidence interval [Cl] 43%-97%), while participants on placebo for the corresponding week had 49% improvement (90% Cl 1%-74%) (p = 0.047). There was no significant difference in the reduction of seizure frequency at the lower ES-481 treatment doses. There were no significant differences in change in frequency of EEG epileptiform/seizure discharges >3 s in duration between the ES-481 and placebo treatments. There was no significance difference in serious treatment-emergent adverse events between the groups (placebo 14.3% vs. ES-481 4.8%) or treatment-emergent adverse events of special interest (e.g., dizziness, drowsiness; placebo 19.0% vs. ES-481 52.4%, p = 0.052). Treatment was well tolerated in the OLE for up to 36 weeks.

SIGNIFICANCE: ES-481 in doses up to 75 mg bid was safe and well tolerated for up to 36 weeks in participants with DRE and demonstrated potential anti-seizure efficacy compared with placebo at this dose.

PLAIN LANGUAGE SUMMARY: This was a first-in-disease, proof-of-concept early-phase trial of a novel anti-seizure medication, ES-481, in adults with a broad group of patients drug-resistant epilepsy, who continue to have seizures despite treatment with currently available medications. ES-481 was generally safe and well tolerated, and participants receiving the highest dose showed fewer seizures compared with placebo. These findings suggest ES-481 may offer a promising new treatment approach for people with difficult-to-control epilepsy, supporting the need for larger future studies.

TRIAL REGISTRATION INFORMATION: Registered at ClinicalTrials.gov ID: NCT04714996 (first submitted and met QC criteria Jan 14, 2021, first posted Jan 20, 2021) and Australian and New Zealand Clinical Trials Registry ID: ACTRN12621000033842 (registered January 15, 2021). First participant/first visit (assessment) occurred on January 29, 2021.