A first in disease trial of the safety, tolerability, and anti‐seizure effects of <scp>ES</scp> ‐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.