Abstract Details

Title Efficacy and Safety of ES-481, a Novel TARP Inhibitor, in Drug-resistant Epilepsy: A Double-blind Randomized Placebo Controlled Phase IIa Trial

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S19 - Epilepsy Clinical Trials and Long-term Studies (3:54 PM-4:06 PM)

Poster/Presentation
Number 003

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.

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).

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.

Authors/Disclosures
Terence J. O'Brien, MD (The Alfred Hospital) PRESENTER	The institution of Prof. O'Brien has received research support from Eisai. The institution of Prof. O'Brien has received research support from UCB. The institution of Prof. O'Brien has received research support from BioGen. The institution of Prof. O'Brien has received research support from ES Theraputics. The institution of an immediate family member of Prof. O'Brien has received research support from Epidarex.
Emma Foster, MD, MBBS (The Alfred Hospital)	The institution of Dr. Foster has received research support from Monash University Bridging Postdoctoral Fellowship. The institution of Dr. Foster has received research support from Sylvia and Charles Viertel Charitable Foundation. The institution of Dr. Foster has received research support from Brain Foundation (Australia). The institution of Dr. Foster has received research support from Australian Epilepsy Research Fund. The institution of Dr. Foster has received research support from LivaNova. The institution of Dr. Foster has received research support from Lundbeck Australia.
Lyn Millist (Alfred Hospital)	No disclosure on file
Jack Germaine (Alfred Health)	No disclosure on file
Stephanie Chamorro (Alfred Health)	No disclosure on file
Caitlin Roberts	No disclosure on file
John-Paul Nicolo, MBBS (Royal Melbourne Hospital)	Dr. Nicolo has nothing to disclose.
Sean Sean (Melbourne Health)	No disclosure on file
Piero Perucca, MD (Melbourne Brain Centre)	The institution of Dr. Perucca has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Perucca has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsia Open. Dr. Perucca has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsia Open. The institution of Dr. Perucca has received research support from NHMRC. The institution of Dr. Perucca has received research support from Epilepsy Foundation. The institution of Dr. Perucca has received research support from Monash University. The institution of Dr. Perucca has received research support from Sanming Project Grant, Shenzhen government. The institution of Dr. Perucca has received research support from Medical Research Future Fund. The institution of Dr. Perucca has received research support from Norman Beischer Medical Research Foundation. The institution of Dr. Perucca has received research support from NHMRC. The institution of Dr. Perucca has received research support from Austin Medical Research Foundation. The institution of Dr. Perucca has received research support from The University of Melbourne and The University of Bonn. The institution of Dr. Perucca has received research support from Austin Medical Research Foundation . Dr. Perucca has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Eisai. Dr. Perucca has received personal compensation in the range of $500-$4,999 for serving as a Speaker with UCB. Dr. Perucca has received personal compensation in the range of $500-$4,999 for serving as a Speaker with LivaNova. Dr. Perucca has a non-compensated relationship as a Member, Central Project Commission with EURAP-International Registry of Antiepileptic Drugs and Pregnancy that is relevant to AAN interests or activities. Dr. Perucca has a non-compensated relationship as a Member, Advisory Board with Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs that is relevant to AAN interests or activities.
Saul Mullen (Austin Health)	No disclosure on file
Heather Robinson	No disclosure on file
Rebecca Wharrie	No disclosure on file
Brittany Walsh	No disclosure on file
David C. Reutens, MD (University of Queensland)	The institution of Dr. Reutens has received research support from Australian Research Council. The institution of Dr. Reutens has received research support from Siemens Health Care. The institution of Dr. Reutens has received research support from Vivazone Pty Ltd. Dr. Reutens has received intellectual property interests from a discovery or technology relating to health care.
Kimberley Irwin (Royal Brisbane and Women's Hospital)	No disclosure on file
Michael Chen	No disclosure on file
Robert Niecestro (ES Therapeutics)	No disclosure on file