EPX-100 Shows Promising Seizure Reduction in Ongoing Open-Label Extension

New data from the open-label extension (OLE) of the ongoing Phase 3 ARGUS (NCT04462770) trial show that EPX-100 (clemizole), developed by Harmony Biosciences, produced a median 50% reduction in countable motor seizure frequency in a cohort of patients with Dravet Syndrome (DS). Researchers say the results reinforce EPX-100’s favorable benefit-risk profile and highlight its potential as a new treatment option for DS.¹

Data from the OLE, presented at the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9, in Atlanta Georgia, showed that 50% (n = 9) of the 18 participants achieved at least a 50% reduction in countable motor seizure frequency per 28 days (CMS-28). In terms of safety, EPX-100 was generally well-tolerated, including patients who had received treatment for more than 2 years and are approaching 3 years in the OLE phase.

Among participants, the most common treatment emergent adverse events (TEAEs; > 5%) were seizures, pyrexia and upper respiratory tract infection. Additionally, there were no significant gastrointestinal adverse events (2%), and no additional laboratory testing or special monitoring is required for the trial.

“The ARGUS trial is one of the most advanced development programs in the 5-HT2 (serotonin) agonist class and the effectiveness, safety and tolerability data of EPX-100 dosed BID from the open-label extension study are very encouraging,” said Kumar Budur, MD, MS, Chief Medical and Scientific Officer at Harmony Biosciences, in a statement. “These initial results support the advancement of our epilepsy franchise as we progress toward the topline data readout from the ARGUS trial in 2026.”¹

EPX-100 is an investigational therapy being studied for the treatment of Dravet syndrome (DS) in the ARGUS trial and Lennox-Gastaut syndrome (LGS) in the LIGHTHOUSE trial. The drug, discovered using a proprietary zebrafish drug screening platform, works by targeting central 5-hydroxytryptamine 2 (5HT-2) serotonin receptors to modulate serotonin signaling and is administered orally twice daily in a liquid formulation.

In its preclinical model, genetically modified scn1Lab zebrafish replicated the genetic mutations and seizure characteristics seen in most patients with DS. These zebrafish expressed voltage-gated sodium channels (Nav1.1) in the central nervous system, allowing researchers to quickly screen compounds for their potential to reduce seizures.

READ MORE: AES Poster Showcases Feasibility of Mobile App to Track Daily Self-Reporting Epilepsy Outcomes

Findings from the initial 16-week, double-blind, placebo-controlled Phase 3 trial of EPX-100 as an adjunctive therapy in children and adults with DS were consistent with those observed in the OLE. Overall, the drug was considered generally safe and well tolerated, and all 24 participants in the OLE cohort continued into this extension phase.²

Safety results from the trial showed 139 recorded treatment-emergent adverse events (TEAEs) in 21 patients (87.5%), of which 28 (33.3%) were deemed related to EPX-100. Upper respiratory tract infection, found in 13.7% of treated patients, was the most common TEAE, followed by generalized tonic-clonic seizure (7.9%), pyrexia (7.2%), and change in seizure presentation (6.5%).

Prior to ARGUS, EPX-100 was assessed in a phase 1 study of adult healthy volunteers aged 24 to 50 years. The early-stage trial enrolled 24 patients, testing escalating single and multiple oral doses (20-80 mg/kg/day) of EPX-100 vs placebo over a 12-week treatment period. Overall, the drug was well tolerated, with no reported clinically significant AEs, and drowsiness/grogginess observed only in the highest dose, which was consistent with evidence of EPX-100 crossing the blood-brain barrier.³

Click here for more AES 2025 coverage.

REFERENCES
1. Harmony Biosciences Presents Clinically Meaningful Open-Label Extension Study Effectiveness Data for EPX-100 in Dravet Syndrome. Harmony Biosciences. News release. December 8, 2025. Accessed December 9, 2025. https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-presents-clinically-meaningful-open-label
2. Ray A, Nomikos G, Rapchak KD, et al. ARGUS: a phase 3 study of EPX-100 (clemizole hydrochloride) as adjunctive therapy in patients with Dravet syndrome. Presented at: International Epilepsy Congress; August 30-September 3, 2025; Lisbon, Portugal.
3. Rao L, Masuoka L, Lee H, Baraban S. EPX-100 as an adjunctive therapy in Dravet syndrome: phase 1 and phase 2 randomized, double-blind, placebo-controlled trials. Presented at: 2022 AES Annual Meeting. Abstract 2.244.