Phase 3 Study to Test 1st Generation Antihistamine EPX-100 in Lennox-Gastaut Syndrome

Author(s):

Key Takeaways

EPX-100 is being tested for efficacy and safety in treating Lennox-Gastaut syndrome in a phase 3 study involving a 20-week period with multiple phases.
Primary endpoints focus on percentage change in major motor seizures, while secondary endpoints include seizure reduction and global impression scores.
Eligibility criteria require stable epilepsy interventions and exclude those with hypersensitivity to EPX-100 or significant health conditions.
EPX-100, originally developed in the 1950s, modulates serotonin pathways and reduces nervous system hyperexcitability, showing potential as a therapeutic agent for seizure conditions.

Harmony Biosciences’ phase 3 study will assess EPX-100, a repurposed antihistamine, as a potential treatment for Lennox-Gastaut syndrome, targeting seizure reduction and improved outcomes.

Kumar Budur, MD, MS

A new phase 3 study (NCT05066217) will test the efficacy and safety of EPX-100 (Harmony Biosciences), a 1^st generation antihistamine agent, as a potential treatment for patients with Lennox-Gastaut syndrome (LGS), a rare epileptic disorder. Overall, the study will enroll patients aged at least 2 years old with LGS who will be followed for a 20-week period, with optional open-label extension after the end of the maintenance phase.¹

Presented at the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9 in San Diego, California, the study design includes a 4-week observation phase, 4-week titration phase, and 12-week maintenance phase to test EPX-100. The study, which includes those with at least 4 countable major motor seizures, will use percentage change in CMMS-28 from baseline through the end of the double-blind period as the primary end point. Safety assessments will include incidence and severity of adverse events (AEs) and clinical laboratory tests.

Senior author Kumar Budur, MD, MS, chief medical officer and scientific officer at Harmony, and colleagues, will also test several secondary end points, such as proportion of patients achieving at least 50% reduction in CMMS-28, percent change in CMMS-28 seizure-free days, and Clinician Global Impression of Change (CGI-C) score. To be included, patients must be at least 14 years of age with a documented history of LGS, characterized by generalized seizures, specific EEG findings, and abnormal cognitive development.

Eligible patients must have onset of seizures before age 11, current countable seizures leading to falls or drops, and an inadequate response to antiseizure medications. Additionally, their epilepsy interventions, including ketogenic diet or vagus nerve stimulation, must be stable for at least 30 days before screening, and they must maintain a stable regimen throughout the study.

Exclusion criteria include a history of hypersensitivity to EPX-100, exposure to investigational drugs or devices within 90 days prior, or conditions like progressive neurological diseases, recent anoxic episodes, or significant cardiac, renal, or hepatic conditions that could impact safety or outcomes. Concurrent use of medications that interact with EPX-100, such as CYP3A4/5 inducers or inhibitors and specific serotonin-related agents, is prohibited.

Clemizole hydrochloride, marketed under the investigational name EPX-100, has a history that spans multiple decades and therapeutic areas. Initially developed in the 1950s, clemizole was approved as an antihistamine to treat allergic conditions such as hay fever and hives. Several years of studies revealed its ability to modulate serotonin pathways and reduce hyperexcitability in the nervous system. Specifically, clemizole was identified as a potential therapeutic agent for conditions involving seizures due to its effects on calcium signaling and its interaction with the serotonin receptor system.

EPX-100 was originally developed by Epygenix; however, in mid-2024, Harmony acquired the company, ultimately taking on the asset.² Currently, the agent is being tested in a phase 3 study, dubbed ARGUS (NCT04462770), which tests its therapeutic effects in patients with Dravet syndrome aged 2 years and older. The placebo-controlled, double-blind, multicenter trial consists of a 4-week observational period, a 16-week double-blind period, and a 3-year open-label extension testing seizure frequency, safety concerns, and how the body processes the drug.³

In a previously conducted phase 1 study of healthy adults, the therapy was considered well-tolerated, with adverse events (AEs) being mild or moderate in nature. The study, which featured 24 adults, showed that drowsiness/grogginess was the only notable AE, observed at the highest (80 mg/kg) dose. Overall, investigators concluded that the agent has the potential to be a safe and effective treatment option for DS.⁴

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REFERENCES
1. Ray A, Nomikos G, Runyan G, et al. A 20-Week Multicenter, Randomized, Double-Blind (DB), Placebo-Controlled, Phase 3 Trial (EPX 100-003) of EPX-100 (Clemizole Hydrochloride) as Adjunctive Therapy in patients with Lennox-Gastaut Syndrome (LGS). Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA. ABSTRACT 003976
2. Harmony Biosciences Acquires Epygenix Therapeutics, Inc., Adding Late-Stage Epilepsy Franchise to Growing Pipeline of Innovative CNS Assets. April 30, 2024. Accessed April 8, 2025. https://ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-acquires-epygenix-therapeutics-inc-adding
3. Discovery in Fish Leads to a Clinical Trial for Dravet syndrome. Dravet Syndrome Foundation. March 28, 2025. Accessed April 8, 2025. https://dravetfoundation.org/discovery-in-fish-leads-to-a-clinical-trial-for-dravet-syndrome/
4. 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