Authors :
Presenting Author: Amit Ray, MD – Harmony Biosciences
Sookyong Koh, MD, PhD – University of Nebraska Medical Center
Elizabeth Donner, MD, FRCPC – Comprehensive Epilepsy Program, Division of Neurology, Hospital for Sick Children
Gewalin Aungaroon, MD – Cincinnati Children’s Hospital Medical Center
Anna Jeong, MD – Harmony Biosciences
Maju Mathews, MD – Harmony Biosciences
George Nomikos, MD, PhD – Harmony Biosciences
Eric Bauer, BS – Harmony Biosciences
Krystle Davis Rapchak, MS – Harmony Biosciences
Kristen Mason, MS – Harmony Biosciences
Scott Baraban, PhD – University of California San Francisco
David Albers, PhD – Harmony Biosciences
Kumar Budur, MD, MS – Harmony Biosciences
Rationale:
EPX-100 (clemizole hydrochloride) is a 5HT2 (serotonin) receptor agonist identified as having antiseizure activity using an innovative and highly predictive SCN1A zebrafish model for Dravet Syndrome (DS).1 A phase 1 study in healthy volunteers demonstrated an acceptable safety/tolerability profile and supported further development. ARGUS, a phase 3, randomized, double-blind (DB), placebo-controlled trial was subsequently initiated to assess EPX-100 as adjunctive therapy in patients with DS. Participants who complete the DB phase can enroll in an open-label extension (OLE) phase investigating the long-term safety and tolerability of EPX-100.
Methods:
OLE participants had met the ARGUS trial inclusion criteria: age ≥2 years and older, clinical diagnosis of DS, seizures not controlled by current antiseizure medication (ASM) regimen, onset of seizures prior to 18 months of age, SCN1A pathogenic variant, ≥4 countable motor seizures per 28-day (CMS-28) baseline period, and a stable regimen of ASMs ≥30 days prior to Visit 1. Eligible patients were randomly assigned (1:1) to receive EPX-100 oral solution (weight-based dosing: 1-4 mg/kg BID, max 80 mg BID) or placebo, in a blinded manner over a 16-week period. Participants who complete the DB phase are eligible to enter an optional 3-year OLE extension phase after a 4-week double dummy titration. Safety analyses include adverse events (AEs), treatment-emergent AEs (TEAEs), electrocardiograms, vital signs, and body weight along with laboratory data. CMS-28 data were also analyzed during the OLE based on participant seizure diary.Results:
As of February 2025, all participants (n=29) who completed the DB phase elected to enroll in the ongoing OLE phase. Seventeen participants had been in the OLE phase for at least 6 months, 15 for at least 1 year, and 1 patient for 2 years. Twenty-three participants had a total of 172 TEAEs; 28 (16%) events were related to study drug. Eleven serious AEs were reported in 6 (20.7%) participants; 1 (0.5%) serious AE was possibly study drug related per the investigator. No deaths were reported. One participant reported an AE leading to treatment discontinuation. The most common TEAEs included change in seizure presentation (14%), upper respiratory tract infection (14%), and pyrexia (8%). Preliminary effectiveness data demonstrates approximately 50% reduction in median CMS-28 compared to study baseline for participants who had at least 6-month exposure to EPX-100 in the OLE phase. Updated safety as well as effectiveness data will be presented.Conclusions:
The preliminary safety, tolerability and effectiveness data for EPX-100 as adjunctive therapy in patients with DS are encouraging. Updated safety and effectiveness data from the OLE phase will be presented.
Reference:
1. Baraban SC, et al. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun. 2013;4:2410.
Funding:
This study was funded by Harmony Biosciences, Plymouth Meeting, PA.