Currently, the ARGUS Trial is enrolling participants with Dravet syndrome to evaluate if Clemizole (EPX-100) can reduce the number of seizures. Clemizole has a long history, from its use as an antihistamine to the exciting discovery (in zebrafish!) that it may be effective at reducing the number of seizures in Dravet syndrome. Today’s blog delves a little deeper into those discoveries and provides information on the currently enrolling study.
What is Clemizole?
Clemizole (clemizole hydrochloride [HCl]) was discovered in the 1950s as a first-generation antihistamine (1) known as Allercur (1) which is no longer on the market today. However, more recent scientific discoveries indicated that clemizole may be an effective therapy to reduce seizures in people with Dravet syndrome and other forms of epilepsy by modifying serotonin signaling (2,3).
Studies Provide Evidence Clemizole Can Prevent Seizures in Fish
The potential for clemizole to act as an antiseizure treatment emerged from drug screens in a zebrafish model of Dravet syndrome (2). It may seem strange to look at drug responses in a fish, but this particular genetic model is responsive to the top-line therapies that work best clinically in people with Dravet syndrome, making it an ideal model for drug screens. In 2011, the Dravet Syndrome Foundation (DSF) helped to fund Dr. Scott Baraban’s lab to perform large-scale drug screens testing the efficacy of thousands of compounds to reduce seizures and prevent mortality in this zebrafish model. Clemizole was remarkably successful at stopping seizures in the zebrafish model of Dravet syndrome (2, 3). Even though it was known to be an antihistamine, the Baraban lab discovered it was likely modulating seizure activity through action on the serotonin signaling pathway (3,4).
Tank to Clinic: Fish Studies Translate into Clinical Studies for Dravet syndrome
A company, Epygenix Therapeutics, was founded to develop clemizole (also called EPX-100) and related compounds for the treatment of seizures in Dravet syndrome and related epilepsies. In 2017, clemizole /EPX-100 received orphan drug status for the treatment of Dravet syndrome, and by 2020 the initial safety studies enabled them to move forward towards studies in people with Dravet syndrome. This was the first example of proof-of-concept studies going straight from zebrafish to human clinical trials- a true ‘tank to clinic’ approach. In 2024, Harmony Biosciences acquired Epygenix Therapeutics and are continuing the clinical studies of EPX-100 in participants with Dravet syndrome.
The ARGUS Trial is Investigating EPX-100 (Clemizole) in Dravet Syndrome
The ARGUS Trial is a Phase 3 study investigating if EPX-100 (Clemizole) can reduce the number of convulsive seizures in participants with Dravet syndrome who are 2 years of age and older (including adults). The study will measure seizure frequency, and monitor for any safety concerns, and investigate how the body processes the study drug. This is a placebo-controlled study, participants will have a 1 in 2 (50% chance) of receiving placebo (a liquid that looks like clemizole/EPX-100 but contains no active medication). Participants who complete the double-blind phase of the study, may have an opportunity for participants to enter an open-label extension phase, where all participants will receive clemizole, to monitor longer-term effects.
The ARGUS study is taking place at many sites globally including the United States, Canada, Europe, and Asia, and new sites are still being added. To find out more about the study, including study site locations, visit ArgusTrial.com.
The study is also listed at clinicaltrials.gov/study/NCT04462770.
You can see all the currently enrolling clinical studies for Dravet syndrome as well as a snapshot of the therapies in the developmental pipeline at DravetClinicalTrials.org.
- Zierz P, Greither H. (1952) Clinical evaluation of allercur, a new antihistaminic. Arztl Wochensch; 7: 704–7.
- Baraban SC, Dinday MT, Hortopan GA. (2013) Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nature Communications 4:2410. doi:10.1038/ncomms3410
- Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. (2017) Clemizole and modulators of serotonin signaling suppress seizures in Dravet syndrome. Brain. 140:669-683. doi:10.1093/brain/aww342
- Griffin A, Jaishankar P, Grandjean J, Olson SH, Renslo AR, Baraban SC. (2019) Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome. Brain Communications. doi: 10.1093/braincomms/fcz008
