EPX-100 for Dravet Syndrome

(ARGUS Trial)

Recruiting at 59 trial locations

Overseen By Eric Bauer

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Epygenix

Must be taking: Aeds

Must not be taking: Carbamazepine, Oxcarbazepine, Phenytoin, Fenfluramine

Disqualifiers: Suicidal thoughts, Cardiac disease, others

Stay on Your Current Meds You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of clemizole hydrochloride (also known as EPX-100) for individuals with Dravet syndrome, a severe form of epilepsy. The researchers aim to determine if this medication can control seizures more effectively than a placebo (a substance with no active drug). Participants will receive either clemizole or a placebo, and those who complete the trial may continue with clemizole for up to three years. Suitable candidates for this trial include individuals who experienced seizures before 18 months of age, have a confirmed SCN1A gene mutation, and have seizures not fully controlled by current medications. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires that participants are on a stable regimen of anti-epileptic drugs (AEDs) for at least 30 days before starting. However, you cannot take certain medications like carbamazepine, oxcarbazepine, phenytoin, or fenfluramine, and you must avoid grapefruit products.

Is there any evidence suggesting that clemizole hydrochloride (EPX-100) is likely to be safe for humans?

Research has shown that clemizole hydrochloride (EPX-100) has been tested for safety in people with Dravet syndrome. In one study, 87.5% of patients experienced some side effects, but most were mild and manageable, indicating the treatment is generally well-tolerated. The treatment is also being developed for Lennox-Gastaut syndrome, which might further support its safety. However, more data is needed to fully understand its safety profile. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Dravet syndrome?

Clemizole Hydrochloride is unique because it offers a new approach to treating Dravet Syndrome, a severe form of epilepsy. Unlike standard treatments like stiripentol and clobazam, which often focus on enhancing the effects of neurotransmitters, clemizole hydrochloride targets histamine receptors, potentially reducing seizures with a different mechanism of action. Researchers are excited about its potential to provide relief for patients who may not respond well to existing medications, offering a fresh hope for managing this challenging condition.

What evidence suggests that clemizole hydrochloride might be an effective treatment for Dravet syndrome?

Studies have shown that clemizole hydrochloride (EPX-100) might help treat people with Dravet syndrome, a severe form of epilepsy. In this trial, participants will receive either clemizole hydrochloride or a placebo at random. Research suggests that EPX-100 is generally safe and well-tolerated, with mostly mild side effects like drowsiness. Earlier trials showed that EPX-100 reduced seizures in patients. The treatment targets specific brain areas believed to cause seizures. These early findings offer hope for those seeking more ways to manage Dravet syndrome. ^{1 2 6 7 8}

Who Is on the Research Team?

Amit Ray, MD

Principal Investigator

Harmony Biosciences Management, Inc.

Are You a Good Fit for This Trial?

This trial is for children and adults aged 2 years and older with Dravet Syndrome who experience frequent convulsive seizures. Participants must be able to maintain a seizure diary, use birth control if applicable, and have not been exposed to the study drug or similar drugs before. They should not have any significant medical conditions that could interfere with the trial.

Inclusion Criteria

I am using birth control and my pregnancy tests are negative.

I am at least 2 years old.

I have been diagnosed with Dravet Syndrome and meet the specific seizure criteria.

Exclusion Criteria

My seizures are caused by a specific condition.

I have used lorcaserin before or am currently using it.

I am taking fenfluramine without an echocardiogram report.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Observational

Participants are observed for baseline seizure activity

4 weeks

Treatment

Participants receive either EPX-100 or placebo in a double-blind manner

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment long-term

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Clemizole Hydrochloride

Trial Overview The study tests EPX-100 (Clemizole HCl) as an additional treatment alongside standard anti-epileptic drugs in patients with Dravet Syndrome. It aims to see if it's safe and effective at controlling seizures compared to a placebo (a substance with no active drug).

How Is the Trial Designed?

Group I: Open-label clemizole HCl Experimental Treatment 2 Interventions

Eligible participants who complete the DB Period will have the option to continue in the OLE Period, during which they will receive clemizole HCL for up to 3 years.

Group II: Double-blind clemizole HCl Experimental Treatment 1 Intervention

Participants will receive their first dose of study drug following randomization.

Group III: Placebo Placebo Group 1 Intervention

Participants will receive their first dose of study drug following randomization.

Who Is Running the Clinical Trial?

Epygenix

Lead Sponsor

Trials

3

Recruited

150+

Liberyx Therapeutics

Collaborator

Trials

1

Recruited

100+

Forest Hills Lab

Industry Sponsor

Trials

3

Recruited

170+

Harmony Biosciences Management, Inc.

Industry Sponsor

Trials

9

Recruited

2,000+

Harmony Biosciences, LLC

Industry Sponsor

Trials

9

Recruited

2,000+

Published Research Related to This Trial

In a comprehensive analysis of safety data from 1957 patients, adjunctive brivaracetam (BRV) showed a treatment-emergent adverse event (TEAE) incidence of 66.9%, slightly higher than the 62.8% observed with placebo, indicating a generally acceptable safety profile.

The most common TEAEs with BRV included somnolence, headache, dizziness, and fatigue, with psychiatric-related TEAEs occurring in 11.3% of patients, suggesting that while BRV is effective for focal seizures, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of adjunctive brivaracetam in epilepsy: In-depth pooled analysis. Brandt, C., Klein, P., Badalamenti, V., et al.[2020]

Perampanel (PER) and brivaracetam (BRV) are new antiseizure drugs that have shown comparable efficacy in treating various epilepsy syndromes, with PER acting on AMPA receptors and BRV targeting SV2A with a faster brain entry.

Both drugs are well tolerated and have the potential to become important options in epilepsy treatment, especially in acute situations like status epilepticus, due to BRV's rapid action and PER's unique mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the pharmacotherapy of epilepsy: brivaracetam and perampanel as broad-spectrum antiseizure drugs for the treatment of epilepsies and status epilepticus. Willems, LM., Bauer, S., Rosenow, F., et al.[2021]

In a study of 15 children with benign childhood epilepsy with centrotemporal spikes (BECCT) and electrical status epilepticus during sleep (ESES), the combination of levetiracetam (LEV) and short-term clonazepam (CZP) led to significant improvements in EEG results and seizure control after two months of treatment.

The combination therapy was effective for 14 out of 15 children, with most showing either significantly reduced EEG discharges or no discharges at follow-up, indicating a promising treatment option with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of levetiracetam combined with short-term clonazepam in treatment of electrical status epilepticus during sleep in children with benign childhood epilepsy with centrotemporal spikes]. Su, TF., Xu, SQ., Chen, L.[2018]

In clinical trials involving 1021 adults and 202 children, eslicarbazepine acetate (ESL) was associated with a low incidence of cutaneous allergic reactions, primarily mild to moderate rashes and pruritus, with serious skin reactions being rare.

While the incidence of rash increased with higher ESL doses, most rash-related adverse events were not deemed related to the treatment, highlighting the overall safety profile of ESL in managing focal seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate. Rogin, J., Resnick, T., Strom, L., et al.[2020]

Stiripentol is the only new drug shown to be effective for treating Dravet syndrome when used alongside valproate and clobazam, based on two independent double-blind controlled trials involving children with the condition.

Stiripentol enhances GABAergic neurotransmission and should be prescribed with reduced doses of valproate and clobazam to minimize side effects, such as loss of appetite and weight, making it a valuable adjunctive therapy for over 500 Dravet patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current therapeutic procedures in Dravet syndrome. Chiron, C.[2012]

A study of 93 caregivers in Germany revealed that patients with Dravet syndrome commonly use a variety of antiepileptic drugs (AEDs), with sodium valproate being the most frequently prescribed, but no clear relationship was found between medication type and seizure frequency.

Despite following clinical guidelines for AED combinations, the treatment did not significantly impact seizure control, highlighting the complexity of managing Dravet syndrome and suggesting a need for further research into effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature. Schubert-Bast, S., Wolff, M., Wiemer-Kruel, A., et al.[2020]

Recent advancements in the management of Dravet Syndrome have led to the approval of new antiseizure medications that show promise in both efficacy and safety, particularly in young children under 5 years old.

Despite these advancements, there is a critical need for more data on the broader needs of patients and families, as evaluating the effectiveness and safety of treatments beyond seizure control remains challenging due to cognitive and behavioral issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety considerations selecting antiseizure medications for the treatment of individuals with Dravet syndrome. Nabbout, R., Chemaly, N., Chiron, C., et al.[2021]

Dravet syndrome, a severe form of epilepsy that begins in infancy, is often linked to mutations in the SCN1A gene, affecting about 85% of patients, and leads to various stages of seizure activity and developmental challenges.

Several potential treatments are being explored, including fenfluramine and STK-001, which target different mechanisms of action, showing promise in early clinical evaluations and animal models for managing the symptoms of Dravet syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome. Miziak, B., Czuczwar, S.[2021]

Bromide was found to be the most effective antiepileptic drug for patients with Dravet syndrome, particularly in those without SCN1A mutations, showing high responder rates of 94.44%.

Carbamazepine should be avoided in patients with SCN1A mutations, as it either had no effect or worsened seizures in all SCN1A-positive patients, highlighting the importance of genotype in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes. Shi, XY., Tomonoh, Y., Wang, WZ., et al.[2016]

Stiripentol is the only medication proven effective for Dravet syndrome in two independent randomized placebo-controlled trials, especially when used alongside valproate and clobazam, and has been safely administered to over 500 children since its approval in 2007.

Due to its mechanism of action as a GABAergic agent, stiripentol can help manage seizures in Dravet syndrome, and it is recommended to start treatment as soon as the diagnosis is confirmed to prevent cognitive decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacologic treatment of Dravet syndrome. Chiron, C., Dulac, O.[2018]

Cenobamate (CNB) has shown significant efficacy as an add-on therapy for adult patients with Dravet syndrome (DS), resulting in over 80% seizure reduction in four patients over a follow-up period of up to 542 days.

No severe adverse events were reported, suggesting that CNB may be a safe option for managing seizures in DS, although further research is needed to determine its effectiveness across all patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of adult Dravet syndrome patients with cenobamate. Makridis, KL., Friedo, AL., Kellinghaus, C., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04462770

NCT04462770 | A Study of EPX-100 (Clemizole ... This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of clemizole hydrochloride (EPX- ...

2. neurology.org neurology.org/doi/10.1212/WNL.0000000000211366

A 20-Week Multicenter, Randomized, Double-Blind (DB), ... This is an upcoming Phase 3 study to determine effectiveness and safety of EPX-100 in patients with LGS.

3. neurologylive.com neurologylive.com/view/phase-3-argus-interim-data-support-safety-epx-100-adjunctive-therapy-dravet-syndrome

Phase 3 ARGUS Interim Data Support Safety of EPX-100 ... EPX-100 demonstrated safety and tolerability in Dravet syndrome patients, with 87.5% experiencing treatment-emergent adverse events, primarily ...

4. aesnet.org aesnet.org/abstractslisting/epx-100-as-an-adjunctive-therapy-in-dravet-syndrome--phase-1-and-phase-2-randomized--double-blind--placebo-controlled-trials

EPX-100-as-an-Adjunctive-Therapy-in-Dravet-Syndrome EPX-100 was well-tolerated with all adverse events being mild or moderate, with drowsiness being the most common finding in Phase 1 trials.

5. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/439336

A Study of EPX-100 (Clemizole Hydrochloride) in ... This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of clemizole ...

6. dravetfoundation.org dravetfoundation.org/discovery-in-fish-leads-to-a-clinical-trial-for-dravet-syndrome/

Discovery in Fish Leads to a Clinical Trial for Dravet ... In 2017, clemizole /EPX-100 received orphan drug status for the treatment of Dravet syndrome, and by 2020 the initial safety studies enabled ...

7. ir.harmonybiosciences.com ir.harmonybiosciences.com/news-releases/news-release-details/harmony-biosciences-present-rare-epilepsy-data-36th

Harmony Biosciences to Present Rare Epilepsy Data at the ... EPX-100, clemizole hydrochloride, is under development for the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). EPX-100 acts ...

8. withpower.com withpower.com/trial/phase-3-syndrome-8-2020-16fd5

EPX-100 for Dravet Syndrome (ARGUS Trial) There is limited safety information available for EPX-100, but initial clinical studies suggest it is being evaluated for safety in treating Dravet Syndrome.