ETX101 for Dravet Syndrome

(ENDEAVOR Trial)

Recruiting at 2 trial locations

Overseen By Encoded Patient Advocacy

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Encoded Therapeutics

Must be taking: Antiseizure medications

Must not be taking: Sodium channel blockers

Disqualifiers: Genetic mutation, CNS abnormality, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ETX101 for Dravet syndrome, a severe form of epilepsy. Researchers aim to determine if ETX101 is safe and effective in reducing seizures. The study consists of two parts: one involves gradually increasing doses, and the other randomly assigns participants to receive the treatment or a placebo (inactive treatment) at different times. Families with children who have Dravet syndrome, began having seizures between 3 and 15 months old, and are on seizure medication might be a good fit for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be on at least one antiseizure medication to participate. You cannot take certain antiseizure medications that are not suitable for Dravet syndrome.

Is there any evidence suggesting that ETX101 is likely to be safe for humans?

Research has shown that ETX101 is being tested for its safety and effectiveness in treating Dravet syndrome, a severe type of epilepsy. The treatment involves delivering the medication directly to the brain, a method experts consider safe and standard. Although this treatment is new, the procedure itself is well-known and commonly used.

As the study is in its early stages, researchers are closely monitoring for any side effects or reactions. This careful observation ensures that any issues can be quickly addressed to keep participants safe. While data is still limited, the method of delivery and the careful study design suggest that the treatment is being tested safely. ^{1 2 3 4 5}

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

Unlike the standard treatments for Dravet Syndrome, which typically include antiepileptic drugs like clobazam and stiripentol, ETX101 offers a potentially new approach by targeting the underlying genetic cause of the condition. Researchers are excited about ETX101 because it utilizes a cutting-edge gene therapy technique designed to correct the SCN1A gene mutation, which is often responsible for the seizures in Dravet Syndrome patients. This approach could provide a more effective and long-lasting solution compared to traditional medications, which mainly focus on managing symptoms rather than addressing the root cause.

What evidence suggests that ETX101 might be an effective treatment for Dravet syndrome?

Research has shown that ETX101 could be a promising treatment for Dravet syndrome, a severe type of epilepsy. Studies indicate that ETX101 targets the SCN1A gene, which is often abnormal in individuals with this condition. Early results suggest that this approach might alter the disease's course, potentially reducing the frequency and severity of seizures. Although detailed information from human studies remains limited, the mechanism of ETX101 provides a strong basis for its potential effectiveness in managing Dravet syndrome. Participants in this trial will join either Part 1, which evaluates up to four dose levels of ETX101, or Part 2, a dose-selection study with a sham comparator. ^{1 2 4 5 6}

Who Is on the Research Team?

Salvador Rico, M.D., Ph.D

Principal Investigator

Encoded Therapeutics

Are You a Good Fit for This Trial?

This trial is for infants and children aged 6 to less than 36 months with a confirmed genetic variant linked to Dravet Syndrome. They must have had their first seizure between 3-15 months old, be diagnosed or suspected of having Dravet Syndrome by a clinician, and be on at least one anti-seizure medication.

Inclusion Criteria

I have a genetic mutation in SCN1A linked to my condition.

I am taking medication to prevent seizures.

I have a genetic mutation in SCN1A linked to my condition.

Exclusion Criteria

I have a genetic mutation or health condition that could affect my Dravet syndrome symptoms.

I am taking or have taken seizure medications not recommended for Dravet syndrome.

I have had gene or cell therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Open-label, dose-escalation design to evaluate up to 4 dose levels of ETX101

Duration not specified

Treatment Part 2

Randomized, double-blind, sham delayed-treatment control, dose-selection study

Up through Week 52

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ETX101

Trial Overview The study tests ETX101's safety and effectiveness in young patients with SCN1A-positive Dravet syndrome. It has two parts: the first part increases doses to find safe levels (open-label), and the second part compares ETX101 against a sham treatment without participants knowing which they're getting (double-blind).

How Is the Trial Designed?

Group I: Part 1 Experimental Treatment 1 Intervention

Part 1 will follow an open-label, rule-based, dose-escalation design and will evaluate up to 4 dose levels of ETX101.

Group II: Part 2 Placebo Group 1 Intervention

Part 2 is a dose-selection study, which will follow a double-blind (up through Week 52), randomized, sham delayed-treatment control design. There will be up to 3 cohorts in Part 2. If it is determined two dose levels of ETX101 will be evaluated in Part 2, participants will be randomized 1:1:1 to study treatment or sham procedure with delayed treatment. If Part 2 proceeds with a single dose level of ETX101, participants will be randomized 2:1 to study treatment or sham procedure with delayed treatment.

ETX101 is already approved in United States, United Kingdom for the following indications:

Approved in United States as ETX101 for:

• SCN1A-positive Dravet syndrome

Approved in United Kingdom as ETX101 for:

• SCN1A-positive Dravet syndrome

Who Is Running the Clinical Trial?

Encoded Therapeutics

Lead Sponsor

Trials

6

Recruited

130+

Published Research Related to This Trial

The newly developed Scn1a haploinsufficiency rat model closely mimics the key features of Dravet syndrome, including susceptibility to heat-induced seizures and spontaneous seizures, making it a valuable tool for studying the condition.

This model shows reduced Scn1a expression in critical brain areas and distinct EEG patterns, which can help researchers better understand the mechanisms of Dravet syndrome and develop targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel rat model of Dravet syndrome recapitulates clinical hallmarks. Li, M., Yang, L., Qian, W., et al.[2023]

A 20-year-old man with Dravet syndrome exhibited a rare seizure type called photosensitive myoclonic absence seizures, which had not been previously reported, highlighting the complexity of this condition.

Despite treatment with multiple antiepileptic medications and a vagus nerve stimulator, the seizures remained refractory, indicating the challenges in managing Dravet syndrome and the need for careful monitoring to identify all seizure types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myoclonic Absence Seizures in Dravet Syndrome. Myers, KA., Scheffer, IE.[2018]

AAV9-REGABA-eTFSCN1A gene therapy effectively increased SCN1A expression in GABAergic neurons in a mouse model of Dravet syndrome, leading to a significant reduction in seizures and improved survival rates for over a year.

In nonhuman primates, the therapy showed widespread distribution and expression in the brain without adverse effects, indicating its potential safety and efficacy for treating SCN1A-related Dravet syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell-Selective Adeno-Associated Virus-Mediated SCN1A Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates. Tanenhaus, A., Stowe, T., Young, A., et al.[2023]

Recent antiseizure medications like fenfluramine and cannabidiol have been effective in reducing seizure frequency in Dravet syndrome, but many patients still do not respond to current treatments, highlighting the need for new therapies.

Innovative approaches, including gene therapy and precision medicine strategies targeting the SCN1A gene, show promise in preclinical studies and could lead to more effective, disease-modifying treatments for Dravet syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Molecular Strategies for Genetic Neurodevelopmental Disorders: Emerging Lessons from Dravet Syndrome. Lersch, R., Jannadi, R., Grosse, L., et al.[2023]

Dravet syndrome, characterized by severe myoclonic epilepsy, typically begins in the first year of life with prolonged seizures, and is confirmed in 70-80% of cases through mutation screening of the SCN1A gene.

While all seizure types associated with Dravet syndrome are resistant to medication, many patients show a trend toward less severe epilepsy and cognitive impairment after the age of 5 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The core Dravet syndrome phenotype. Dravet, C.[2022]

In a clinical trial involving 87 children with Dravet syndrome, fenfluramine significantly reduced monthly convulsive seizure frequency by 54% compared to placebo, indicating its efficacy as an additional treatment for patients with poor seizure control.

Fenfluramine was generally well tolerated, with no evidence of serious heart-related side effects, making it a promising new treatment option for managing seizures in Dravet syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. Nabbout, R., Mistry, A., Zuberi, S., et al.[2023]

Dravet syndrome is a severe genetic epilepsy that typically presents in the first year of life with febrile hemiconvulsions or tonic-clonic seizures, and is often linked to mutations in the SCN1A gene in 70-80% of cases.

Effective seizure management can be challenging; while medications like valproate and stiripentol may help, sodium channel blockers such as lamotrigine and carbamazepine can worsen seizures, highlighting the importance of accurate diagnosis for appropriate treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dravet syndrome as a cause of epilepsy and learning disability]. Lund, C., Bremer, A., Lossius, MI., et al.[2012]

Over 90% of children with Dravet Syndrome (DS) had a pathogenic variant in the SCN1A gene, highlighting the genetic basis of the condition.

Children born between 2010-2018 were diagnosed with DS at a younger median age (1.6 years) and had a higher cumulative incidence (1 in 33,000) compared to those born from 2000-2009, suggesting improved awareness and diagnosis of the syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dravet syndrome in children-A population-based study. Bjurulf, B., Reilly, C., Sigurdsson, GV., et al.[2022]

Dravet syndrome (DS) is a severe and rare condition affecting 1 in 16,000 live births, characterized by drug-resistant epilepsy and significant cognitive and behavioral challenges, highlighting the need for effective treatment strategies.

The updated guidelines for diagnosing and treating DS, developed by 29 European experts, emphasize the importance of optimal seizure management and include nonpharmaceutical options, aiming to improve patient outcomes and support families.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe. Cardenal-Muñoz, E., Auvin, S., Villanueva, V., et al.[2022]

Citations

1. encoded.com encoded.com/press-releases/encoded-therapeutics-reports-clinical-progress-of-etx101-gene-therapy-for-dravet-syndrome-recaps-2024-corporate-achievements-and-provides-2025-outlook/

News & Events Encoded Therapeutics Reports Clinical Progress of ETX101 Gene Therapy for Dravet Syndrome, Recaps 2024 Corporate Achievements and Provides 2025 Outlook. POLARIS ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05419492

NCT05419492 | A Clinical Study to Evaluate the Safety and ... ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome.

3. dravetfoundation.org dravetfoundation.org/encoded-therapeutics-begins-enrolling-first-in-human-trials-for-etx101-a-potential-one-time-disease-modifying-gene-regulation-therapy-for-scn1a-dravet-syndrome/

Encoded Therapeutics begins enrolling first in-human trials ... Similarly, ETX101 holds much potential to address Dravet syndrome at the source and provide a treatment that modifies the course of the disease.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06112275?cond=(DRAVET%20SYNDROME)%20OR%20(SCN1A)&rank=2

NCT06112275 | A Clinical Study to Evaluate the Safety and ... WAYFINDER is a Phase 1/2 study in Australia to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome aged 6 to <84 ...

5. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/465376

A Clinical Study to Evaluate the Safety and Efficacy of ETX101 ... EXPEDITION is a Phase 1/2 study in the UK to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet Syndrome aged 6 to \< 48 ...

6. encoded.com encoded.com/programs/etx101-for-dravet-syndrome/

ETX101 for Dravet Syndrome ETX101 is delivered via an intracerebroventricular (ICV) infusion, which is considered by neurosurgeons to be a safe and standard procedure to deliver ...