A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome (Australia Only)

Study Overview
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Brief Summary
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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 36 to 83 months (3 to <7 years). The study follows an open-label, dose-escalation design.

Official Title
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WAYFINDER: A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome

Conditions
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Dravet Syndrome

Intervention / Treatment
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* Drug: ETX101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have a predicted loss of function pathogenic or likely pathogenic SCN1A variant. Participant must have experienced their first convulsive seizure between the ages of 3 and 15 months. Participant must have a clinical diagnosis of Dravet syndrome or the treating clinician must have a high clinical suspicion of a diagnosis of Dravet syndrome. Participant is receiving at least one prophylactic antiseizure medication. Exclusion Criteria: Participant has another genetic mutation or clinical comorbidity which could potentially confound the typical Dravet phenotype. Participant has a known central nervous system structural and/or vascular abnormality (indicated by an MRI or CT scan of the brain). Participant has an abnormality that may interfere with CSF distribution and/or has an existing ventriculoperitoneal shunt. Participant is currently taking or has taken antiseizure medications (ASMs) at a therapeutic dose that are contraindicated in Dravet syndrome, including sodium channel blockers. Participant has experienced seizure freedom for a period of 4 consecutive weeks within the 6-month period prior to informed consent. Participant has previously received gene or cell therapy. Participant is currently enrolled in a clinical trial or receiving an investigational therapy. Participant has clinically significant underlying liver disease.

Ages Eligible for Study
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Minimum Age: 36 Months
Maximum Age: 83 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort X<br>Cohort X will consist of 2 participants and will evaluate ETX101 dose level 1. | Drug: ETX101<br>* ETX101 is composed of a non-replicating, recombinant adeno-associated viral serotype 9 (rAAV9) vector used to deliver a GABAergic regulatory element (reGABA) and an engineered transcription factor that increases transcription of the SCN1A gene (eTFSCN1A).<br>|
| Experimental: Cohort Y<br>Cohort Y will consist of 2 participants and will evaluate ETX101 dose level 2. | Drug: ETX101<br>* ETX101 is composed of a non-replicating, recombinant adeno-associated viral serotype 9 (rAAV9) vector used to deliver a GABAergic regulatory element (reGABA) and an engineered transcription factor that increases transcription of the SCN1A gene (eTFSCN1A).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants experiencing any treatment-emergent adverse events (AEs), serious adverse events (SAEs), related AEs, AEs with severity Grade ≥ 3, AEs resulting in study discontinuation, and AEs with a fatal outcome. |  | Day 1 through Study Completion, an average of 5 years | 
| Percent change from Baseline in monthly countable seizure frequency (MCSF) at Week 52, with countable seizures defined as generalized tonic-clonic/clonic, focal motor with clearly observable clinical signs, tonic bilateral, and atonic seizures. |  | Between the 8-week baseline period and the 48-week post-dosing assessment period (defined as Week 5 to Week 52 following administration of ETX101) | 
| Proportion of participants free from episodes of prolonged seizures and/or status epilepticus at Week 52. |  | Week 5 through Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with ≥ 90% reduction in monthly countable seizure frequency (MCSF) from Baseline at Week 52. |  | Between the 8-week baseline period and the 48-week post-dosing assessment period (defined as Week 5 to Week 52 following administration of ETX101) | 
| Change from Baseline in the Vineland Adaptive Behavior Scales - Third Edition score at Week 52. |  | Baseline through Week 52. Standard scores are normalized to a mean and SD of 100 and 15, respectively, and are not bounded by a range. Higher scores correspond to better outcomes. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DEE, Dravet, SCN1A, developmental and epileptic encephalopathy, Dravet Syndrome, SCN1A-positive, SCN1A+