AMT-260 Gene Therapy Study in Adults With Unilateral Refractory Mesial Temporal Lobe Epilepsy

Study Overview
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Brief Summary
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This is a study of AMT-260 in Adults with Unilateral Refractory Mesial Temporal Lobe Epilepsy (MTLE). It is designed to investigate the Safety, Tolerability, and Efficacy of AMT-260 in Adults with MTLE Administered via Magnetic Resonance Imaging (MRI)-guided Convection-enhanced Delivery (CED).

Detailed Description
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The first-in-human Phase I/IIa U.S. trial consists of two parts. The first part is a multi-center, open-label trial with two dosing cohorts of six patients each to assess safety, tolerability, and first signs of efficacy of AMT-260 in patients with refractory unilateral MTLE. The second part is expected be a randomized, controlled trial to generate proof of concept (POC) data.

Official Title
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A Multi-center, Phase 1/2a, First-in-human (FIH) Study Investigating the Safety, Tolerability, and Efficacy of AMT-260 in Adults With Unilateral Refractory Mesial Temporal Lobe Epilepsy (MTLE) Administered Via Magnetic Resonance Imaging (MRI)-Guided Convection-enhanced Delivery (CED)

Conditions
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Mesial Temporal Lobe Epilepsy

Intervention / Treatment
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* Genetic: AAV9-hSyn1-miGRIK2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult, 18-65 years of age, inclusive, capable of giving informed consent. Diagnosis of unilateral refractory MTLE for ≥360 days, confirmed by an Epilepsy Monitoring Unit. History of seizures with on average ≥ 2 focal onset impaired awareness seizures per 30-day period during the Retrospective Period (3 months prior to screening). Currently on a stable type and dose regimen of up to a maximum of 4 approved ASDs, for ≥3 months prior to the Retrospective Period. Confirmed unilateral hippocampal pathology and concordant unilateral seizure focus Montreal Cognitive Assessment (MoCA) total score ≥26. No evidence of focal neurocognitive dysfunction, inconsistent with disease pathology- related MRI and (18F)FDG-PET findings. Women of childbearing potential (WOCBP) and fertile male subjects must be willing and able to use highly effective methods of birth control consistently and correctly throughout the study and for ≥360 days following AMT-260 administration. For WOCBP only: Negative pregnancy test. Exclusion Criteria: Implanted devices that would contraindicate MRI; MRI-compatible devices must be implanted ≥3 months prior to Screening (vagus nerve stimulation devices will be up to discretion of the Investigator). Any other contraindications for generalized anesthesia or surgery. Medications that could confound clinical (e.g., antipsychotic medication and anti-viral therapy) and laboratory evaluations or could affect a subject's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule. Any psychogenic nonepileptic seizures within the last year. Any seizures with contralateral or extra-temporal ictal onset on EEG. Previous major disease-unrelated neurosurgical intervention due to intracranial tumor, trauma, or bleeding and/or history of previous intracranial surgery for treatment of epileptic seizures. Magnetic resonance imaging evidence of epileptogenic, extra-temporal lesions, or dual temporal lobe pathology.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: AMT-260 starting dose<br>N# of treated - 6 | Genetic: AAV9-hSyn1-miGRIK2<br>* AMT-260 is an AAV9 gene therapy product that locally delivers miRNA silencing technology to target the GRIK2 gene and suppress aberrantly expressed GluK2 containing kainate receptors. Intervention will be a one-time intracerebral administration of AMT-260.<br>* Other names: AMT-260;|
| Experimental: Cohort 2: AMT-260 adapted dose<br>N# of treated - 6 Dose is dependent on the DSMB recommendation. | Genetic: AAV9-hSyn1-miGRIK2<br>* AMT-260 is an AAV9 gene therapy product that locally delivers miRNA silencing technology to target the GRIK2 gene and suppress aberrantly expressed GluK2 containing kainate receptors. Intervention will be a one-time intracerebral administration of AMT-260.<br>* Other names: AMT-260;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Occurrence of Adverse Events during the period of 1 year after AMT-260 administration, including seriousness, severity, and causal relationship to AMT-260. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure Frequency | Change in seizure frequency, comparing baseline to the 1 year period after AMT-260 administration. | 1 year | 
| Quality of Life in Epilepsy Inventory-31 (QOLIE 31) | Change from baseline in responses to the QOLIE-31 questionnaire will be assessed on the following subscales; seizure worry, overall quality of life, emotional well-being, energy-fatigue, cognitive function, medication effects, and social functioning. | 1 year | 
| Patient Health Questionnaire (PHQ9) | Change from baseline in responses to the PHQ9 will be used to assess the level of depression in participants throughout the study. | 1 year | 
| State Trait Anxiety Inventory (STAI) | Change from baseline in responses to the STAI questionnaire will be used to assess trait anxiety and state anxiety in participants throughout the study. | 1 year | 
| Pittsburgh Sleep Quality Index (PSQI) | Change from baseline in responses to the PSQI questionnaire will be assessed on the following components; subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. | 1 year | 
| miRNA in human biofluid (copies/qPCR reaction). | Stem-loop RT-qPCR analyses will be used to measure miRNA in Cerebrospinal fluid, Blood Serum, Urine, Saliva. | 1 year | 
| AAV9 vector in human biofluid (copies/qPCR reaction). | qPCR analyses will be used to measure AAV9 vector shedding in Cerebrospinal fluid, Blood Serum, Urine, Saliva. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Temporal Lobe, Hippocampal Sclerosis, Epileptic Syndromes