A First-in-Human Study in Pediatric Patients With Ocular CLN2 Disease

Study Overview
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Brief Summary
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This is a first-in-human, open-label, single ascending dose study of RGX-381 for the treatment of ocular manifestations of CLN2 (Batten disease).

Detailed Description
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This is a first-in-human, open-label, single ascending dose study of RGX-381, a gene therapy for the potential treatment of ocular manifestations of CLN2 (Batten disease). RGX-381 is being studied as a potential treatment of ocular manifestations of neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Children with CLN2 disease have a non-working gene (set of instructions) that causes an enzyme called tripeptidyl-peptidase 1 (TPP1) to be missing or not working in their bodies. Without enough TPP1, cells cannot break down certain molecules in the body, so these storage materials build up and start to hurt the body, particularly the central nervous system (the brain and spine) and retinal cells (eyes); cause seizures; and change how children with CLN2 disease grow, act, think, and see. After eligibility has been confirmed, the participant's eyes will be assigned as the treated eye and the control fellow eye. Due to the symmetry in the clinical course of CLN2 ocular disease, untreated fellow eyes will serve as controls for the contralateral, treated eyes.

Official Title
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A First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With RGX 381 for the Ocular Manifestations Associated With Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease

Conditions
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Neuronal Ceroid Lipofuscinosis Type 2

Intervention / Treatment
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* Genetic: RGX-381


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A participant is eligible to be included in the study only if all of the following criteria apply: Has biallelic CLN2 mutations. Has decreased leukocyte TPP1 activity. Has clinical signs or symptoms consistent with CLN2 disease (eg, developmental delay, developmental decline, seizure, vision loss, or other signs/symptoms) OR an older sibling with confirmed CLN2 diagnosis. Is currently receiving biweekly ICV ERT treatment with cerliponase alfa. Meets baseline disease condition according to age, retinal thickness, and visual acuity criteria ( varies by treatment arm) Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Any ocular or systemic condition that, in the opinion of the investigator, would prevent administration and evaluation of the investigational product or interpretation of participant safety or study results (eg, significant lens or corneal opacities, glaucoma, amblyopia, gross retinal anatomical abnormality, etc). Prior participation in a gene therapy study Prior participation in another ocular clinical trial, except an intravitreal cerliponase alfa trial where a subject has received a maximum of 3 injections Prior intraocular injections of any kind, except an intravitreal cerliponase alfa trial where a subject has received a maximum of 3 injections Participation in a clinical study with an investigational drug in the past six months prior to screening, except for intracerebroventricular cerliponase alfa. Ocular surgery within the prior six months. Known sensitivity or contraindications to medications planned for use in the peri-operative period. Contraindications to systemic immunosuppression Any other condition that would not allow the potential participant to complete follow-up examinations during the study or, in the opinion of the investigator, makes the potential participant unsuitable for the study

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 144 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Main Treatment Arm<br>2×10^10 GC/eye | Genetic: RGX-381<br>* One time subretinal dose in study eye<br>* Other names: Gene Therapy (AAV9.CB7.hCLN2);|
| Experimental: Cohort 2: Main Treatment Arm<br>6×10^10 GC/eye | Genetic: RGX-381<br>* One time subretinal dose in study eye<br>* Other names: Gene Therapy (AAV9.CB7.hCLN2);|
| Experimental: Expansion Cohort: Early Treatment Arm<br>Dose level to be determined based on Independent Data Monitoring Committee review. | Genetic: RGX-381<br>* One time subretinal dose in study eye<br>* Other names: Gene Therapy (AAV9.CB7.hCLN2);|
| Experimental: Expansion Cohort: Main Treatment Arm<br>Dose level to be determined based on Independent Data Monitoring Committee review. | Genetic: RGX-381<br>* One time subretinal dose in study eye<br>* Other names: Gene Therapy (AAV9.CB7.hCLN2);|
| Experimental: Expansion Cohort: Late Treatment Arm<br>Dose level to be determined based on Independent Data Monitoring Committee review. | Genetic: RGX-381<br>* One time subretinal dose in study eye<br>* Other names: Gene Therapy (AAV9.CB7.hCLN2);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of participants with ocular and overall AE and SAEs | To evaluate the safety and tolerability of RGX-381 through Day 360 in participants with CLN2 disease | 360 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Change in SD-OCT measures and appearance of retinal layers over-time | To assess retinal structural changes with SD-OCT | 360 days | 
| Pharmacodynamics: TPP1 Expression | To assess TPP1 expression as measured in Aqueous Humor | 360 days | 
| Vector Shedding | As detected by qualitative polymerase chain reaction (qPCR) in urine and tears | 360 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLN2, Batten Disease