Study of Efficacy and Safety of Voretigene Neparvovec in Japanese Patients With Biallelic RPE65 Mutation-associated Retinal Dystrophy

Study Overview
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Brief Summary
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The purpose of this study is to provide safety and efficacy data for voretigene neparvovec, administered as subretinal injection, in Japanese patients with biallelic RPE65 mutation-associated retinal dystrophy.

Detailed Description
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This is an open-label, single-arm study to evaluate the safety and efficacy of bilateral subretinal administration of voretigene neparvovec in Japanese patients with biallelic RPE65 mutation-associated retinal dystrophy. Assessments will include full-field light sensitivity threshold testing, visual fields, visual acuity, vector shedding, immunogenicity and adverse events. Participants will be monitored for 5 years after treatment.

Official Title
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An Open-label, Single-arm Study to Provide Efficacy and Safety Data of Voretigene Neparvovec Administered as Subretinal Injection in Japanese Patients With Biallelic RPE65 Mutation-associated Retinal Dystrophy

Conditions
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Biallelic RPE65 Mutation-associated Retinal Dystrophy

Intervention / Treatment
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* Genetic: voretigene neparvovec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese participants with biallelic RPE65 mutation-associated retinal dystrophy; molecular diagnosis of RPE65 mutation must be confirmed by a Novartis designated laboratory in Japan. Age four years or older. Visual acuity worse than 20/60 (both eyes) and/or visual field less than 20 degrees in any meridian as measured by a III4e isopter or equivalent (both eyes). Sufficient viable retinal cells as determined by non-invasive means, such as optical coherence tomography (OCT) and/ or ophthalmoscopy. Must have either: An area of retina within the posterior pole of > 100 µm thickness shown on OCT, or ≥ 3 disc areas of retina without atrophy or pigmentary degeneration within the posterior pole, or Remaining visual field within 30 degrees of fixation as measured by a III4e isopter or equivalent Exclusion Criteria: Any prior participation in a study in which a gene therapy vector was administered. Participation in a clinical study with an investigational drug in the past 6 months from screening visit. Known hypersensitivity to any of the study treatments including excipients or to medications planned for use in the peri-operative period. Unable to reliably perform the FST assessment. Use of retinoid compounds or precursors that could potentially interact with the biochemical activity of the RPE65 enzyme in the past 6 months from screening visit. Prior intraocular surgery within 6 months from screening visit. Prior use of any medicines that, in the opinion of the investigator, may have caused retinal damage (e.g., sildenafil or related compounds, hydroxychloroquine, chloroquine, thioridazine, any other retino-toxic compounds) Pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of study. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function.

Ages Eligible for Study
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Minimum Age: 4 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Voretigene neparvovec<br>1.5 E11 vg (0.3 mL subretinal injection in each eye, 6-18 days apart) | Genetic: voretigene neparvovec<br>* Voretigene neparvovec is an adeno-associated viral type 2 (AAV2) gene therapy vector driving expression of normal human retinal pigment epithelium 65 kDa protein (hRPE65) gene.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in full-field light sensitivity threshold | Full-field light sensitivity threshold (FST) is evaluated using white light, as averaged over both eyes. | Baseline, Day 30, 90, 180, 270, and Year 1 after second eye injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in visual field | Visual Field is assessed using the sum total degrees for VF, averaged over both eyes, as measued using Goldmann kinetic perimetry testing with a III4e target. | Baseline, Day 14, 30, 90, 180, 270, and Year 1, 2, 3, 4, 5 after second eye injection | 
| Change from Baseline in macular threshold | Macular threshold is assessed as averaged over both eyes, as measured using Humphrey static visual field testing. | Baseline, Day 14, 30, 90, 180, 270, and Year 1, 2, 3, 4, 5 after second eye injection | 
| Change from Baseline in visual acuity | Visual acuity is assessed as averaged over both eyes. | Baseline, Day 1, and 3 after first eye injection; Day 1, 3, 14, 30, 90, 180, 270, and Year 1, 2, 3, 4, 5 after second eye injection | 
| Change from Baseline in FST for long-term period | FST is assessed using white light, as averaged over both eyes. | Baseline, Year 2, 3, 4 and 5 after second eye injection | 
| Proportion of subject with the presence of vector shedding of voretigene neparvovec during the study period | Assessed as the presence of vector in peripheral blood or collected tear. | Baseline, Day 0, 1 and 3 after first eye injection; Day 0, 1, 3, 14, 30, 90, 180, 270, and Year 1 after second eye injection | 
| Proportion of subject with the presence of immunogenicity of voretigene neparvovec during the study period | Assessed as presence of systemic cell-mediated or humoral responses to capsid or transgene product . | Baseline, Day 30, 90, 180, 270, and Year 1 after second eye injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LTW888, voretigene neparvovec, Biallelic RPE65 mutation-associated retinal dystrophy, Japanese patients