Safety and Efficacy of rAAV2tYF-GRK1-RPGR in Subjects With X-linked Retinitis Pigmentosa Caused by RPGR Mutations

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector (rAAV2tYF-GRK1-RPGR) in patients with X-linked retinitis pigmentosa caused by RPGR mutations.

Detailed Description
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This study includes a non-randomized, open-label, Phase 1/2 dose escalation portion, and a Phase 2 randomized, controlled, masked dose expansion portion. Approximately 30 participants will be enrolled into the dose escalation portion of the study. Each participant will receive the study agent by subretinal injection in one eye on a single occasion. Enrollment will begin with the lowest dose and will proceed to higher doses only after review of safety data by a Data and Safety Monitoring Committee (DSMC). Within groups 1 through 3 and 5 and 6, enrollment of participants will be staggered by at least 2 weeks to allow adequate time for review of safety information by the investigators and sponsor. Within Group 4, enrollment of the first 3 pediatric participants will be staggered by at least 2 weeks to allow adequate time for review of safety information by the investigators and sponsor. Study agent administration will occur on Day 0. There are a total of 15 visits over approximately 36 months, and long-term follow-up evaluations annually at years 4 and 5. After the phase 1/2 portion of the study is completed, approximately 12 participants, who were not part of the Phase 1/2 portion of the study, will be enrolled into the dose expansion portion of the study. These participants will be randomized in a 1:1 ratio to 1 of 2 treatment groups (i.e., Group 1 [low dose] and Group 2 [high dose]). Each participant will receive the assigned dose of AGTC-501 in one eye on a single occasion.

Official Title
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A Phase 1/2 Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of AGTC-501 (rAAV2tYF-GRK1-RPGR) and a Phase 2 Randomized, Controlled, Masked, Multi-center Study Comparing Two Doses of AGTC-501 in Male Subjects With X-linked Retinitis Pigmentosa Confirmed by a Pathogenic Variant in the RPGR Gene

Conditions
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X-Linked Retinitis Pigmentosa

Intervention / Treatment
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* Biological: rAAV2tYF-GRK1-RPGR


Participation Criteria
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Eligibility Criteria
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Phase 1/2 Dose Escalation Inclusion Criteria: Male subjects between the ages of 6-50 years old with a documented RPGR mutation within exons 1-14 and/or ORF15 from a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; Clinical diagnosis of X-linked retinitis pigmentosa (XLRP); Best-corrected visual acuity not better than 78 ETDRS letters (20/32) in the study eye; Also meet the other requirements of the study as specified in the protocol Phase 1/2 Dose Escalation Exclusion Criteria: • Have other known retinal disease mutations or previously received an AAV gene therapy product, as well as being unable or unwilling to meet the requirements of the study Phase 2 Dose Expansion Inclusion Criteria: Males between the ages of 8-50 years old with a clinical diagnosis of XLRP with a confirmed RPGR mutation who also meet the other requirements of the study Have at least one documented pathogenic or likely pathogenic variant in the RPGR gene within exons 1-14 and/or ORF15 from Molecular Vision Laboratory (MVL), a CLIA-certified laboratory. Both eyes: Have a BCVA no better than 75 letters (20/32) and no worse than 35 letters (20/200) in both eyes based on an ETDRS chart at each screening visit. Pediatric subjects unable to read the ETDRS letters may utilize a tumbling E chart for BCVA assessments. Phase 2 Dose Expansion Exclusion Criteria • Have other known retinal disease mutations or previously received an AAV gene therapy product, as well as being unable or unwilling to meet the requirements of the study

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Phase 1/2 Dose Escalation<br>Male subjects at least 18 y/o treated with Dose 1 of rAAV2tYF-GRK1-RPGR study drug. | Biological: rAAV2tYF-GRK1-RPGR<br>* Adeno-associated virus vector expressing a human RPGR gene<br>|
| Experimental: Group 2: Phase 1/2 Dose Escalation and Low Dose Group Phase 2 Dose Expansion<br>Phase 1/2 Dose Escalation: male subjects at least 18 y/o treated with Dose 2 of rAAV2tYF-GRK1-RPGR study drug. Phase 2 Dose Expansion: male subjects at least 8 y/o treated with Dose 2 of rAAV2tYF-GRK1-RPGR study drug. This will be the low dose group for the phase 2 expansion. | Biological: rAAV2tYF-GRK1-RPGR<br>* Adeno-associated virus vector expressing a human RPGR gene<br>|
| Experimental: Group 3 and Group 4 Phase 1/2 Dose Escalation<br>Group 3 male subjects at least 18 y/o and Group 4 male subjects at least 6 y/o treated with Dose 3 of rAAV2tYF-GRK1-RPGR study drug. | Biological: rAAV2tYF-GRK1-RPGR<br>* Adeno-associated virus vector expressing a human RPGR gene<br>|
| Experimental: Group 5 Phase 1/2 Dose Escalation and High Dose Group Phase 2 Dose Expansion<br>Phase 1/2 Dose Escalation: male subjects at least 18 y/o treated with Dose 5 of rAAV2tYF-GRK1-RPGR study drug. Phase 2 Dose Expansion: male subjects at least 8 y/o treated with Dose 5 of rAAV2tYF-GRK1-RPGR study drug. This will be the high dose group for the phase 2 expansion. | Biological: rAAV2tYF-GRK1-RPGR<br>* Adeno-associated virus vector expressing a human RPGR gene<br>|
| Experimental: Group 6 Phase 1/2 Dose Escalation<br>Male subjects at least 18 y/o treated with Dose 6 of rAAV2tYF-GRK1-RPGR study drug. | Biological: rAAV2tYF-GRK1-RPGR<br>* Adeno-associated virus vector expressing a human RPGR gene<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1/2 Dose Escalation: Number and proportion of Adverse Events |  | Day 0 - Month 36 | 
| Phase 1/2 Dose Escalation: Number and proportion of participants experiencing abnormal clinically relevant hematology or clinical chemistry parameters. |  | Day 0 - Month 36 | 
| Phase 2 Dose Expansion: The difference in the proportion of responding eyes between treated and control eyes in low dose group and high dose group. |  | Day 0 - Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1/2 Dose Escalation: Changes from baseline in visual function as measured by mesopic microperimetry in the treated eye compared to the untreated eye |  | Day 0 - Month 36 | 
| Phase 1/2 Dose Escalation: Changes from baseline in visual acuity |  | Day 0 - Month 36 | 
| Phase 1/2 Dose Escalation: Changes from baseline in retinal structure as assessed by spectral-domain optical coherence tomography (SD-OCT) |  | Day 0 - Month 36 | 
| Phase 1/2 Dose Escalation: Changes from baseline in quality of life questionnaire responses |  | Day 0 - Month 36 | 
| Phase 2 Dose Expansion: Proportion of responding eyes in treated eyes versus control eyes in the low dose and high dose group measured by mobility test |  | Day 0 - Month 12 | 
| Phase 2 Dose Expansion: Proportion of responding eyes in treated eyes versus control eyes in the low dose and high dose group measured by visual function |  | Day 0 - Month 12 | 
| Phase 2 Dose Expansion: Difference in mean change from baseline in Visual Acuity in treated eyes versus control eyes in the low dose and high dose groups |  | Day 0 - Month 12 | 
| Phase 2 Dose Expansion: Difference in mean change from baseline in the EZ area, as measured by SD-OCT, in treated eyes versus control eyes in the low dose group and high dose group |  | Day 0 - Month 12 | 
| Phase 2 Dose Expansion: Changes from baseline in quality of life questionnaire responses |  | Day 0 - Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XLRP, retinal degeneration, RPGR, adeno-associated virus, gene therapy, AAV