Safety and Efficacy Trial of AAV Gene Therapy in Patients With CNGB3 Achromatopsia (A Clarity Clinical Trial)

Study Overview
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Brief Summary
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This will be a non-randomized, open-label, Phase 1/2 study of the safety and efficacy of AGTC-401 administered to one eye by subretinal injection in individuals with achromatopsia caused by mutations in the CNGB3 gene. The primary study endpoint will be safety and the secondary study endpoint will be efficacy.

Detailed Description
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This will be a non-randomized, open-label, Phase 1/2 study of the safety and efficacy of AGTC-401 administered to one eye by subretinal injection in individuals with achromatopsia caused by mutations in the CNGB3 gene. The primary study endpoint will be safety and the secondary study endpoint will be efficacy. Subjects will be enrolled sequentially in seven dosing groups. Subjects in Groups 1, 2, 3, 4, 5, and 6 will be at least 18 years of age and will receive varying dose levels of study agent. Subjects in Group 4a will be 6 to 17 years of age and will receive the same dose as Group 4. Subjects in Groups 5a and 7 will be between 4 and 8 years of age. Subjects in Group 5a will receive the same dose as Group 5, and subjects in Group 7 will receive the maximum tolerated dose identified in Groups 1, 2, 3, 4, 4a, 5, 5a, and 6. Safety will be monitored by evaluation of ocular and non-ocular adverse events and hematology and clinical chemistry parameters. Efficacy parameters will include visual acuity, light discomfort testing, color vision, static visual field, ERG, adaptive optics retinal imaging, functional MRI (fMRI), color brightness test and OCT.

Official Title
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A Multiple-Site, Phase 1/2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing CNGB3 in Patients With Congenital Achromatopsia Caused by Mutations in the CNGB3 Gene

Conditions
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Achromatopsia

Intervention / Treatment
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* Biological: rAAV2tYF-PR1.7-hCNGB3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria include: Male or female subjects with documented mutations in both alleles of the CNGB3 gene; Retinal disease consistent with a clinical diagnosis of achromatopsia; At least 18 years of age for Groups 1, 2, 3, 4, 5 and 6. At least 6 years of age for Group 4a, and 4-8 years of age for Groups 5a and 7; Able to perform tests of visual and retinal function; Visual acuity in the study eye not better than 55 ETDRS letters (Snellen equivalent 20/80) based on the average of two examinations at the baseline visit; Acceptable laboratory parameters; For females of childbearing potential: A negative pregnancy test within 2 days before administration of study agent. Exclusion Criteria include: Best-corrected visual acuity difference between the two eyes of > 15 ETDRS letters (3 lines); Evidence of degenerative myopia in the study eye; Pre-existing eye conditions that would contribute to vision loss in either eye or increase the risk of subretinal injection in the study eye.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 2.0 x 10^11 vg/mL of AGTC-401<br>Subjects at least 18 y/o treated with 2.0 x 10^11 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 2: 4.0 x 10^10 vg/mL of AGTC-401<br>Subjects at least 18 y/o treated with 4.0 x 10^10 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 3: 1.2 x 10^11 vg/mL of AGTC-401<br>Subjects at least 18 y/o treated with 1.2 x 10^11 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 4: 3.6 x 10^11 vg/mL of AGTC-401<br>Subjects at least 18 y/o treated with 3.6 x 10^11 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 4a: 3.6 x 10^11 vg/mL of AGTC-401<br>Subjects 6 to 17 y/o treated with 3.6 x 10^11 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 5: 1.1 x 10^12 vg/mL of AGTC-401<br>Subjects at least 18 y/o treated with 1.1 x 10^12 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 5a: 1.1 x 10^12 vg/mL of AGTC-401<br>Subjects 4 to 8 y/o treated with 1.1 x 10^12 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 6: 3.2 x 10^12 vg/mL of AGTC-401<br>Subjects at least 18 y/o treated with 3.2 x 10^12 vg/mL of rAAV2tYF-PR1/7-hCNGB3 study drug. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|
| Experimental: Group 7: MTD of AGTC-401<br>Subjects 4 to 8 y/o treated with a maximum tolerated dose of rAAV2tYF-PR1/7-hCNGB3 study drug determined by Groups 1-6. | Biological: rAAV2tYF-PR1.7-hCNGB3<br>* rAAV2tYF-PR1.7-hCNGB3 is a non-replicating, rep/cap-deleted, recombinant adeno-associated virus vector that expresses the CNGB3 gene.<br>* Other names: AGTC-401;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Proportion of participants experiencing grade 3 or greater adverse events | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual acuity | Changes in best corrected visual acuity compared to pre-treatment | 1 year | 
| Light aversion | Changes in light discomfort testing compared to pre-treatment | 1 year | 
| Color vision | Changes in color vision testing compared to pre-treatment | 1 year |