FOCUS: A Phase I/II First in Human Study to Evaluate the Safety and Efficacy of GT005 Administered in Subjects With Dry AMD

Study Overview
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Brief Summary
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This is an open label first in human Phase I/II multicentre study of GT005 in subjects with Macular Atrophy due to AMD

Detailed Description
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This study will evaluate the safety, the dose response and efficacy (anatomical and functional visual outcomes) of three doses of GT005 administered as a single subretinal injection in genetically defined subjects with Macular Atrophy due to Age-related Macular Degeneration (AMD). Following consent, subjects will undergo a number of ophthalmic and clinical assessments to determine eligibility for inclusion in the study. Once eligibility is confirmed, subjects will be enrolled, receive treatment, and will be followed for 48 weeks, with the option to be followed for a further 4 years in long-term follow up after completing week 48. This study is terminating early due to the interim analysis demonstrating lack of treatment efficacy. No additional subjects will be randomized or dosed. The trial is not ending early because of medical problems or concerns.

Official Title
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FOCUS: An Open Label First in Human Phase I/II Multicentre Study to Evaluate the Safety, Dose Response and Efficacy of GT005 Administered as a Single Subretinal Injection in Subjects With Macular Atrophy Due to AMD

Conditions
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Dry Age-related Macular Degeneration, Macular Degeneration, Retinal Disease, Eye Diseases, Retinal Degeneration, Geographic Atrophy, Macular Atrophy

Intervention / Treatment
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* Biological: GT005
* Biological: GT005
* Biological: GT005
* Biological: GT005
* Device: GT005/ Device: Orbit™ Subretinal Delivery System
* Device: GT005/ Device: Orbit™ Subretinal Delivery System
* Device: GT005/ Device: Orbit™ Subretinal Delivery System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to give consent to study participation Have a clinical diagnosis of GA secondary to AMD in the study eye, as determined by the Investigator, and a diagnosis of AMD in the contralateral eye (except if the subject is monocular) Cohorts 1 to 6: GA lesion(s) total size in the study eye must be ≥1.25mm2 and ≤17.5mm2. Cohort 7: GA lesion(s) total size in the study eye must be ≥1.25mm2 GA lesion(s) in the study eye must reside completely within the FAF fundus image Cohorts 1 to 3: BCVA of ≤50 letters (6/36 Snellen acuity equivalent or worse) using ETDRS charts in the study eye Cohorts 4 to 7: BCVA of ≥24 letters (6/95 and 20/320 Snellen acuity equivalent or better) using ETDRS charts in the study eye Aged ≥55 years Able to attend all study visits and complete the study procedures Women of child-bearing potential need to have a negative urine pregnancy test within two weeks prior to receiving the drug. A pregnancy test is not required for postmenopausal women (defined as being at least 12 consecutive months without menses) or those surgically sterilised (those having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral oophorectomy) Exclusion Criteria: Have evidence or history of Choroidal Neovascularisation (CNV) in the study eye. Subjects are permitted to have CNV in the fellow eye defined as either: Non-exudative/sub-clinical fellow eye CNV identified at screening, or Known history of fellow eye CNV with either ≥2 years since diagnosis or with no active treatment required in 6 months prior to screening Presence of moderate/severe non-proliferative diabetic retinopathy or worse in the study eye Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the study eye History of intraocular surgery in the study eye within 12 weeks prior to Screening (Visit 1). Yttrium aluminum garnet capsulotomy is permitted if performed >10 weeks prior to Visit 1 Have clinically significant cataract that may require surgery during the study period in the study eye Presence of moderate to severe glaucomatous optic neuropathy in the study eye; uncontrolled IOP despite the use of more than two topical agents; a history of glaucoma-filtering or valve surgery is also excluded Axial myopia of greater than -8 diopters in the study eye Have received any investigational product for the treatment of GA within the past 6 months or 5 half-lives (whichever is longer), other than nutritional supplements such as the Age-Related Eye Disease Study (AREDS) formula Have received a gene or cell therapy at any time Have a contraindication to the specified protocol corticosteroid regimen Are unwilling to use two forms of contraception (one of which being a barrier method) for 90 days post-dosing, if relevant Active malignancy within the past 12 months, except for: Appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with a stable prostate-specific antigen (PSA) ≥12 months Have any other significant ocular or non-ocular medical or psychiatric condition which, in the opinion of the Investigator, may either put the subject at risk or may influence the results of the study Cohorts 5 to 7 only: presence of metallic objects or implanted stimulator devices in or near the head, including cochlear implants, deep brain stimulators, vagus nerve stimulators, and other implanted electrodes or stimulators

Ages Eligible for Study
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Minimum Age: 55 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
Interventional Model Description: A dose escalation study of the safety and efficacy of a single subretinal injection of GT005 in subjects with Macular Atrophy due to AMD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GT005 Dose 1<br>A single dose of GT005 will be administered via subretinal injection | Biological: GT005<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor<br>|
| Experimental: GT005 Dose 2<br>A single dose of GT005 will be administered via subretinal injection | Biological: GT005<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor<br>|
| Experimental: GT005 Dose 3<br>A single dose of GT005 will be administered via subretinal injection | Biological: GT005<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor<br>|
| Experimental: GT005 Dose 1, 2 or 3<br>A single dose of GT005 will be administered via subretinal injection. This dose will be determined by dose levels determined to be tolerable in Arms 1,2 and 3 | Biological: GT005<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor<br>|
| Experimental: GT005 Dose 2 with Orbit Subretinal Delivery System<br>A single dose of GT005 will be administered with subretinal injection via suprachoroidal cannulation approach | Device: GT005/ Device: Orbit™ Subretinal Delivery System<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor Device: Orbit™ Subretinal Delivery System<br>|
| Experimental: GT005 Dose 3 with Orbit Subretinal Delivery System<br>A single dose of GT005 will be administered with subretinal injection via suprachoroidal cannulation approach | Device: GT005/ Device: Orbit™ Subretinal Delivery System<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor Device: Orbit™ Subretinal Delivery System<br>|
| Experimental: GT005 Dose 3 with Orbit Subretinal Delivery Sysem<br>A single dose of GT005 will be administered with subretinal injection via suprachoroidal cannulation approach | Device: GT005/ Device: Orbit™ Subretinal Delivery System<br>* A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor Device: Orbit™ Subretinal Delivery System<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of ocular and non-ocular Treatment Emergent AEs (TEAEs) and Treatment-Emergent Serious AEs (TESAEs) Severe Adverse Events (TEAE/TESAE) | Proportion of patients with TEAEs/TESAEs after subretinal injection of GT005 | 240 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term safety of GT005 at 3 doses | Incidence of ocular and non-ocular treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) up to 240 weeks | 240 weeks | 
| Visual Acuity | Change from baseline in BCVA (Best Corrected Visual Acuity) and LLVA (Low Luminance Visual Acuity) score via ETDRS (Early Treatment Diabetic Retinopathy Study) chart | 240 weeks | 
| Macular Sensitivity | Change from baseline in macular sensitivity as assessed by mesopic Microperimetry | 240 weeks | 
| Geographic Atrophy | Change from baseline in GA size as assessed by fundus autofluorescence | 240 weeks | 
| Rate of successful delivery of Balanced Salt Solution (BSS) or BSS PLUS to the subretinal space (US only) | Proportion of subjects with successful delivery of BSS or BSS PLUS to subretinal space | Day 1 | 
| Rate of successful delivery of GT005 to the subretinal space (US only) | Proportion of subjects with successful delivery of GT005 to subretinal space | Day 1 | 
| Incidence of device-related AEs and SAEs (US only) | Proportion of subjects with device related AEs and SAEs after subretinal delivery with Orbit SDS | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dry Age-related Macular Degeneration (Dry AMD), AMD, Atrophic AMD, Geographic Atrophy (GA), Dry-AMD, Dry AMD