NG101 AAV Gene Therapy in Subjects With Wet Age-Related Macular Degeneration

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and preliminary efficacy of NG101 AAV gene therapy administered by subretinal injections into a single selected eye as a single selected dose for patients with wet age-related macular degeneration (wAMD).

Detailed Description
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This is a Phase 1/2a, multicenter, open-label, dose escalation study to evaluate the safety, tolerability, and preliminary efficacy of NG101 AAV gene therapy, administered by subretinal injection in patients with active wAMD symptoms. The study will be conducted at approximately 6 sites in Canada and the USA.

Official Title
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A Phase 1/2a Open-label Study to Evaluate Safety, Tolerability and Preliminary Efficacy of NG101 AAV Gene Therapy in Subjects With Wet Age-Related Macular Degeneration

Conditions
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Age-Related Macular Degeneration

Intervention / Treatment
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* Genetic: NG101 AAV gene therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects ≥ 50 and ≤ 89 years of age with a diagnosis of active subfoveal CNV secondary to wAMD in the Study Eye BCVA between 20/63 and 20/400 in the Study Eye, with BCVA decrement primarily attributable to wAMD Administration of at least 3 anti-VEGF injections in the past 6 months, the most recent of which was within 2 months prior to Screening. Must be pseudo phakic (status post cataract surgery) in the Study Eye Female subjects must be either: (1) of non-childbearing potential; or (2) of childbearing potential and using an acceptable method of birth control with a negative pregnancy test: Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to the performance of any study-related procedures Willingness and ability to comply with schedule for follow-up visits and postoperative evaluations Exclusion Criteria: CNV or macular edema in the Study Eye secondary to any causes other than AMD Any condition preventing visual acuity improvement in the Study Eye, e.g., fibrosis, atrophy, or retinal pigment epithelial tear in the center of the macula Any ophthalmic condition that precludes adequate ophthalmic examination or requires ancillary testing Retinal detachment or history of retinal detachment in the Study Eye Active uncontrolled glaucoma with intraocular pressure (IOP) ≥ 30 mmHg despite treatment with more than 2 glaucoma medications, advanced glaucoma with cup-to-disc ratio of ≥ 0.9, visual field defects secondary to glaucoma that involve the macula, and/or optic atrophy from glaucoma History of intravitreal therapy in the Study Eye, such as intravitreal steroid injection or an investigational product, other than anti-VEGF therapy, in the 6 months prior to Screening History of vitrectomy, trabeculectomy, glaucoma tube-shunt procedure, minimally invasive glaucoma surgery (MIGS) device, or other filtration surgery in the Study Eye Any prior treatment with photodynamic therapy or retinal laser for the treatment of wAMD Any prior therapeutic radiation in the region of the Study Eye such as whole brain radiation, proton beam radiation, gamma knife treatment, or plaque brachytherapy Any previous intraocular or refractive surgery on the Study Eye within 6 months Any previous gene therapy in the Study Eye Presence of an ocular implant in the Study Eye at Screening, excluding intraocular lens and custom flex iris prosthesis Any diabetic retinopathy or other retinal vascular disease including retinal vein occlusion, retinal artery occlusion, retinal arterial macro aneurysm, ocular ischemic syndrome, retinal vasculitis, vitritis, posterior uveitis Any medically uncontrolled diabetes, defined as HbA1C > 8.0 History of ocular melanoma History of any known inherited retinal disease Currently taking any anticoagulant therapy, which is deemed medically necessary and cannot be permanently stopped at least 2 weeks prior to NG101 injection, excluding prophylactic low-dose aspirin therapy Any underlying systemic diseases as severe cardiovascular, cerebrovascular, and neurodegenerative diseases, including active malignancy and immunocompromised conditions. Active hepatitis B or C History of human immunodeficiency virus (HIV), active tuberculosis, and/or syphilis Any significant illness that would preclude study compliance and follow-up Subjects who, in the Investigator's opinion, lack the mental capacity to provide written informed consent for study participation

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 89 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: Dose Escalation Study with 3 dose cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NG101 Gene Therapy Group 1<br>Single subretinal injection of 1x10^9 vector genomes of NG101 AAV gene therapy | Genetic: NG101 AAV gene therapy<br>* Sub retinal injection of NG101 (a non-replicating adeno-associated virus serotype 8 (AAV8) vector<br>* Other names: NG101;|
| Experimental: NG101 Gene Therapy Group 2<br>Single subretinal injection of 3x10^9 vector genomes of NG101 AAV gene therapy | Genetic: NG101 AAV gene therapy<br>* Sub retinal injection of NG101 (a non-replicating adeno-associated virus serotype 8 (AAV8) vector<br>* Other names: NG101;|
| Experimental: NG101 Gene Therapy Group 3<br>Single subretinal injection of 8x10^9 vector genomes of NG101 AAV gene therapy | Genetic: NG101 AAV gene therapy<br>* Sub retinal injection of NG101 (a non-replicating adeno-associated virus serotype 8 (AAV8) vector<br>* Other names: NG101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Incidence and severity of ocular and non-ocular adverse events (AEs) for each cohort | Day 0 (pre-treatment) and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ocular and Non -Ocular Adverse Events after week 24 | Incidence and severity of ocular and non-ocular AEs after Week 24 to Week 260 for each cohort | Day 0 (pre-treatment) and from Week 24 to Week 260 | 
| Systemic Immunogenic Response | Change in concentration of expressed aflibercept protein in vitreous samples | Day 0, Week 12, 24, 52, and 104 | 
| Systemic Immunogenic Response | Change in concentration of expressed aflibercept protein in serum samples | Day -7 Weeks 4, 12, and 104 | 
| Systemic Immunogenic Response | Change in AAV vector (NG101) genome copies as measured by PCR in blood samples | Day -7, Week 4, and week 12 | 
| Systemic Immunogenic Response | Change in concentration of Anti-NG101 Transgene protein antibodies, Anti-AAV8 Neutralizing antibodies, and Anti-AAV8 Antibodies in serum samples | Day -7, Week 4, week 8, week 12, week 24, week 52, and week 104 | 
| Signs of CNV Activity | Change of 1 or more signs of CNV activity assessed by Optical coherence tomography | At every visit from Screening through Week 104 | 
| Central Retinal Thickness (CRT) | Change in CRT assessed with OCT | from Screening to Weeks 260 | 
| Best Corrected Visual Acuity (BCVA) | Change in BCVA assessed with Early Treatment Diabetic Retinopathy Study (ETDRS) scale | from Screening to Weeks 260 | 
| Cumulative Number of Rescue Therapy Injections | The cumulative number of rescue therapy injections per subject to maintain CNV control | From Week 24 to Week 260 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wet macular degeneration