4D-150 in Patients With Neovascular (Wet) Age-Related Macular Degeneration

Study Overview
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Brief Summary
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Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment

Detailed Description
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This Phase 1/2 trial is a prospective, multicenter, Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment who have demonstrated a clinical response consistent with anti-VEGF activity. The trial consists of Dose Escalation, Dose Expansion, Steroid Optimization and Population Extension Cohorts. After receiving one time administration of 4D-150 by intravitreal injection, subjects will undergo assessments at monthly intervals for 24 months to assess safety and efficacy outcomes. Only subjects that received 4D-150 will then enter a long-term follow-up (LTFU) period to assess long-term safety of 4D-150 gene therapy and duration of clinical activity through year 5 (60 months).

Official Title
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A Phase 1/2 Dose-Escalation and Randomized, Controlled, Masked Expansion Trial of Intravitreal 4D-150 Gene Therapy in Adults With Neovascular (Wet) Age-Related Macular Degeneration

Conditions
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Neovascular (Wet) Age-Related Macular Degeneration

Intervention / Treatment
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* Biological: 4D-150 IVT
* Biological: Aflibercept IVT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥50 years of age Diagnosed with macular CNV secondary to AMD BCVA ETDRS Snellen equivalent for dose escalation between  20/32 and  20/320, or for dose expansion and population extension between  20/25 and 20/200, for steroid optimization between  20/25 and  20/640 Currently receiving anti-VEGF treatment in the study eye and has demonstrated a clinical response consistent with anti-VEGF activity within 12 months prior to screening Exclusion Criteria: Any condition preventing visual acuity improvement in the study eye Prior treatment with photodynamic therapy or retinal laser in the study eye History of uveitis in either eye Any other pre-existing eye conditions or surgical complications that would preclude participation in an interventional clinical trial or interfere with the interpretation of study endpoints

Ages Eligible for Study
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Minimum Age: 50 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: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: In Dose Escalation, the safety and tolerability of multiple dose levels of 4D-150 will be examined following an open-label, 3+3 dose escalation design (n=3-5 per dose level). In Dose Expansion, subjects (n=50) will be randomized to receive one of 2 dose levels of 4D-150 (n=20 for each dose level) based on results from Dose Escalation, or aflibercept (n=10). In Steroid Optimization (n=up to 40) and Population Extension (n=up to 45) Cohorts, subjects will be assigned sequentially to receive 4D-150 at doses cleared by the DSMC.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4D-150 Dose Escalation up to 4 dose levels<br>4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1. | Biological: 4D-150 IVT<br>* 4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept<br>|
| Experimental: 4D-150 Dose Expansion Dose 1<br>4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1. | Biological: 4D-150 IVT<br>* 4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept<br>|
| Experimental: 4D-150 Dose Expansion Dose 2<br>4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1. | Biological: 4D-150 IVT<br>* 4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept<br>|
| Active Comparator: 4D-150 Dose Expansion Control<br>Aflibercept at a fixed regimen will be administered. | Biological: Aflibercept IVT<br>* Commercially available Active Comparator Other Name: Eylea<br>|
| Experimental: 4D-150 Steroid Optimization<br>4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1. | Biological: 4D-150 IVT<br>* 4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept<br>|
| Experimental: 4D-150 Population Extension Dose 1<br>4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1. | Biological: 4D-150 IVT<br>* 4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept<br>|
| Experimental: 4D-150 Population Extension Dose 2<br>4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1. | Biological: 4D-150 IVT<br>* 4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), including clinically significant changes in safety parameters |  | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to receiving the first supplemental aflibercept injection |  | 52 weeks | 
| Percentage of subjects requiring supplemental aflibercept injections over 52 weeks |  | 52 weeks | 
| Number of supplemental aflibercept injections over 52 weeks |  | 52 weeks | 
| Change from baseline in BCVA over time (up to 52 weeks) as assessed using the ETDRS Visual Acuity Chart |  | 52 weeks | 
| Change from baseline in central subfield thickness (CST) over time (up to 52 weeks) measured by spectral domain optical coherence tomography (SD-OCT) |  | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMD, Age-related macular degeneration, Exudative AMD, Exudative age-related macular degeneration, Neovascular AMD, Neovascular age-related macular degeneration, Wet age-related macular degeneration, Wet macular degeneration, Wet AMD, wAMD, Retinal gene therapy, Intravitreal gene therapy