Phase 3 Randomized Trial of Intravitreal 4D-150 vs. Aflibercept in Adults with Neovascular Age-Related Macular Degeneration
- Trial ID
- 2025-521349-25-00
- Protocol
- 4D-150-C004
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the non-inferiority of a single intravitreal injection of 4D-150 compared to aflibercept administered every 8 weeks in terms of the mean change in best-corrected visual acuity (BCVA) from baseline to Week 52 in adults with neovascular age-related macular degeneration. The study also evaluates the efficacy, safety, and durability of the intervention. Additional assessments include the evaluation of immunogenicity.
Participants
This clinical trial involves 182 participants diagnosed with neovascular age-related macular degeneration. The study population consists of both male and female adults, specifically those aged 50 years or older. Eligible subjects must present with active subfoveal, juxtafoveal, or extrafoveal macular neovascularization characterized by exudation on optical coherence tomography. Inclusion criteria require a specific best-corrected visual acuity range and a central subfield thickness of 500 μm or less in the study eye. Participants may be treatment-naïve or have a history of limited intravitreal anti-VEGF therapy. Additionally, subjects must agree to use barrier methods of contraception for three months following the initial administration to mitigate potential fluid transmission risks.
Plans and Procedures
This Phase 3, randomized, double-masked, active-controlled trial is designed to evaluate the efficacy, safety, and durability of a single intravitreal injection of zunibergene rocparvovec compared to aflibercept administered every 8 weeks in adults with macular neovascularization secondary to age-related macular degeneration. The primary efficacy endpoint is the mean change from baseline in best-corrected visual acuity at Week 52. The study methodology involves a screening visit to assess eligibility, including requirements for visual acuity, central retinal thickness, and lesion characteristics via optical coherence tomography and fluorescein angiography. Following screening, participants receive their assigned treatment. Secondary endpoints include the mean annualized number of injections and changes in retinal thickness through Week 104. Participant involvement extends through the primary assessment period, with data collected to monitor clinical response and safety. The trial is expected to conclude by January 2029.
Treatment
Zunibergene rocparvovec, referred to as 4D-150, is an experimental solution for injection administered via a single intravitreal route. The dosage is specified as 3 ×10^10 vector genomes.
Aflibercept is used as an active comparator. It is provided as an Eylea 40 mg/mL solution for injection in a pre-filled syringe. The administration involves a 2 mg dose via intravitreal use on a Q8W schedule.
Difluprednate is utilized as an auxiliary background treatment. It is administered through topical use.
Efficacy
The primary efficacy objective is to evaluate the non-inferiority of a single injection of 4D-150 compared to aflibercept in adults with macular neovascularization secondary to age-related macular degeneration. The primary endpoint is the mean change from baseline in best-corrected visual acuity (BCVA) as measured by the ETDRS letter score at Week 52.
Secondary efficacy assessments include:
- The mean annualized number of aflibercept injections from Week 4 through Weeks 52 and 104.
- The incidence and timing of aflibercept injections from Week 4 through Weeks 52 and 104.
- The proportion of subjects in the 4D-150 arm not requiring aflibercept injections from Week 4 through Weeks 52 and 104.
- The time to first aflibercept injection after Week 4 in the 4D-150 arm.
- The mean change from baseline in central subfield thickness (CST) over time through Weeks 52 and 104.
- The mean change from baseline in BCVA ETDRS letter score over time through Weeks 52 and 104.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent before any protocol-specific assessment is performed
- Ability to comply with the protocol-specified procedures and visits, in the Investigator’s judgment
- ≥50 years of age at time of consent
- Agree to use a barrier method (e.g. condom) during intercourse for 3 months after Day 1 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period.
- MNV secondary to nAMD with IVT anti-VEGF treatment history in the study eye, defined as EITHER: a. Treatment naïve, i.e. no prior IVT anti-VEGF therapy, OR b. Previously treated with no more than 4 IVT anti-VEGF injections due to nAMD and received diagnosis of nAMD no more than 6 months prior to the Screening Visit AND Documented evidence of anatomical improvement and visual stability/improvement in response to previous IVT anti-VEGF treatment, as determined by the Investigator
- Active subfoveal MNV or juxtafoveal/ extrafoveal MNV with a subfoveal component (where activity is defined as evidence of SRF, IRF, subretinal hyperreflective material, or leakage) identified by fluorescein angiography (FA) or spectral domain optical coherence tomography (SD-OCT) , in the study eye, at the Screening Visit confirmed by the Reading Center
- MNV lesion in the study eye of any type (i.e. predominantly classic, minimally classic, or occult [including polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) at the Screening Visit, confirmed by the Reading Center, which exhibits all of the following characteristics: a. Total lesion size of 9 disc areas or less (inclusive of blood, fibrosis, atrophy or neovascularization) on FA b. MNV component area at least 50% of total lesion size on FA c. MNV exudation (i.e. presence of fluid) on SD-OCT
- CST ≤500μm in the study eye at Screening visit, confirmed by the Reading Center
- Demonstrated clinical response to aflibercept and functional stability in the study eye: a. From Week −5 to Week −1: a ≥ 15% reduction in CST or complete resolution of IRF and/or SRF, determined by SD-OCT and confirmed by the Reading Center b. At Day 1: BCVA measurement must not have decreased by 15 ETDRS letters or more compared to BCVA at the Screening visit
- BCVA between 25 and 78 ETDRS letters, inclusive (20/320-20/32 Snellen equivalent) in the study eye at the Screening Visit
- BCVA ≥34 ETDRS letters (~20/200 Snellen equivalent) in the contralateral eye at the Screening Visit
- Study eye amenable to IVT injection identified by the Investigator prior to Week −5
Exclusion Criteria
- Ocular Conditions: a. MNV due to causes other than nAMD in either eye b. Fibrosis, atrophy, or subretinal hemorrhage in the foveal central subfield (1 mm diameter), retinal pigment epithelial tear, macular hole, vitreomacular traction, Stargardt disease, drug induced maculopathies, macular edema not due to nAMD, or retinal neovascular occlusion, in the study eye as determined by the Reading Center at the Screening Visit c. History of retinal detachment in the study eye d. Any active ocular inflammation or active ocular or periocular infection in either eye (e.g. infectious blepharoconjunctivitis) at any time between the Screening Visit and Randomization. e. History of intraocular inflammation (e.g. endophthalmitis), or uveitis in either eye, or presence of any cells or flare in the anterior chamber or any cells or haze in the vitreous in the study eye at any time prior to Randomization. f. History of latent ocular or periocular infection (e.g. ocular syphilis, herpetic eye disease) g. History of steroid-induced ocular hypertension or steroid-induced glaucoma in either eye h. Intraocular pressure (IOP) <6 mmHg (by Goldmann tonometry) in the study eye i. Any history of ocular hypotony or ciliary body dysfunction/pathology in either eye as determined by the Investigator j. Glaucoma or intraocular hypertension requiring more than 2 topical medications for control (defined as IOP <22 mm Hg) in the study eye k. Any other pre-existing eye conditions or surgical complications that in the opinion of the Investigator would preclude participation in an interventional clinical trial or interfere with the interpretation of study endpoints.
- Ocular Treatments/Interventions in the Study Eye: a. Any prior or concomitant treatment for MNV or vitreomacular-interface abnormalities, other than allowed prior IVT anti-VEGF, including, but not restricted to IVT therapy (e.g. steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention b. Aphakia, pseudophakia with anterior chamber intraocular lens, or significant violation of the posterior capsule with the exception of yttrium-aluminum garnet (YAG) with posterior chamber lens implantation c. History of the following surgeries and procedures: cataract surgery associated with complications, incisional glaucoma surgery (e.g. trabeculectomy), glaucoma tube or shunt placement, pars plana vitrectomy, corneal transplant, sub-macular surgery, retinal detachment surgery, ranibizumab injection implant (Susvimo™), macular laser or extensive panretinal photocoagulation, radiation therapy. d. Uncomplicated cataract surgery, YAG laser posterior capsulotomy, or glaucoma laser treatment in the 3 months prior to the Screening Visit e. Any concurrent intraocular condition (e.g. amblyopia, aphakia, retinal detachment, cataract, diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the opinion of the Investigator, could either reduce the potential for visual improvement or require medical or surgical intervention during the study f. Any prior exposure to brolucizumab
- Prior/Concomitant Medications (Systemic or in Either Eye): a. Receiving or anticipated to receive a systemic drug that inhibits VEGF pathways, e.g. bevacizumab, sunitinib, pazopanib b. Ever received or anticipated to receive IVT complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol) in either eye c. History of serious allergy, hypersensitivity, or contraindications to fluorescein and/or trial-specified interventions (e.g. 4D-150 excipients, aflibercept, povidone-iodine)
- Prior Interventional Trial Participation: a. Received an investigational drug, agent, device, or therapy (ocular or non-ocular) in the 3 months or at least 5 half-lives (whichever is longer) prior to Screening b. Any prior gene therapy (ocular or non-ocular) and/or ocular stem cell therapy
- Systemic Conditions and Considerations: a. Major illness or major surgical procedure in the 28 days prior to the Screening Visit b. Uncontrolled blood pressure, defined as resting average systolic value ≥160 mmHg and/or average diastolic value ≥100 mmHg, based on triplicate measurements at 1-minute intervals at Screening. If blood pressure exceeds these values, measurements can be repeated up to 3 times within the Screening Visit window. Blood pressure medications should be at stable dose/regimen for at least 28 days prior to Screening. c. Acute coronary syndrome, myocardial infarction or coronary artery revascularization, cerebrovascular accident, transient ischemic attack within 6 months of the Screening Visit d. Any history of syphilis (whether or not treated) e. History of autoimmune condition that may predispose to the development of uveitis, including, but not limited to Behcet disease, spondyloarthropathies, multiple sclerosis, HLA-B27 syndrome, Crohn’s disease, sarcoidosis, lupus, or rheumatoid arthritis f. Any documented active or suspected malignancy, or history of malignancy within 12 months prior to Screening, except appropriately treated/resected localized tumor with low risk for recurrence (e.g. treated local basal cell or squamous cell carcinoma of the skin, noninvasive bladder cancer, prostate cancer stage 1 or 2 with stable prostate-specific antigen for 6 months, or any cancer considered surgically cured) g. Intercurrent illness or condition that, in the opinion of the Investigator, may place the subject at an unacceptable risk, prevent the subject from completing the trial, or confound interpretation of trial results h. Female of child-bearing potential, per (CTFG, 2020).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 29 Dec 2025 | 14 |
 France | Recruiting | 29 Dec 2025 | 12 |
 Germany | Recruiting | 29 Dec 2025 | 16 |
 Hungary | Recruiting | 29 Dec 2025 | 100 |
 Italy | Recruiting | 29 Dec 2025 | 10 |
 Latvia | Recruiting | 29 Dec 2025 | 60 |
 Lithuania | Recruiting | 29 Dec 2025 | 58 |
 Portugal | Recruiting | 29 Dec 2025 | 18 |
 Spain | Recruiting | 29 Dec 2025 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Eylea 40 mg/mL solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVITREAL USE | 2 | 9999 | PRD3456172 |
4D-150 | Test | SOLUTION FOR INJECTION | INTRAVITREAL USE | 9999 | 9999 | PRD12495478 |
Eylea 40 mg/mL solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVITREAL USE | 2 | 9999 | PRD3117105 |
Eylea 40 mg/mL solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVITREAL USE | 2 | 9999 | PRD3117102 |
DIFLUPREDNATE | Other | — | TOPICAL USE | 9999 | 20 | SUB07131MIG |
Eylea 40 mg/mL solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAVITREAL USE | 2 | 9999 | PRD701247 |