Inclusion Criteria

Participants will be considered eligible for participation in the study if all of the following inclusion criteria are satisfied:

General Inclusion Criteria:

1. Male or female participants, ≥18 years of age.
2. Participants with a diagnosis of diabetes mellitus (DM; Type 1 or Type 2), as defined by the World Health Organization (WHO) and/or American Diabetes Association with an onset of disease at any time prior to enrollment. Stable DM currently managed with use of oral antihyperglycemic agents, insulin, or other injectable drugs.
3. Hemoglobin A1c (HbA1c) <10% at the Screening Visit.
4. Able to understand, and willingness to sign, the informed consent and to provide access to personal health information via Health Insurance Portability and Accountability Act (HIPAA) authorization.
5. Willingness and ability to comply with all scheduled visits, restrictions, and assessments.
6. For women of childbearing potential, or men with female partners of childbearing potential, agreement to the use of an appropriate form of contraception at the Screening Visit and for the duration of the study.

Ocular Inclusion Criteria for the Study Eye:

7. Previously diagnosed with macular edema associated with diabetic retinopathy (DR) at any time. DME is defined as macular thickening by spectral domain-optical coherence tomography (SD-OCT) involving the center of the macula: central subfield retinal thickness (CST) of ≥325 µm at the Screening Visit as confirmed by the Central Reading Center (CRC).
8. For previously treated participants: demonstrated anatomical response (ie, reduction in fluid on SD-OCT) to previous treatment with anti-VEGF medications (ie, aflibercept, bevacizumab, faricimab, ranibizumab, or biosimilars) in the study eye.
9. For previously treated participants: at least 1 injection of anti-VEGF in the past 12 months, the most recent anti-VEGF treatment for DME must not have been administered less than 12 weeks prior to the Screening Visit.
10. Best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 35 letters (20/200 Snellen equivalent) to 78 letters (20/32 Snellen equivalent) in the study eye at the Screening Visit and at Baseline (Day 1).
11. Sufficiently clear ocular media and adequate pupillary dilation to allow acquisition of good quality CFPs (including ETDRS 7 modified fields or 4 wide-angle fields to permit grading of diabetic retinopathy and assessment of the retina) and other imaging modalities.

Exclusion Criteria:

Participants who meet any of the following exclusion criteria will be excluded from the study. All SD-OCT, CFP, and FA criteria listed below will be confirmed by the Central Reading Center (CRC) at the Screening Visit.

Ocular Exclusion Criteria for the Study Eye Only:

1. Any signs of high-risk PDR on clinical examination as per the Investigator, or imaging evaluated by the CRC at the Screening Visit, and defined as:
   1. Any vitreous or pre-retinal hemorrhage due to diabetic retinopathy.
   2. Neovascularization elsewhere (NVE) ≥1/2 disc area within an area equivalent to the standard mydriatic ETDRS 7-field on clinical examination or on color fundus photography (CFP).
   3. Neovascularization of the optic disc (NVD) ) ≥1/3 disc area on clinical examination.
   4. Any neovascularization of the iris (NVI).
2. Any evidence or documented history of panretinal photocoagulation (PRP) treatment or macular laser photocoagulation within 12 weeks prior to the Screening Visit.
3. For previously treated participants: IVT anti-VEGF treatment within 12 weeks prior to the Screening Visit.
4. Evidence of macular edema due to any cause other than diabetes.
5. Ocular pathology that prohibits or an inability to obtain ocular images (ie, SD-OCT) as judged by the CRC.
6. Intraocular surgery (including cataract surgery or radiotherapy) in the study eye within 12 weeks prior to the Screening Visit.
7. Any prior intraocular or periocular (subtenon) steroid use within 6 months prior to the Screening Visit.
8. Any history of EYP-1901 IVT insert or Iluvien, Ozurdex, or Susvimo implants at any time prior to the Screening Visit; history of IVT anti-VEGF brolucizumab within 12 months prior to the Screening visit.
9. History of glaucoma-filtering surgery, tube shunts, or minimally invasive glaucoma surgery (MIGS).
10. Uncontrolled ocular hypertension or glaucoma in the study eye (defined as intraocular pressure [IOP] >25 mmHg or a cup to disc ratio ≥0.8 despite treatment with 2 or more classes of antiglaucoma medication and any such condition which the Investigator feels may require glaucoma-filtering surgery while in the study.
11. Any current or history of ocular disease other than DME that may confound assessment of the macula or affect central vision (eg, significant macular ischemia, subretinal fibrosis or scar, age-related macular degeneration, choroidal neovascularization, geographic or foveal atrophy, dense subfoveal hard exudates, retinal embolus, retinal vein occlusion, uveitis, angioid streaks, histoplasmosis, active or inactive cytomegalovirus, pathological myopia, retinal detachment, vitreomacular traction, macular hole, significant cataract, preretinal fibrosis, or epiretinal membrane involving the fovea or disrupting the macular architecture of the study eye).
12. Any concurrent intraocular condition (eg, cataract or glaucoma) that, in the opinion of the Investigator, would either require surgical intervention during the study to prevent or treat visual loss that might result from that condition or impact interpretation of the study results.
13. Historical or active intraocular inflammation (grade trace or above) in the study eye, other than expected findings from routine cataract surgery.
14. History of vitreoretinal surgery
15. Aphakia or pseudophakia with the absence of the posterior capsule in the study eye (yttrium aluminum garnet [YAG] capsulotomy is permitted).
16. History of corneal transplant.

Ocular Exclusion Criteria for Either Eye:

17. BCVA using ETDRS charts <30 letters (20/250 Snellen equivalent) in the fellow eye.
18. Prior participation in a clinical trial involving investigational anti-angiogenic drugs administered in either eye within 16 weeks prior to the Screening Visit.
19. Prior participation in a clinical trial involving investigational ocular gene therapy trial for either eye.
20. Any history of idiopathic or immune-mediated uveitis in either eye.
21. Active ocular inflammation or active infection in either eye at Baseline (Day 1).

General Exclusion Criteria:

22. The presence of any other systemic or ocular condition which, in the judgement of the Investigator, could make the participant inappropriate for entry into this study.
23. Uncontrolled blood pressure (defined as systolic >180 mmHg and/or diastolic >100 mmHg), based on the average of 3 readings taken with the participant in a resting state.
24. Untreated DM or initiation of anti-diabetic oral medication, insulin or other injectable drugs within 3 months prior to the Screening Visit or anticipated change of anti-diabetic medications during the study.
25. Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis within 6 months prior to the Screening Visit or anticipated to require hemodialysis or peritoneal dialysis at any time during the study.
26. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of EYP-1901 IVT insert or aflibercept or may impact interpretation of the study results or exposes the participant at risk for complications in the opinion of the Investigator.
27. Current treatment for any active systemic infection.
28. Previous use of systemic anti-VEGF agents at any time in the past 3 months.
29. Use of oral corticosteroids (prednisone >10 mg/day or equivalent) within 30 days prior to the Screening Visit.
30. Transient ischemic attack, stroke, any cerebral vascular accident or myocardial infarction within the past 6 months prior to the Screening Visit.
31. Any malignancy or active cancer within the past 12 months; however, treated basal cell carcinoma and squamous cell carcinoma may be excluded from this criterion at the discretion of the Investigator.
32. Intolerance, contraindication, or hypersensitivity to topical anesthetics, dyes, povidone iodine, mydriatic medications, or any of the ingredients of the EYP-1901 IVT insert.
33. Hypersensitivity to aflibercept and/or its excipients.
34. History of allergy to fluorescein, not amenable to treatment.
35. Historical or active diagnosis of any medical or psychological condition that could interfere with the ability of the participant to give informed consent, or to comply with study or follow-up procedures.
36. Previous participation in any ocular r non-ocular (systemic) disease studies of investigational drugs within 30 days prior to the Screening Visit (excluding vitamins and minerals).
37. Use of anti-mitotic or anti-metabolite therapy for the treatment of cancer within 30 days or 5 elimination half-lives of the Screening Visit, whichever is longer.
38. Requirement for continuous use of any protocol-prohibited medications or treatments.
39. Pregnant or nursing females; females of childbearing potential who are unwilling to use an acceptable method of contraception during the study outlined in the protocol.

Inclusion Criteria
Individuals eligible to participate in the trial must meet the following inclusion criteria:

General Inclusion Criteria

1. Signed informed consent before any protocol-specific assessment is performed
2. Ability to comply with the protocol-specified procedures and visits, in the Investigator’s judgment
3. ≥50 years of age at time of consent
4. 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.

Ocular Inclusion Criteria

1. MNV secondary to nAMD with IVT anti-VEGF treatment history in the study eye, defined as EITHER:
   1. Treatment naïve MNV secondary to nAMD in the study eye OR
   2. 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 IV anti-VEGF treatment, as determined by the Investigator
2. Active subfoveal MNV or juxtafoveal/ extrafoveal MNV with a subfoveal component (where activity is defined as evidence of SRF, subretinal hyperreflective material, or leakage) identified by fundus fluorescein angiography (FA) or spectral domain optical coherence tomography (SD-OCT) in the study eye, at the Screening Visit, confirmed by the Reading Center
3. 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:
   1. Total lesion size of 9 disc areas or less (inclusive of blood, fibrosis, atrophy or neovascularization) on FA
   2. MNV component area at least 50% of total lesion size on FA
   3. MNV exudation (i.e. presence of fluid) on SD-OCT
4. CST ≤500µm in the study eye at Screening visit, confirmed by the Reading Center
5. Demonstrated clinical response to aflibercept and functional stability in the study eye:
   1. 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
   2. At Day 1: BCVA measurement must not have decreased by 15 ETDRS letters or more compared to BCVA at the Screening visit
6. BCVA between 25 and 78 ETDRS letters, inclusive (20/320 – 20/32 Snellen equivalent) in the study eye at Screening Visit
7. BCVA ≥34 ETDRS letters (~20/200 Snellen equivalent) in the contralateral eye at the Screening Visit
8. Study eye amenable to IVT injection identified by the Investigator prior to Week −5

Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate:

Ocular Exclusion Criteria

1. Ocular Conditions:
   1. MNV due to causes other than nAMD in either eye
   2. 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
   3. History of retinal detachment in the study eye
   4. 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
   5. 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
   6. History of latent ocular or periocular infection (e.g. ocular syphilis, herpetic eye disease)
   7. History of steroid-induced ocular hypertension or steroid-induced glaucoma in either eye
   8. IOP < 6mmHg (by Goldman tonometry) in the study eye
   9. Any history of ocular hypotony or ciliary body dysfunction/pathology in either eye as determined by the Investigator
   10. Glaucoma or intraocular hypertension requiring more than 2 topical medications for control (defined as IOP <22 mm Hg) in the study eye
       
       Note: Fixed combination glaucoma eye drops (e.g. COSOPT®, SIMBRINZA®) are considered two medications
   11. 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.
2. Ocular Treatments/Interventions in the Study Eye:
   1. Any prior or concomitant treatment for MNV or vitreomacular-interface abnormalities, including, but not restricted to IVT therapy (e.g. anti-VEGF, steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention
   2. 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
   3. 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.Note: Laser to treat peripheral retinal tears is not exclusionary
   4. Uncomplicated cataract surgery, YAG laser posterior capsulotomy, or glaucoma laser treatment in the 3 months prior to the Screening Visit
   5. 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 studyNote: Lens nuclear opacity ≥ 3.0 or posterior subcapsular opacity >0 by AREDS or any significant lens opacity as determined by the Investigator is exclusionary
   6. Any prior exposure to brolucizumab

Additional Exclusion Criteria

3. Prior/Concomitant Medications (Systemic or in Either Eye):
   1. Receiving or anticipated to receive a systemic drug that inhibits VEGF pathways, e.g. bevacizumab, sunitinib, pazopanib
   2. Ever received or anticipated to receive IVT complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol) in the either eye
   3. History of serious allergy, hypersensitivity, or contraindications to fluorescein and/or trial-specified interventions (e.g. 4D-150 excipients, aflibercept, povidone-iodine)
4. Prior Interventional Trial Participation:
   1. 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
   2. Any prior gene therapy (ocular or non-ocular) and/or ocular stem cell therapy
5. Systemic Conditions and Additional Considerations:
   1. Major illness or major surgical procedure in the 28 days prior to the Screening Visit
   2. 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.
   3. Acute coronary syndrome, myocardial infarction or coronary artery revascularization, cerebrovascular accident, transient ischemic attack within 6 months of the Screening Visit
   4. Any history of syphilis (whether or not treated)
   5. 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
   6. 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)
   7. 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
   8. Female of child-bearing potential (per (CTFG, 2020)), defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Individual-Level Criteria
Inclusion

Individuals must meet all of the following inclusion criteria to be eligible to participate in the run-in phase of the study:

1. Age ≥ 50 years
2. Have the capacity to consent on his/her own behalf and follow instructions
3. Must understand English or Spanish
4. At least one eye that meets the study eye criteria listed below
5. Ability to cooperate with required visit procedures
6. Able to successfully and independently complete at least one self-scanning session on the Home OCT device located at the enrolling clinical site
7. Participant’s home has a table with a smooth, flat surface close to an electrical outlet to support placement of the Home OCT device for 2 years (device dimensions are 9.8” wide × 14.2” deep × 16.9” high)
8. Able to set up the Home OCT device by themselves or with assistance from others in their household (device is 16 pounds without packaging, 17.8 pounds with packaging)
9. Lives in an area with cell phone reception of 4G or above, or the location in which the Home OCT device will be placed has Wi-Fi connectivity (for the Home OCT data to be properly uploaded to the cloud)
10. Has a telephone number (home or cell) for Notal to call and provide Home OCT assistance and reminders
11. Participant is willing to perform once daily Home OCT monitoring tests for 2 years without significant interruption (such as travel of more than 14 days at a time)
12. Patients who spend part of the year in a different location will be permitted to enroll in the study if another DRCR clinical site is located near their second home, and they are willing to be seen at that location during follow-up. Additionally, their second home must meet the requirements for Home OCT device use specified above.

 Exclusion

1. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status that may preclude successful completion of follow-up)
2. Known allergy or hypersensitivity to any component of the study drug or any drug used in the injection prep (including povidone iodine prep)
3. Participation in an investigational trial that involved treatment within 30 days of screening with any drug that has not received regulatory approval for the indication being studied.
   1. The participant should not receive or use any other drug or device in the study eye that is not FDA approved during the study.
4. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years
   1. Women who are potential study participants should be questioned about the potential for pregnancy at baseline and prior to each injection. Women of childbearing potential will be required to have pregnancy testing or use an acceptable method of pregnancy prevention. Pregnancy test is required for all women of childbearing potential at screening. Investigator judgment is used to determine when a pregnancy test is needed during follow-up.
   2. Childbearing potential is defined as less than 12 months post-menopausal or not surgically sterile.
   3. Acceptable methods of pregnancy prevention are condom with spermicide, hormonal contraception, or IUDs.
5. Participant is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next 2 years
6. Use of pentosan polysulfate, chloroquine, or hydroxychloroquine (Plaquenil®) within the last 5 years, or planned use during the next 2 years
7. Use, or plan to use, any at-home device related to monitoring nAMD not provided by the study, including ForeseeHome®, within the next 2 years
   1. Potential participants currently using ForeseeHome® may be enrolled if they 378 agree to stop use prior to randomization.

Study Eye Criteria
Inclusion

1. Best corrected E-ETDRS visual acuity ≥24 ETDRS letters (approximately 20/320 or better (Snellen))
2. Previously untreated, active MNV lesion (i.e., any intraretinal or subretinal fluid on OCT) secondary to age-related macular degeneration
3. MNV or sequelae of the MNV (i.e., pigment epithelium detachment, subretinal or sub-RPE hemorrhage, or subretinal, sub-RPE or intraretinal fluid) involving the foveal center
4. ≥ 1 intermediate drusen (>63 microns) in either eye OR late AMD (MNV or macular atrophy) in the contralateral eye

 Exclusion

1. History of rhegmatogenous retinal detachment, macular hole, or lamellar hole
2. History of vitrectomy
3. YAG capsulotomy performed within 1 month prior to the baseline visit.
4. History of trabeculectomy or Baerveldt or Ahmed tube for uncontrolled glaucoma
5. Minimally Invasive Glaucoma Surgery (MIGS) devices are allowed
6. History of retinal vein occlusion
7. Previous treatment for MNV (intravitreal injection of any anti-VEGF or anti-VEGF/anti-Ang2 agent, or any other AMD therapy)
8. Prior treatment with intravitreal injection of any anti-VEGF or anti-VEGF/anti-Ang2 agent or with macular laser for any indication
9. Treatment with intravitreal corticosteroids within the last 6 months
10. Current use of pegcetacoplan
11. Intraocular surgery (including cataract surgery) within 4 months prior to the baseline visit, or anticipated within the next 6 months
12. Active or recent (within 4 weeks) intraocular inflammation (grade trace or above)
13. Any condition that may preclude adequate imaging of the macula (e.g., dense cataract or other media opacity, severe ptosis)
14. The Notal Vision Monitoring Center must review the in-office Home OCT scan to confirm no pathology is affecting the quality of the image prior to randomization
15. Fibrosis or macular atrophy involving the foveal center
16. Epiretinal membrane distorting the foveal center
17. Significant vitreomacular traction in the foveal center
18. Aphakia
19. MNV due to other causes, such as ocular histoplasmosis, central serous retinopathy, or pathologic myopia
20. Retinal pigment epithelial tear involving the foveal center
21. Current vitreous hemorrhage
22. Polypoidal choroidal vasculopathy (PCV)
23. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis
24. High myopia; defined as 8 or more diopters of myopia or clinical evidence of high myopia
25. Uncontrolled glaucoma
26. Intraocular pressure must be<30 mmHg, with no more than one topical glaucoma medication, and no documented glaucomatous field loss for the eye to be eligible
27. Diabetic retinopathy worse than diabetic retinopathy severity level 35
28. Progressive retinal or other ocular diseases, such as amblyopia or ischemic optic neuropathy, which can affect visual acuity or are likely to affect visual acuity within the next 2 years
29. Any concurrent retinal vascular disease such as that, in the opinion of the investigator, could require medical or surgical intervention during the 2-year follow-up period

Inclusion Criteria
Ocular Inclusion Criteria

1. Patients with MESI, with a central subfield thickness (CST) of ≥320 microns on SD-OCT in the Study Eye at Screening.
2. BCVA score of ≥25 and ≤78 ETDRS letters (between ~20/25 and 20/320 Snellen equivalent) in the Study Eye at Screening.
3. PEAK: Patients with MESI, with a CST of ≥400 microns on SD-OCT in the Study Eye at Day 1 and BCVA score of ≥25 and ≤70 ETDRS letters (between 20/40 and ~20/320 Snellen equivalent) in the Study Eye at Day 1.

4. 4. Active macular leakage in the Study Eye as evidenced by fluorescein angiogram at Screening.
   5. Diagnosis of active or inactive non-infectious intraocular inflammation, acute or chronic, in the Study Eye.
   6. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result of MESI.

Inclusion Criteria
At Screening Visit 1:

1. At least 50 years of age or older at Day 1.
2. Eligible to receive intraocular aflibercept therapy as per the FDA labels for the treatment of nAMD (Note: non-exudative CNV secondary to AMD is exclusionary)
3. Have adequate ocular media and adequate pupillary dilation in the study eye to permit good quality fundus imaging.
4. Treatment naïve juxtafoveal and/or subfoveal CNV secondary to nAMD with leakage involving the fovea prior to Screening, or have a diagnosis of nAMD in study eye within 4 months prior to or at screening and received 1 to 3 consecutive monthly (approximately every 4 weeks) anti-VEGF injections of any type (except Beovu®) with last injection approximately 4 weeks prior to Screening, with a CNV lesion of any type (i.e., predominantly classic, minimally classic, or occult [including polypoidal choroidal vasculopathy and retinal angiomatous proliferation]) that exhibits all of the following characteristics in the study eye at Screening as confirmed by CRC: (Note: For subjects who screen failed in the OTX-TKI-2023-AMD-301 study, or recently diagnosed with nAMD [within 4 months prior to screening], historical images could be used for eligibility assessment.)
   1. For treatment naïve or experienced study eye, A total lesion size (including blood, atrophy, fibrosis, and neovascularization) of ≤9-disc areas on fundus FA. Any macular hemorrhage should be resolved by Baseline (Day 1) prior to randomization, as assessed by the Investigator.
   2. For treatment naïve study eye, the CNV component area must be ≥50% of the total lesion size on FA
   3. For treatment naïve or experienced study eye, presence of active CNV confirmed on FA (evidence of leakage)
   4. For treatment naïve study eye, CNV exudation confirmed on SD-OCT (presence of intraretinal and/or subretinal fluid measured from ILM to RPE layer).
5. Have a BCVA ETDRS letter score of at least 34 or greater (approximately 20/200) in the study eye at Screening.
6. Have a CSFT ≤350 μm (measured from ILM to RPE layer) in the study eye at Week -12, confirmed by CRC.
7. Have a CSFT ≤ 350 μm (measured from ILM to RPE layer) in the study eye at Week -8 and < 35 μm increase from the lowest CSFT at any prior visits, confirmed by a CRC.
8. Are female who is postmenopausal for at least 12 months prior to Screening or surgically sterile; or male or female of childbearing potential willing to use two forms of adequate contraception from Screening until they exit the study.
9. Are able and willing to comply with all study requirements and visits.
10. Have provided written informed consent.

Exclusion Criteria

Individuals are not eligible for study participation if they meet any of the following criteria:

1. Presence of a disease other than CNV due to AMD in the study eye that could affect vision or safety assessments.
2. Monocular subject or BCVA score of <20 ETDRS letters or 20/400 in fellow eye at Screening.
3. Have evidence of a scar, fibrosis, or atrophy of >50% of the total lesion in the study eye.
4. Currently or previously treated with Syfovre® or Izervay™ for geographic atrophy in study eye. For fellow eye, treatment with Syfovre® or Izervay™ for geographic atrophy within 3 months prior to Screening.
5. Have previous laser photocoagulation or verteporfin photodynamic therapy (PDT) to the macula in the study eye.
6. Have history of intraocular surgery in the study eye including:
   1. cataract surgery or keratorefractive surgery (laser-assisted in-situ keratomileusis [LASIK], photorefractive keratectomy [PRK], etc.) or any anterior segment surgery within 3 months of Screening or
   2. have expectation of penetrating keratoplasty, vitrectomy, cataract surgery, or LASIK or any other intraocular surgery during the study period or
   3. have a history of vitreoretinal surgery (including vitrectomy) or other ocular surgeries including scleral buckle or glaucoma filtering/shunt surgery.
7. Have received gene therapy treatment or ranibizumab port delivery system (PDS, [Susvimo™]) for any reason in either eye.
8. Aphakia or sulcus intraocular lens in the study eye.
9. Have a history of significant ocular infection (bacterial, viral, or fungal) within the previous 3 months, or history of herpetic ocular diseases (including herpes simplex virus, varicella zoster, or cytomegalovirus retinitis) or toxoplasmosis gondii or chronic/recurrent inflammatory eye disease (i.e., scleritis, uveitis, corneal edema) in either eye.
10. Have evidence of a rhegmatogenous retinal detachment or visually significant/severe epiretinal membrane, vitreomacular traction syndrome, macular hole, tear of the retinal pigment epithelium in the macula, or other macular pathology deemed visually significant by the Investigator in the study eye.
11. Have a history of or presence of vitreous hemorrhage due to any other cause except posterior vitreous detachment in the study eye. Subject is still eligible if history of past hemorrhagic posterior vitreous detachment has resolved.
12. Have advanced glaucoma with uncontrolled IOP ≥25 mmHg despite IOP-lowering treatment in the study eye.
13. Have presence of other causes of CNV, e.g., pathologic myopia (spherical equivalent ≥ –8 diopters, or axial length of 26 mm or more), choroidal rupture, ocular histoplasmosis syndrome, or multifocal choroiditis in the study eye.
14. Have any current systemic or ocular treatment in the study eye with TKIs or systemic treatment with anti-VEGF agents.
15. Have ocular malignancy including choroidal melanoma in either eye.
16. Are receiving concurrent treatment with medications known to be toxic to the retina, lens, or optic nerve (e.g., chlorpromazine, phenothiazines, tamoxifen, hydroxychloroquine, pentosan polysulfate etc.).
17. Have a need for chronic therapy with systemic, intraocular or peri-ocular, or topical ocular corticosteroids in the study eye (>7 days) or have known allergy to fluorescein (e.g., bronchospasm, rash, etc.), or to any component of the study products.
18. Have symptomatic or unstable coronary artery disease, angina, congestive heart failure, or an arrhythmia requiring active procedural management (management with medications is permissible) within the last 30 days of the screening visit.
19. Have uncontrolled hypertension (defined as >160/100 mmHg, despite anti-hypertensive treatment).
20. Have a history of or presence of uncontrolled systemic disease or a debilitating disease (e.g., active malignancy within 2 years, Parkinson’s disease, dementia, liver failure, kidney failure requiring dialysis, progressive worsening of an inflammatory, autoimmune or pulmonary disease).
21. Had a myocardial infarction or other cardiovascular event (e.g., stroke) within the previous 6 months.
22. Have uncontrolled diabetes (defined as HbA1c >12%) despite treatment at Screening. Diabetic medication(s) could be adjusted if necessary and HbA1c should be repeated at Week -4 for eligibility assessment.
23. Are female and pregnant or breastfeeding or intend to become pregnant during the study.
24. Have participated in any study involving an investigational drug either in the US or outside the US within the past 30 days from Screening.
25. Are an employee of the site that is directly involved in the management, administration, or support of the study, or an immediate family member of the same.

Inclusion Criteria
At Screening Visit 1:

1. Treatment naïve for nAMD in either eye at screening.
2. Have macular choroidal neovascularization due to nAMD who have had visual loss or would be expected to develop visual loss during the course of the study.
3. If foveal intraretinal and/or subretinal fluid is present on SD-OCT, it shall not exceed 500 µm (CSFT) as determined by Investigator.
4. Are eligible to receive intraocular aflibercept therapy for the treatment of nAMD.
5. Have a BCVA ETDRS letter score of at least 54 or greater (~ 20/80) in either eye.
6. Have adequate ocular media and adequate pupillary dilation in the study eye to permit good quality fundus imaging.
7. Are female who is postmenopausal for at least 12 months prior to screening or surgically sterile; or male or female of childbearing potential willing to use two forms of adequate contraception from screening until they exit the study.
8. Are able and willing to comply with all study requirements and visits.
9. Have provided written informed consent.

At Day 1:

10. Are older than 50 years of age at Day 1.
11. Have BCVA of at least 84 ETDRS letter score (~ 20/20 Snellen equivalent) at Day 1; OR have an increase of at least 10 ETDTS letters of BCVA from Screening (Visit 1) BCVA.
12. Have a CSFT of 350 µm or less in study eye at Day 1 as determined by Investigator.

Exclusion Criteria

1. Have presence of a disease other than CNVM due to AMD in the study eye that could affect vision or safety assessments.
2. Monocular subjects or a BCVA score of 20/200 in fellow eye at screening.
3. Have evidence of a scar, fibrosis, or atrophy of > 50% of the total lesion in the study eye.
4. Currently or previously treated Geographic Atrophy in study eye.
5. Have previous laser photocoagulation to the macula in the study eye.
6. Have history of intraocular surgery including cataract surgery or keratorefractive surgery (LASIK, PRK, etc.) or any anterior segment surgery in the study eye within 6 months of screening or have expectation of penetrating keratoplasty, vitrectomy, cataract surgery, or LASIK or any other intraocular surgery during the study period in the study eye or have a history of vitreoretinal surgery (including vitrectomy) or other ocular surgeries including scleral buckle or glaucoma filtering/shunt surgery in the study eye.
7. Have received gene therapy treatment or PDS in the fellow eye.
8. Have aphakia in the study eye.
9. Have a history of significant ocular infection (bacterial, viral, or fungal) within the previous 3 months, or history of herpetic ocular diseases (including herpes simplex virus, varicellazoster, or cytomegalovirus retinitis) or toxoplasmosis gondii or chronic/recurrent inflammatory eye disease (i.e., scleritis, uveitis, corneal edema).
10. Have evidence of a rhegmatogenous retinal detachment or visually significant/severe epiretinal membrane, macular hole, tear of the retinal pigment epithelium in the macula, or other macular pathology deemed significant by the Investigator in the study eye.
11. Have a history of or presence of vitreous hemorrhage in the study eye. Subject is still eligible if history of past hemorrhagic posterior vitreous detachment has resolved.
12. Have advanced glaucoma or uncontrolled IOP ≥ 25 mmHg despite treatment.
13. Have a history of receiving glaucoma filtration surgery in the study eye.
14. Have presence of other causes of CNV, e.g., pathologic myopia (spherical equivalent ≥ –8 diopters, or axial length of 26 mm or more), choroidal rupture, ocular histoplasmosis syndrome, or multifocal choroiditis in the study eye.
15. Have any current systemic or ocular treatment with TKIs or systemic treatment with antiVEGF agents.
16. Have an ocular malignancy including choroidal melanoma in either eye.
17. Are receiving concurrent treatment with medications known to be toxic to the retina, lens, or optic nerve (e.g., chlorpromazine, phenothiazines, tamoxifen, etc.).
18. Have a need for chronic therapy with systemic, intravitreal, or topical ocular corticosteroids or have known allergy to fluorescein (e.g., bronchospasm, rash, etc.), or to any component of the study products.
19. Have symptomatic or unstable coronary artery disease, angina, congestive heart failure, or an arrhythmia requiring active procedural management (management with medications is permissible) within the last 30 days of the injection of the implant.
20. Have uncontrolled hypertension (> 160/100 mmHg, despite medical treatment).
21. Have a history of or presence of uncontrolled systemic or debilitating disease.
22. Had a myocardial infarction or other cardiovascular event (e.g., stroke) within the previous 6 months.
23. Have uncontrolled diabetes as deemed by the Investigator.
24. Are female and pregnant or breastfeeding or intend to become pregnant during the study.
25. Have participated in any study involving an investigational drug either in the US or outside the US within the past 30 days.
26. Are an employee of the site that is directly involved in the management, administration, or support of the study, or an immediate family member of the same.

Ocular Inclusion Criteria

Where applicable, ocular inclusion criteria will be confirmed or assessed by the independent, masked image reading center.

1. Active, treatment-naïve choroidal neovascularization (CNV) secondary to AMD, including subfoveal, juxtafoveal, and extrafoveal lesions, or retinal angiomatous proliferations (RAP) lesions with a CNV component that affects the central subfield, as evidenced by FA or OCT in the Study Eye at Screening.
2. The CNV area in the Study Eye must be at least 50% of total lesion size in FA at Screening.
3. The lesion area in the Study Eye must be <30 mm² (12-disc areas) and can include any CNV lesion subtype.
4. Intra- and/or subretinal fluid affecting the central subfield of the Study Eye on OCT at Screening.
5. BCVA ETDRS score between 78 and 25 letters (Snellen equivalent ~20/32 and 20/320) inclusive, in the Study Eye at screening and reconfirmed at Day 1.
6. Decrease in vision in the Study Eye determined by the Investigator to be primarily the result of wAMD. Only one eye per participant is eligible to participate in the study. If both eyes are eligible to become the Study Eye, the eye with worse BCVA at screening will be selected as the Study Eye. If both eyes are eligible and have the same BCVA, the decision of which eye to select as the Study Eye will be made by the Investigator.

General Inclusion Criteria

7. Male or female ≥50 years of age.
8. Capable of giving signed informed consent, as described in Appendix 1, which includes compliance with the protocols and restrictions listed in the informed consent form (ICF) and in this protocol.
9. For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 90 days after the last dose of study intervention.
10. A woman is considered of childbearing potential if she is post-menarchal, has not reached a post-menopausal state (≥12 months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.
11. Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices.
12. Contraception methods that do not result in a failure rate of <1% per year such as cap, diaphragm, or sponge with spermicide, or male or female condom with or without spermicide, are not acceptable.
13. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
14. For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm, as defined below:
15. With female partners of childbearing potential, men must remain abstinent or use a condom and encourage their female partner to use one of the approved contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 120 days (30 days plus a 90-day spermatogenesis cycle) after the last dose of study intervention. Men must refrain from donating sperm during this same period.
16. Ability and willingness to undertake all the scheduled visits and assessments.

Ocular Exclusion Criteria

Where applicable, ocular exclusion criteria will be determined by an independent, masked image reading center.

1. BCVA of hand motion or worse in the non-Study Eye or non-physical presence of a non-Study Eye (i.e., monocular).
2. OCT CST > 900 microns at Screening or Day 1.
3. Active or suspected ocular or periocular infection or inflammation in either eye at Screening or on Day 1.
4. CNV secondary to other causes in the Study Eye, including pathologic myopia, angioid streaks, prior trauma, ocular histoplasmosis, or others.
5. Any history of macular pathology unrelated to AMD but affecting vision or contributing to subretinal or intraretinal fluid, such as central serous chorioretinopathy.
6. Fibrosis or atrophy of >50% of the lesion size and/or involving the foveal center of the Study Eye at Screening.
7. Subretinal blood affecting the foveal center of the Study Eye and/or more than 50% of the lesion size at Screening.
8. Retinal pigment epithelium tear or rip in the Study Eye at Screening or on Day 1.
9. Any approved or investigational treatment for neovascular AMD (other than oral vitamin supplements) in the Study Eye at any time.
10. Prior macular laser (e.g., thermal laser or photodynamic therapy laser) in the Study Eye.
11. Any history or evidence of a concurrent ocular condition present in the Study Eye, that in the opinion of the Investigator could require either medical or surgical intervention or affect macular edema (ME) or alter visual acuity during the study (e.g., vitreomacular traction, epiretinal membrane).
12. History of cataract surgery and/or minimally invasive glaucoma surgery (MIGS) in the Study Eye within 2 months of screening.
13. History of Yttrium-Aluminum Garnet (YAG) laser capsulotomy in the Study Eye within 2 months of screening.
14. Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite treatment with antiglaucoma medication) in the Study Eye.
15. History of glaucoma-filtering surgery (trabeculectomy or tube shunt) in the Study Eye.
16. History of retinal detachment or treatment or surgery for retinal detachment in the Study Eye.
17. History of uveitis in either eye.
18. Significant media opacities, including cataract, in the Study Eye that might interfere with visual acuity, assessment of safety, OCT or fundus photography.
19. Cataract in the Study Eye that in the judgment of the Investigator is expected to require surgical extraction within 12 months of Screening.
20. Aphakia in the Study Eye.
21. Prior vitrectomy in the Study Eye.
22. Prior intraocular steroids in the Study Eye, or use of periocular steroids (sub-Tenons) within 2 months from Screening. Prior use of topical steroids is not exclusionary at any time.
23. Current vitreous hemorrhage or history of vitreous hemorrhage in the Study Eye within 3 months of Screening.
24. History of corneal transplant in the Study Eye.
25. Insufficient OCT image quality in the Study Eye at Screening or Day 1, which impedes accurate image segmentation and grading.

General Exclusion Criteria

26. Women who are pregnant or lactating or intending to become pregnant during the study.
27. Women of child-bearing potential must have a negative urine pregnancy test result within 28 days prior to Day 1. If the urine pregnancy test is positive, it must be confirmed with a serum pregnancy test prior to Day 1.
28. Uncontrolled blood pressure defined as a systolic value ≥180 mmHg or diastolic value ≥100 mmHg while at rest at screening or on Day 1.

• If a participant’s initial blood pressure measurement exceeds these values, up to two additional readings may be taken later the same day or on a different day during the screening period. If a participant’s blood pressure is controlled by antihypertensive medications, the participant must be on a stable medication regimen continuously for 21 days prior to Day 1.

29. Kidney failure requiring renal transplant, hemodialysis or peritoneal dialysis or expected to require renal transplant, hemodialysis, or peritoneal dialysis during the study.
30. Recent history (within the 6 months prior to screening) of myocardial infarction, stroke, transient ischemic attack, acute congestive heart failure, or any acute coronary event.
31. History of a medical condition that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product.
32. History of hypersensitivity to intravitreal agents such as aflibercept or ranibizumab or to any component of tarcocimab-ted, tabirafusp-ted, ophthalmic dye (fluorescein), dilating drops, or any of the anesthetic or antimicrobial preparations used during the study, as assessed by the Investigator.
33. Active cancer within the 12 months prior to screening except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin cancer, and prostate cancer.
34. Treatment with systemic anti-VEGF therapeutics within 90 days prior to screening.
35. Participation in an investigational study within 30 days prior to the screening visit that involved treatment with any investigational drug (excluding vitamins and minerals) or investigational devices, except for non-therapeutic ophthalmic imaging devices.

Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for this study.

1. Able and willing to provide informed consent (or have a legally authorized representative who is able and willing to provide informed consent) prior to any study assessments and procedures and comply with the study requirements and visits.
2. Male or female with a diagnosis of CNV secondary to nAMD in the study eye, with nAMD disease activity (i.e., any fluid [IRF or SRF] present on SD-OCT) at Screening Visit 1 (Day -56 to -49).
3. At least 50 years old at Screening Visit 1 (Day -56 to -49).
4. ETDRS BCVA letter score ≥ 35 and ≤ 78 (approximate Snellen equivalent of 20/200 to 20/32) in the study eye at Screening Visit 1 (Day -56 to -49) with no loss of vision ≥ 5 ETDRS letters from Screening Visit 1 (Day -56 to -49) to Day 1.
5. ETDRS BCVA letter score ≥ 35 (approximate Snellen equivalent of 20/200 or better) in the non-study eye at Screening Visit 1 (Day -56 to -49).
6. Demonstrated a meaningful anatomic response to anti-VEGF therapy, as determined by the CRC based on SD-OCT images of the study eye collected at Screening Visit 1 (Day – 56 to Day -49) and at Day 1. A meaningful anatomic response is defined as either:
   1. Complete resolution of fluid (SRF/IRF) at Day 1, OR
   2. A reduction in CST at Day 1 from Screening Visit 1 (Day -56 to Day -49) of:
      1. 10% for participants with CST > 300 µm at Screening Visit 1
      2. 5% for participants with CST ≤ 300 µm at Screening Visit 1
7. Able to reliably use eye drops per protocol, according to the Investigator’s judgment.
8. Women of childbearing potential (i.e., postmenarcheal, has not reached a postmenopausal state [> 12 continuous months of amenorrhea with no identified cause other than menopause], or has not undergone surgical sterilization [removal of both ovaries and/or uterus]) must have a negative pregnancy test during screening and agree to use an acceptable form of contraception that results in a failure rate < 1% per year (e.g., bilateral tubal ligation; surgical sterilization of the participant’s sole male partner; oral, implantable, or injectable hormonal contraceptives that inhibit ovulation; hormone-releasing intrauterine devices; copper intrauterine devices) or agree to remain abstinent (refrain from heterosexual intercourse). Of note, contraception methods that do not result in a failure rate of < 1% per year (e.g., male or female condom with or without spermicide; cap, diaphragm, or sponge with spermicide) are not acceptable. The reliability of sexual abstinence should be evaluated in relation to the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
9. Sexually active male participants must agree to use an acceptable form of contraception that results in a failure rate < 1% per year during the study, if their female partners are of childbearing potential.

Exclusion Criteria
Participants who meet any of the following criteria will be excluded from the study.

General Exclusion Criteria

1. History of a medical condition (systemic disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding) giving reasonable suspicion of a condition that contraindicates the use of Ixo-vec, compromises the participant’s ability to comply with the planned study activities, or that might affect the interpretation of the results of the study or render the participant at high risk for treatment complications in the opinion of the Investigator. History of severe COVID-19 infection may meet this exclusion criteria if, in the opinion of the Investigator, it is likely to lead to any of the complications listed above.
2. Received any prior gene therapy.
3. Received any non-gene therapy IMP or medical device in the study eye within 3 months of Screening Visit 1 (Day -56 to Day -49) or 5 half-lives of the IMP prior to dosing with Ixo-vec, whichever is longer.
4. History of allergy, hypersensitivity, or contraindications to the use of any product or its excipients administrated within this protocol including aflibercept, corticosteroids (i.e., difluprednate), or fluorescein dye or sodium fluorescein used in angiography (mild allergy amenable to treatment is allowable).
5. Evidence of poorly controlled diabetes or glycated hemoglobin (HbA1c) ≥ 8.0% from Screening Visit 1 (Day -56 to Day -49) to Week 1.
6. Female participants who are pregnant or breastfeeding or who intend to become pregnant or breastfeed in the future.
7. History or evidence of any of the following cardiovascular diseases:
   1. Myocardial infarction in the 6-month period prior to Day
   2. Uncontrolled hypertension defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg, despite using blood pressure-lowering medication within the screening period. If blood pressure-lowering medications are required, participant should be on a stable dose of the same medication continuously for 30 days prior to Day 1.
   3. Stroke in the 6-month period prior to Day 1.
8. Any history of ongoing bleeding disorders. The use of aspirin or other anticoagulants (e.g., Factor Xa inhibitors) is permitted.
9. Use of systemic immunosuppressive drugs (e.g., intravenous steroids, methotrexate, azathioprine, cyclosporin, secukinumab, denosumab, and anti-tumor necrosis factors [TNFs], such as adalimumab, infliximab, etanercept) within the 90 days prior to Screening Visit 1 (Day -56 to Day -49). Low stable doses of corticosteroids (defined as ≤ 10 mg prednisolone / prednisolone or equivalent dose) are permitted, as well as any inhaled, nasal or dermal steroid use.
10. Received anti-VEGF IVT injection in the study eye within 28 days prior to Screening Visit 1 (Day -56 to -49) or systemic anti-VEGF therapy during the 3-month period prior to Screening Visit 1 (Day -56 to Day -49).
11. History of malignancy within the 5 years prior to Screening Visit 1 (Day -56 to Day -49), except for the following adequately treated:
    1. Local basal cell or squamous cell carcinoma of the skin.
    2. Carcinoma in situ of the cervix or breast.
    3. Papillary, non-invasive bladder cancer.
    4. Prostate cancer Stage 1 and 2 for which observation is clinically indicated with stable prostate-specific antigen for 6 months.
    5. Any other cancer that has been in complete remission for at least 2 years or considered surgically cured.
12. Positive for human immunodeficiency virus (HIV) infection or hepatitis B or C virus at Screening Visit 1 (Day -56 to Day -49) unless having received a documented cure for hepatitis C virus.
13. History of COVID-19 or syphilis within 6 weeks prior to Week 1.
14. Any febrile illness within 1 week prior to Day 1.

Ocular Exclusion Criteria

15. Any active ocular or periocular infection (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in the study eye from Screening Visit 1 (Day -56 to Day -49) to Week 1.
16. Evidence of the total area of scar or macular fibrosis making up ≥ 50% of the total lesion area, atrophy, or other structural damage in the center of the fovea in the study eye as confirmed by the CRC at Screening Visit 1 (Day -56 to Day -49).
17. Central subfield of the study eye affected by fibrosis or geographic atrophy, assessed by color fundus photography (CFP) at Screening Visit 1 (Day -56 to Day -49) and confirmed by the CRC.
18. Evidence of subretinal hemorrhage that is either 50% or more of the total lesion area, or if the blood is under the fovea and is ≥ 1 disc area in size in the study eye, as confirmed by the CRC at Screening Visit 1 (Day -56 to Day -49) (if blood is under the fovea, fovea must be surrounded 270 degrees by visible CNV).
19. Any history or evidence of a concurrent intraocular condition in the study eye, including retinal diseases other than nAMD, that, in the judgment of the Investigator, could reduce the potential for visual improvement, confound assessment of the macula or require medical or surgical intervention during the study.
20. History or evidence of the following in the study eye:
    15. Intraocular or refractive surgery within 90 days prior to Screening Visit 1 (Day -56 to Day -49).
    16. Any previous penetrating keratoplasty or vitrectomy.
    17. Any previous panretinal photocoagulation.
    18. Any previous submacular surgery, other surgical intervention (including port delivery system) or laser treatment for age-related macular degeneration.
21. Any history or evidence of retinal detachment (with or without repair) or retinal pigment epithelium rip/tear in the study eye, as determined by the Investigator during screening or at Day 1.
22. Aphakia and/or complete or partial absence of posterior capsule at Screening Visit 1 (Day -56 to Day -49) or cataract extraction or yttrium aluminum garnet (YAG) laser capsulotomy in the study eye within 3 months prior to Screening Visit 1 (partial absence of the posterior capsule due to YAG laser capsulotomy performed > 3 months prior to Screening Visit 1 is acceptable).
23. Uncontrolled ocular hypertension or glaucoma in the study eye from Screening Visit 1 (Day -56 to Day -49) to Week 1 (defined as IOP > 22 mmHg despite treatment with antiglaucoma medication, or according to Investigator’s judgment) or current use of ≥ 2 IOP lowering medications or normal tension glaucoma/suspect in the study eye.
24. Any history of IOP elevation related to topical steroid administration in either eye.
25. Any history of uveitis or inflammation (grade trace or above) except mild anticipated post-operative inflammation that resolved in either eye.
26. Any history of intraocular or periocular steroid treatment for any ocular condition (e.g., IVT Triesence®, Iluvien®, or Ozurdex®) within 6 months prior to Screening Visit 1 (Day -56 to Day -49).
27. Any history of treatment with complement inhibitors (e.g., pegcetacoplan and avacincaptad pegol) for geographic atrophy in the study eye.
28. Known history of ocular herpes simplex virus, varicella-zoster virus, or cytomegalovirus, including viral uveitis, retinitis, or keratitis in either eye.
29. Previous therapeutic radiation near the region of the study eye.

Inclusion Criteria
Individuals eligible to participate in the trial must meet the following inclusion criteria:

General Inclusion Criteria

1. Signed informed consent before any protocol-specific assessment is performed
2. Ability to comply with the protocol-specified procedures and visits, in the Investigator’s judgment
3. ≥50 years of age at time of consent
4. Agree to use a barrier method (e.g. condom) during intercourse for 6 months after Day 1 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period.

Ocular Inclusion Criteria

5. Treatment naïve MNV secondary to nAMD in the study eye
6. Active subfoveal MNV or juxtafoveal/ extrafoveal MNV with a subfoveal component (where activity is defined as evidence of SRF, subretinal hyperreflective material, or leakage) identified by fundus fluorescein angiography (FA) or spectral domain optical coherence tomography (SD-OCT) in the study eye, at the Screening Visit, confirmed by the Reading Center
7. 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:
   5. Total lesion size of 9 disc areas or less (inclusive of blood, fibrosis, atrophy or neovascularization) on FA
   6. MNV component area at least 50% of total lesion size on FA
   7. MNV exudation (i.e. presence of fluid) on SD-OCT
8. CST ≤500µm in the study eye at Screening visit, confirmed by the Reading Center
9. Demonstrated clinical response to aflibercept and functional stability in the study eye:
10. 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
11. At Day 1: BCVA measurement must not have decreased by 15 ETDRS letters or more compared to BCVA at the Screening visit
12. BCVA between 25 and 78 ETDRS letters, inclusive (20/320 – 20/32 Snellen equivalent) in the study eye at Screening Visit
13. BCVA ≥34 ETDRS letters (~20/200 Snellen equivalent) in the contralateral eye at the Screening Visit
14. Study eye amenable to IVT injection identified by the Investigator prior to Week −5

Ocular Exclusion Criteria

1. Ocular Conditions:
   1. MNV due to causes other than nAMD in either eye
   2. 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
   3. History of retinal detachment in the study eye
   4. 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.
   5. 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.
   6. History of latent ocular or periocular infection (e.g. ocular syphilis, herpetic eye disease)
   7. History of steroid-induced ocular hypertension or steroid-induced glaucoma in either eye
   8. IOP < 6mmHg (by Goldman tonometry) in the study eye
   9. Any history of ocular hypotony or ciliary body dysfunction/pathology in either eye as determined by the Investigator
   10. Glaucoma or intraocular hypertension requiring more than 2 topical medications for control (defined as IOP <22 mm Hg) in the study eye
       Note: Fixed combination glaucoma eye drops (e.g. COSOPT®, SIMBRINZA®) are considered two medications
   11. 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.
2. Ocular Treatments/Interventions in the Study Eye:
   1. Any prior or concomitant treatment for MNV or vitreomacular-interface abnormalities, including, but not restricted to IVT therapy (e.g. anti-VEGF, steroids, tissue plasminogen activator, ocriplasmin, C3F8, air), periocular pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic therapy, diode laser, transpupillary thermotherapy, or ocular surgical intervention
   2. 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
   3. 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.
      Note: Laser to treat peripheral retinal tears is not exclusionary
   4. Uncomplicated cataract surgery, YAG laser posterior capsulotomy, or glaucoma laser treatment in the 3 months prior to the Screening Visit
   5. 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
      Note: Lens nuclear opacity ≥ 3.0 or posterior subcapsular opacity >0 by AREDS or any significant lens opacity as determined by the Investigator is exclusionary

Additional Exclusion Criteria

3. Prior/Concomitant Medications (Systemic or in Either Eye):
   3. Receiving or anticipated to receive a systemic drug that inhibits VEGF pathways, e.g. bevacizumab, sunitinib, pazopanib
   4. Ever received or anticipated to receive IVT complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol) in the either eye
   5. History of serious allergy, hypersensitivity, or contraindications to fluorescein and/or trial-specified interventions (e.g. 4D-150 excipients, aflibercept, povidone-iodine)
4. Prior Interventional Trial Participation:
   3. 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
   4. Any prior gene therapy (ocular or non-ocular) and/or ocular stem cell therapy
5. Systemic Conditions and Additional Considerations:
   3. Major illness or major surgical procedure in the 28 days prior to the Screening Visit
   4. 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.
   5. Acute coronary syndrome, myocardial infarction or coronary artery revascularization, cerebrovascular accident, transient ischemic attack within 6 months of the Screening Visit
   6. Any history of syphilis (whether or not treated)
   7. 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
   8. 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)
   9. 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
   10. Female of child-bearing potential (per (CTFG, 2020)), defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Inclusion Criteria

Participants must meet ALL of the following criteria to be eligible to participate in this study. An independent Central Reading Center will confirm lesion eligibility prior to randomization.

1. Fellow eyes treated with an approved anti-complement drug for GA for at least 4 weeks prior to study entry may continue treatment with no washout. Fellow eyes treated with an approved anti-complement drug for GA for fewer than 4 weeks should not be enrolled in the study. GA-treatment naive fellow eyes should, in the opinion of the Investigator, be unlikely to need treatment for GA in the fellow eye for at least the first year of the study.
2. Participant must be at least 50 years of age at the time of signing the informed consent.
3. Able and willing to participate in a 24-month study with monthly visits.
4. Diagnosis of GA of the macula secondary to AMD as determined by the Investigator and confirmed by the independent Central Reading Center.
5. The GA lesion must have the following characteristics as determined by the independent Central Reading Center based on assessment of FAF imaging at screening. If both eyes are confirmed to be eligible by the independent Central Reading Center, the determination of the study eye selection is in the opinion of the Investigator.
   1. Well-demarcated GA with a total area (baseline lesion size) ≥2.5 mm2 and ≤ 17.5 mm2.
   2. If GA is multifocal, at least one focal lesion must measure ≥1.25 mm2 with the overall aggregate area of GA as specified above in 5a.
   3. Presence of hyper autofluorescence, any pattern, in the junctional zone of the GA. Absence of hyper autofluorescence (i.e., pattern = none) is exclusionary.
   4. The entire GA lesion must be completely visualized on the macula centered image and must be able to be imaged in its entirety and not contiguous with any peripapillary atrophy.
6. Normal luminance BCVA of 45 to 83 letters using ETDRS charts (20/25 to 20/100 Snellen equivalent, inclusive). a. If BCVA at screening and baseline are different by 10 or more letters, the participant will be considered a screen failure at the baseline visit. Baseline BCVA must meet eligibility criteria. Sex and Contraceptive/Barrier Requirements or Female Participants
7. A female participant is eligible if she is not pregnant or breastfeeding, and one of the following conditions applies:
   1. Is a woman of non-childbearing potential (WONCBP) (defined as having undergone surgical sterilization or being postmenopausal [i.e., greater than 50 years old with amenorrhea for at least 12 months without an alternative medical cause]). OR
   2. Is the WOCBP using a contraceptive method that is highly effective, with a failure rate of <1%, during the study intervention period and for at least 30 days after the last dose of study intervention.
   3. WOCBP must have a negative pregnancy test (PT) within 24 hours before the first dose of study intervention.
   4. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Informed Consent

8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol.

Exclusion Criteria

Participants are excluded from the study if ANY of the following criteria apply.

1. Geographic atrophy due to other causes than AMD such as Stargardt disease, cone-rod dystrophy, pathologic myopia, or toxic maculopathies (eg, plaquenil maculopathy) in either eye.
2. Any evidence of CNV in the study eye: a. Any history of CNV of any cause based on medical history. b. Evidence of prior or active CNV or related findings (eg, retinal pigment epithelial rips or tears) based on FAF, spectral domain optical coherence tomography (SD-OCT) imaging, Intravenous fluorescein angiography (IVFA) and color fundus photo as assessed by the Central Reading Center.
3. Spherical equivalent of -8.00 diopters (D) myopia or higher in the study eye.
4. Uncontrolled glaucoma in the study eye (Intraocular pressure (IOP) >25 mmHg despite treatment with anti-glaucoma medication) or history of neovascular glaucoma.
5. History of glaucoma filtration surgery, minimally invasive glaucoma surgery involving an implant, or vitrectomy surgery, or other procedure in the study eye that could affect drug distribution and/or clearance.
6. History of uncomplicated cataract surgery less than 3 months prior to dosing in the study eye.
7. Any ophthalmic condition that may require surgery during the study period in the study eye.
8. Ocular trauma in the study eye within the preceding 6 months.
9. Any active ocular/intraocular infection or inflammation in either eye (eg, blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, uveitis).
10. History of idiopathic or autoimmune-associated uveitis in either eye.
11. Any current or prior ocular disease, other than GA, that in the opinion of the Investigator could interfere with the conduct of the study including, but not limited to, insufficient pupil dilation, retinal or optic nerve disease, media opacity, or aphakia in the study eye. Prior/Concomitant Therapy
12. History of any prior IVT treatment for any indication in the study eye.
13. Any prior treatment for AMD in the study eye (eg, pharmacological, surgical, radiation, thermotherapeutic, or laser intervention), except oral supplements or minerals.
14. Previous participation in any studies of investigational medications within 3 months or 5 half-lives of the active ingredient (whichever is longer) prior to the start of study treatment. Note: Clinical studies solely involving observation, over-the-counter vitamins, supplements, or diets are not exclusionary.
15. Known hypersensitivity to ANX007 or any of the excipients in the ANX007 solution (as described in the ANX007 Investigator’s Brochure (IB) Table 1) or other ANX molecules (e.g., ANX005).
16. Known hypersensitivity to fluorescein.
17. Active alcohol or substance abuse/dependence or any other reason that makes it unlikely that the participant will comply with study procedures.
18. History of current systemic medical or psychiatric conditions or any other reason, including laboratory findings, that may, in the opinion of the Investigator, contraindicate the use of an investigational medication, affect interpretation of study results, preclude adherence to the study visit schedule, or safe participation in the study.